For children with Crohn’s disease, fecal calprotectin levels below 300 mcg indicated mucosal healing, while values below 100 mcg signified deep healing in a multicenter, 151-patient study.

Sensitivity was 80% for mucosal healing and 71% for deep healing, while specificities were 81% and 92%, respectively, said Inbar Nakar of the Hebrew University of Jerusalem, with her associates. In line with prior studies, adding C-reactive protein (CRP) to fecal calprotectin improved neither sensitivity or specificity, the researchers wrote in Clinical Gastroenterology and Hepatology.

Bowel healing is a crucial goal in Crohn’s disease (CD). Because pediatric transmural healing had not been studied, the researchers analyzed data from the ImageKids study, a multicenter effort to develop magnetic resonance enterography (MRE) measures for CD patients aged 6-18 years. Participants averaged 14 years old with a standard deviation of 2 years. Assessments included MRE, complete ileocolonoscopic evaluation, CRP, and fecal calprotectin. The researchers defined mucosal healing as a Simple Endoscopic Severity Index in Crohn’s Disease score below 3, transmural healing as an MRE visual analog score below 20 mm, and deep healing as transmural plus mucosal healing.

Nearly one-third of patients had healing only in the mucosa or the bowel wall, but not both; 6% had mucosal healing but transmural inflammation, and 25% of children had transmural healing but mucosal inflammation. In addition, 14% of children had deep healing, and 55% of children had both mucosal and transmural inflammation. Those findings highlight “the discrepancy between mucosal and transmural inflammation and the importance of evaluating the disease by both ileocolonoscopy and imaging,” the researchers wrote.

Median calprotectin levels varied significantly by healing status (P less than .001). They were lowest (10 mcg/g) for deep healing, followed by either transmural or mucosal inflammation, and were highest (median, 810 mcg/g) when children had both mucosal and transmural inflammation. Calprotectin in children with deep healing had an area under the receiver operating characteristic curve value of 0.93 (95% confidence interval, 0.89- 0.98). In contrast, CRP level identified children with deep healing with an AUROC value of only 0.81 (95% CI, 0.71-0.90).

Although “calprotectin level is driven primarily by mucosal healing, [it] is still superior to CRP,” the investigators concluded. “Although a calprotectin cutoff [less than] 300 mcg/g predicted mucosal healing, a lower cutoff of [less than] 100 mcg/g may be more suitable to predict deep healing.” However, they emphasized that fecal calprotectin level is only moderately accurate in predicting mucosal or transmural healing in children with CD. They advised physicians to “be familiar with the predictive values of each cutoff before incorporating them in clinical decision making.”

An educational grant from AbbVie funded the ImageKids study. AbbVie was not otherwise involved in the study. Two coinvestigators disclosed ties to AbbVie and other pharmaceutical companies. There were no other disclosures.

SOURCE: Nakar I et al. Clin Gastroenterol Hepatol. 2018 Mar 2. doi: 10.1016/j.cgh.2018.01.024.

For children with Crohn’s disease, fecal calprotectin levels below 300 mcg indicated mucosal healing, while values below 100 mcg signified deep healing in a multicenter, 151-patient study.

Sensitivity was 80% for mucosal healing and 71% for deep healing, while specificities were 81% and 92%, respectively, said Inbar Nakar of the Hebrew University of Jerusalem, with her associates. In line with prior studies, adding C-reactive protein (CRP) to fecal calprotectin improved neither sensitivity or specificity, the researchers wrote in Clinical Gastroenterology and Hepatology.

Bowel healing is a crucial goal in Crohn’s disease (CD). Because pediatric transmural healing had not been studied, the researchers analyzed data from the ImageKids study, a multicenter effort to develop magnetic resonance enterography (MRE) measures for CD patients aged 6-18 years. Participants averaged 14 years old with a standard deviation of 2 years. Assessments included MRE, complete ileocolonoscopic evaluation, CRP, and fecal calprotectin. The researchers defined mucosal healing as a Simple Endoscopic Severity Index in Crohn’s Disease score below 3, transmural healing as an MRE visual analog score below 20 mm, and deep healing as transmural plus mucosal healing.

Nearly one-third of patients had healing only in the mucosa or the bowel wall, but not both; 6% had mucosal healing but transmural inflammation, and 25% of children had transmural healing but mucosal inflammation. In addition, 14% of children had deep healing, and 55% of children had both mucosal and transmural inflammation. Those findings highlight “the discrepancy between mucosal and transmural inflammation and the importance of evaluating the disease by both ileocolonoscopy and imaging,” the researchers wrote.

Median calprotectin levels varied significantly by healing status (P less than .001). They were lowest (10 mcg/g) for deep healing, followed by either transmural or mucosal inflammation, and were highest (median, 810 mcg/g) when children had both mucosal and transmural inflammation. Calprotectin in children with deep healing had an area under the receiver operating characteristic curve value of 0.93 (95% confidence interval, 0.89- 0.98). In contrast, CRP level identified children with deep healing with an AUROC value of only 0.81 (95% CI, 0.71-0.90).

Although “calprotectin level is driven primarily by mucosal healing, [it] is still superior to CRP,” the investigators concluded. “Although a calprotectin cutoff [less than] 300 mcg/g predicted mucosal healing, a lower cutoff of [less than] 100 mcg/g may be more suitable to predict deep healing.” However, they emphasized that fecal calprotectin level is only moderately accurate in predicting mucosal or transmural healing in children with CD. They advised physicians to “be familiar with the predictive values of each cutoff before incorporating them in clinical decision making.”

An educational grant from AbbVie funded the ImageKids study. AbbVie was not otherwise involved in the study. Two coinvestigators disclosed ties to AbbVie and other pharmaceutical companies. There were no other disclosures.

SOURCE: Nakar I et al. Clin Gastroenterol Hepatol. 2018 Mar 2. doi: 10.1016/j.cgh.2018.01.024.

For children with Crohn’s disease, fecal calprotectin levels below 300 mcg indicated mucosal healing, while values below 100 mcg signified deep healing in a multicenter, 151-patient study.

Sensitivity was 80% for mucosal healing and 71% for deep healing, while specificities were 81% and 92%, respectively, said Inbar Nakar of the Hebrew University of Jerusalem, with her associates. In line with prior studies, adding C-reactive protein (CRP) to fecal calprotectin improved neither sensitivity or specificity, the researchers wrote in Clinical Gastroenterology and Hepatology.

Bowel healing is a crucial goal in Crohn’s disease (CD). Because pediatric transmural healing had not been studied, the researchers analyzed data from the ImageKids study, a multicenter effort to develop magnetic resonance enterography (MRE) measures for CD patients aged 6-18 years. Participants averaged 14 years old with a standard deviation of 2 years. Assessments included MRE, complete ileocolonoscopic evaluation, CRP, and fecal calprotectin. The researchers defined mucosal healing as a Simple Endoscopic Severity Index in Crohn’s Disease score below 3, transmural healing as an MRE visual analog score below 20 mm, and deep healing as transmural plus mucosal healing.

Nearly one-third of patients had healing only in the mucosa or the bowel wall, but not both; 6% had mucosal healing but transmural inflammation, and 25% of children had transmural healing but mucosal inflammation. In addition, 14% of children had deep healing, and 55% of children had both mucosal and transmural inflammation. Those findings highlight “the discrepancy between mucosal and transmural inflammation and the importance of evaluating the disease by both ileocolonoscopy and imaging,” the researchers wrote.

Median calprotectin levels varied significantly by healing status (P less than .001). They were lowest (10 mcg/g) for deep healing, followed by either transmural or mucosal inflammation, and were highest (median, 810 mcg/g) when children had both mucosal and transmural inflammation. Calprotectin in children with deep healing had an area under the receiver operating characteristic curve value of 0.93 (95% confidence interval, 0.89- 0.98). In contrast, CRP level identified children with deep healing with an AUROC value of only 0.81 (95% CI, 0.71-0.90).

Although “calprotectin level is driven primarily by mucosal healing, [it] is still superior to CRP,” the investigators concluded. “Although a calprotectin cutoff [less than] 300 mcg/g predicted mucosal healing, a lower cutoff of [less than] 100 mcg/g may be more suitable to predict deep healing.” However, they emphasized that fecal calprotectin level is only moderately accurate in predicting mucosal or transmural healing in children with CD. They advised physicians to “be familiar with the predictive values of each cutoff before incorporating them in clinical decision making.”

An educational grant from AbbVie funded the ImageKids study. AbbVie was not otherwise involved in the study. Two coinvestigators disclosed ties to AbbVie and other pharmaceutical companies. There were no other disclosures.

SOURCE: Nakar I et al. Clin Gastroenterol Hepatol. 2018 Mar 2. doi: 10.1016/j.cgh.2018.01.024.

Native to North and East Asia, buckwheat has been grown in China for more than 2,000 years and has been used in traditional medicine to treat varicose veins.^1,2 This highly adaptable plant – the most common species of which are Fagopyrum esculentum (common buckwheat or sweet buckwheat), and F. tataricum (which grows in more mountainous regions) – has acclimated to cultivation in North America, as well.¹ Increasingly popular as a healthy grain option, buckwheat flour has been touted for beneficial effects on diabetes, obesity, hypertension, hypercholesterolemia, and constipation.¹ It has also gained attention for its association with some allergic reactions.

SandraKavas/iStock /Getty Images Plus

Wound Healing

In 2008, van den Berg et al. performed an in vitro investigation of the antioxidant and anti-inflammatory qualities of buckwheat honey for consideration in wound healing. American buckwheat honey from New York was found to be the source of the most salient activities, with such properties attributed to its abundant phenolic components. The researchers suggested that these phenols might impart antibacterial activity, while the low pH and high free acid content of the buckwheat honey could contribute to healing wounds.⁴

Antioxidant Activity

The antioxidant capacity, along with other traits, characterizing the sprouts of common buckwheat (F. esculentum) and tartary buckwheat (F. tataricum) was evaluated by Liu et al. in 2008. Rutin is the main flavonoid found in both species, with fivefold higher levels identified in tartary buckwheat in this study. Ethanol extracts of tartary buckwheat also exhibited greater free radical scavenging activity and superoxide scavenging activity, compared with common buckwheat. Both buckwheat species displayed antioxidant activity on human hepatoma HepG2 cells, with tartary buckwheat more effective in diminishing cellular oxidative stress, which the authors attributed to its greater rutin and quercetin levels.⁵

Zhou et al. studied the protective effects of buckwheat honey on hydroxyl radical-induced DNA damage in 2012, finding that all studied honeys more effectively protected DNA in non–site specific rather than site-specific systems.⁶

Photoprotection

In a 2005 screening of 47 antioxidant substances and study of their effects on UV-induced lipid peroxidation, Trommer and Neubert reported that buckwheat extract significantly lowered radiation levels, as did extracts of St. John’s Wort, melissa, and sage. They concluded that their in vitro findings supported the inclusion of such ingredients in photoprotective cosmetic formulations or sunscreens pending the results of in vivo experiments with these compounds.⁷

In 2006, Hinneburg et al. evaluated the antioxidant and photoprotective activity of a buckwheat herb extract, also comparing its photoprotective characteristics to those of a commercial UV absorber. In an assay with 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH), buckwheat extract exhibited significantly more antioxidant activity than did pure rutin, with buckwheat observed to more effectively block UV-induced peroxidation of linoleic acid as compared with rutin and the commercial UV absorber. The researchers concluded that including antioxidants such as buckwheat extract in photoprotective formulations may serve to maximize skin protection in such products.⁸

Buckwheat Sensitivity

Conclusion

Because it is a popular component in many diets around the world, especially Japan, Korea, Russia, and Poland, as well as other Asian and European countries, South Africa, Australia, and North America,⁴ it is reasonable to expect that we’ll see more research on buckwheat. For now, there are indications to suggest that more investigations are warranted to determine whether this botanical agent will have a meaningful role in the dermatologic armamentarium.

References

1. Li SQ et al. Crit Rev Food Sci Nutr. 2001 Sep;41(6):451-64.

2. Dattner AM. Dermatol Ther. 2003;16(2):106-13.

3. Hinneburg I et al. J Agric Food Chem. 2005 Jan 12;53(1):3-7.

4. van den Berg AJ et al. J Wound Care. 2008 Apr;17(4):172-4, 176-8.

5. Liu CL et al. J Agric Food Chem. 2008 Jan 9;56(1):173-8.

6. Zhou J et al. Food Chem Toxicol. 2012 Aug;50(8):2766-73.

7. Trommer H et al. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

8. Hinneburg I et al. Pharmazie. 2006 Mar;61(3):237-40.

9. Geiselhart S et al. Clin Exp Allergy. 2018 Feb;48(2):217-24.
 

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

Native to North and East Asia, buckwheat has been grown in China for more than 2,000 years and has been used in traditional medicine to treat varicose veins.^1,2 This highly adaptable plant – the most common species of which are Fagopyrum esculentum (common buckwheat or sweet buckwheat), and F. tataricum (which grows in more mountainous regions) – has acclimated to cultivation in North America, as well.¹ Increasingly popular as a healthy grain option, buckwheat flour has been touted for beneficial effects on diabetes, obesity, hypertension, hypercholesterolemia, and constipation.¹ It has also gained attention for its association with some allergic reactions.

SandraKavas/iStock /Getty Images Plus

Wound Healing

In 2008, van den Berg et al. performed an in vitro investigation of the antioxidant and anti-inflammatory qualities of buckwheat honey for consideration in wound healing. American buckwheat honey from New York was found to be the source of the most salient activities, with such properties attributed to its abundant phenolic components. The researchers suggested that these phenols might impart antibacterial activity, while the low pH and high free acid content of the buckwheat honey could contribute to healing wounds.⁴

Antioxidant Activity

The antioxidant capacity, along with other traits, characterizing the sprouts of common buckwheat (F. esculentum) and tartary buckwheat (F. tataricum) was evaluated by Liu et al. in 2008. Rutin is the main flavonoid found in both species, with fivefold higher levels identified in tartary buckwheat in this study. Ethanol extracts of tartary buckwheat also exhibited greater free radical scavenging activity and superoxide scavenging activity, compared with common buckwheat. Both buckwheat species displayed antioxidant activity on human hepatoma HepG2 cells, with tartary buckwheat more effective in diminishing cellular oxidative stress, which the authors attributed to its greater rutin and quercetin levels.⁵

Zhou et al. studied the protective effects of buckwheat honey on hydroxyl radical-induced DNA damage in 2012, finding that all studied honeys more effectively protected DNA in non–site specific rather than site-specific systems.⁶

Photoprotection

In a 2005 screening of 47 antioxidant substances and study of their effects on UV-induced lipid peroxidation, Trommer and Neubert reported that buckwheat extract significantly lowered radiation levels, as did extracts of St. John’s Wort, melissa, and sage. They concluded that their in vitro findings supported the inclusion of such ingredients in photoprotective cosmetic formulations or sunscreens pending the results of in vivo experiments with these compounds.⁷

In 2006, Hinneburg et al. evaluated the antioxidant and photoprotective activity of a buckwheat herb extract, also comparing its photoprotective characteristics to those of a commercial UV absorber. In an assay with 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH), buckwheat extract exhibited significantly more antioxidant activity than did pure rutin, with buckwheat observed to more effectively block UV-induced peroxidation of linoleic acid as compared with rutin and the commercial UV absorber. The researchers concluded that including antioxidants such as buckwheat extract in photoprotective formulations may serve to maximize skin protection in such products.⁸

Buckwheat Sensitivity

Conclusion

Because it is a popular component in many diets around the world, especially Japan, Korea, Russia, and Poland, as well as other Asian and European countries, South Africa, Australia, and North America,⁴ it is reasonable to expect that we’ll see more research on buckwheat. For now, there are indications to suggest that more investigations are warranted to determine whether this botanical agent will have a meaningful role in the dermatologic armamentarium.

References

1. Li SQ et al. Crit Rev Food Sci Nutr. 2001 Sep;41(6):451-64.

2. Dattner AM. Dermatol Ther. 2003;16(2):106-13.

3. Hinneburg I et al. J Agric Food Chem. 2005 Jan 12;53(1):3-7.

4. van den Berg AJ et al. J Wound Care. 2008 Apr;17(4):172-4, 176-8.

5. Liu CL et al. J Agric Food Chem. 2008 Jan 9;56(1):173-8.

6. Zhou J et al. Food Chem Toxicol. 2012 Aug;50(8):2766-73.

7. Trommer H et al. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

8. Hinneburg I et al. Pharmazie. 2006 Mar;61(3):237-40.

9. Geiselhart S et al. Clin Exp Allergy. 2018 Feb;48(2):217-24.
 

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

Native to North and East Asia, buckwheat has been grown in China for more than 2,000 years and has been used in traditional medicine to treat varicose veins.^1,2 This highly adaptable plant – the most common species of which are Fagopyrum esculentum (common buckwheat or sweet buckwheat), and F. tataricum (which grows in more mountainous regions) – has acclimated to cultivation in North America, as well.¹ Increasingly popular as a healthy grain option, buckwheat flour has been touted for beneficial effects on diabetes, obesity, hypertension, hypercholesterolemia, and constipation.¹ It has also gained attention for its association with some allergic reactions.

SandraKavas/iStock /Getty Images Plus

Wound Healing

In 2008, van den Berg et al. performed an in vitro investigation of the antioxidant and anti-inflammatory qualities of buckwheat honey for consideration in wound healing. American buckwheat honey from New York was found to be the source of the most salient activities, with such properties attributed to its abundant phenolic components. The researchers suggested that these phenols might impart antibacterial activity, while the low pH and high free acid content of the buckwheat honey could contribute to healing wounds.⁴

Antioxidant Activity

The antioxidant capacity, along with other traits, characterizing the sprouts of common buckwheat (F. esculentum) and tartary buckwheat (F. tataricum) was evaluated by Liu et al. in 2008. Rutin is the main flavonoid found in both species, with fivefold higher levels identified in tartary buckwheat in this study. Ethanol extracts of tartary buckwheat also exhibited greater free radical scavenging activity and superoxide scavenging activity, compared with common buckwheat. Both buckwheat species displayed antioxidant activity on human hepatoma HepG2 cells, with tartary buckwheat more effective in diminishing cellular oxidative stress, which the authors attributed to its greater rutin and quercetin levels.⁵

Zhou et al. studied the protective effects of buckwheat honey on hydroxyl radical-induced DNA damage in 2012, finding that all studied honeys more effectively protected DNA in non–site specific rather than site-specific systems.⁶

Photoprotection

In a 2005 screening of 47 antioxidant substances and study of their effects on UV-induced lipid peroxidation, Trommer and Neubert reported that buckwheat extract significantly lowered radiation levels, as did extracts of St. John’s Wort, melissa, and sage. They concluded that their in vitro findings supported the inclusion of such ingredients in photoprotective cosmetic formulations or sunscreens pending the results of in vivo experiments with these compounds.⁷

In 2006, Hinneburg et al. evaluated the antioxidant and photoprotective activity of a buckwheat herb extract, also comparing its photoprotective characteristics to those of a commercial UV absorber. In an assay with 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH), buckwheat extract exhibited significantly more antioxidant activity than did pure rutin, with buckwheat observed to more effectively block UV-induced peroxidation of linoleic acid as compared with rutin and the commercial UV absorber. The researchers concluded that including antioxidants such as buckwheat extract in photoprotective formulations may serve to maximize skin protection in such products.⁸

Buckwheat Sensitivity

Conclusion

Because it is a popular component in many diets around the world, especially Japan, Korea, Russia, and Poland, as well as other Asian and European countries, South Africa, Australia, and North America,⁴ it is reasonable to expect that we’ll see more research on buckwheat. For now, there are indications to suggest that more investigations are warranted to determine whether this botanical agent will have a meaningful role in the dermatologic armamentarium.

References

1. Li SQ et al. Crit Rev Food Sci Nutr. 2001 Sep;41(6):451-64.

2. Dattner AM. Dermatol Ther. 2003;16(2):106-13.

3. Hinneburg I et al. J Agric Food Chem. 2005 Jan 12;53(1):3-7.

4. van den Berg AJ et al. J Wound Care. 2008 Apr;17(4):172-4, 176-8.

5. Liu CL et al. J Agric Food Chem. 2008 Jan 9;56(1):173-8.

6. Zhou J et al. Food Chem Toxicol. 2012 Aug;50(8):2766-73.

7. Trommer H et al. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

8. Hinneburg I et al. Pharmazie. 2006 Mar;61(3):237-40.

9. Geiselhart S et al. Clin Exp Allergy. 2018 Feb;48(2):217-24.
 

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

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Falls have long been a major hazard for older adults—accounting for the largest percentage of deaths from unintentional injuries. Each year, about 1 in 4 older adults in the US reports falling, and an estimated 3 million emergency department visits every year are related to falls.

According to the CDC, things are getting worse. Overall, deaths due to falls among older adults increased 31% from 2007- 2016, a rate of 3% per year. The rate increased in every demographic category except among American Indians/Alaska Natives, with the largest increase (4%) among people aged ≥ 85 years. Nationwide, nearly 30,000 older adults died from fall-related causes in 2016.

But falls are not an inevitable part of aging, the CDC reminds. Advanced age is a well-known independent risk factor; other risk factors include reduced activity, chronic conditions (including incontinence), prescription medications (which may act synergistically on the central nervous system), and changes in gait and balance. The CDC says health care providers can address the problem by asking patients about falls, assessing gait and balance, reviewing medications, and prescribing interventions such as strength and balance exercises or physical therapy.

Initiatives such as CDC’s STEADI (Stopping Elderly Accidents, Deaths, and Injuries) can help with risk assessment, patient education, and interventions (https://www.cdc.gov/steadi).

Falls have long been a major hazard for older adults—accounting for the largest percentage of deaths from unintentional injuries. Each year, about 1 in 4 older adults in the US reports falling, and an estimated 3 million emergency department visits every year are related to falls.

According to the CDC, things are getting worse. Overall, deaths due to falls among older adults increased 31% from 2007- 2016, a rate of 3% per year. The rate increased in every demographic category except among American Indians/Alaska Natives, with the largest increase (4%) among people aged ≥ 85 years. Nationwide, nearly 30,000 older adults died from fall-related causes in 2016.

But falls are not an inevitable part of aging, the CDC reminds. Advanced age is a well-known independent risk factor; other risk factors include reduced activity, chronic conditions (including incontinence), prescription medications (which may act synergistically on the central nervous system), and changes in gait and balance. The CDC says health care providers can address the problem by asking patients about falls, assessing gait and balance, reviewing medications, and prescribing interventions such as strength and balance exercises or physical therapy.

Initiatives such as CDC’s STEADI (Stopping Elderly Accidents, Deaths, and Injuries) can help with risk assessment, patient education, and interventions (https://www.cdc.gov/steadi).

Falls have long been a major hazard for older adults—accounting for the largest percentage of deaths from unintentional injuries. Each year, about 1 in 4 older adults in the US reports falling, and an estimated 3 million emergency department visits every year are related to falls.

According to the CDC, things are getting worse. Overall, deaths due to falls among older adults increased 31% from 2007- 2016, a rate of 3% per year. The rate increased in every demographic category except among American Indians/Alaska Natives, with the largest increase (4%) among people aged ≥ 85 years. Nationwide, nearly 30,000 older adults died from fall-related causes in 2016.

But falls are not an inevitable part of aging, the CDC reminds. Advanced age is a well-known independent risk factor; other risk factors include reduced activity, chronic conditions (including incontinence), prescription medications (which may act synergistically on the central nervous system), and changes in gait and balance. The CDC says health care providers can address the problem by asking patients about falls, assessing gait and balance, reviewing medications, and prescribing interventions such as strength and balance exercises or physical therapy.

Initiatives such as CDC’s STEADI (Stopping Elderly Accidents, Deaths, and Injuries) can help with risk assessment, patient education, and interventions (https://www.cdc.gov/steadi).

In 2006, the Society of Hospital Medicine (SHM) first published The Core Competencies in Hospital Medicine: A Framework for Curricular Development (henceforth described as the Core Competencies) to help define the role and expectations of hospitalists.^1,2 The Core Competencies provided a framework for evaluating clinical skills and professional expertise within a rapidly developing field and highlighted opportunities for growth. Since the initial development and publication of the Core Competencies, changes in the healthcare landscape and hospitalist practice environment have prompted this revision.

Over the past decade, the field of hospital medicine has experienced exponential growth. In 2005, just over 16,000 hospitalists were practicing in the United States. By 2015, that number had increased to an estimated 44,000 hospitalists, accounting for approximately 6% of the physician workforce.³ Hospitalists have expanded the scope of hospital medicine in many ways. In their roles, hospitalists lead and participate in hospital-based care models that emphasize interprofessional collaboration and a focus on the delivery of high-quality and cost-effective care across a variety of clinical domains (eg, the Choosing Wisely initiative).⁴ They are also engaged in patient safety and quality initiatives that are increasingly being used as benchmarks to rate hospitals and as factors for hospital payment (eg, Hospital Inpatient Value-Based Purchasing Program).⁵ In fact, the American Board of Internal Medicine (ABIM) created a Focused Practice in Hospital Medicine Maintenance of Certification program in response to the growing number of internists choosing to concentrate their practice in the hospital setting. This decision by the ABIM underscores the value that hospitalists bring to improving patient care in the hospital setting. The ABIM also recognizes the Core Competencies as a curricular framework for a focused practice in hospital medicine.⁶

Changes within the educational environment have demanded attentive and active participation by many hospitalists. For example, in 2012, the Accreditation Council for Graduate Medical Education (ACGME) introduced the Milestones Project, a new outcomes-based framework designed to more effectively assess learner performance across the 6 core competencies.⁷ These milestones assessments create intentional opportunities to guide the development of physicians during their training, including in the inpatient environments in which hospitalists practice. Where applicable, existing Core Competencies learning objectives were compared with external sources such as the individual ACGME performance milestones for this revision.

The Core Competencies focus on adult hospital medicine. The Pediatric Hospital Medicine Core Competencies are published separately.⁸ Importantly, the Core Competencies document is not intended to define an absolute set of clinical, procedural, or system-based topics described in textbooks or used by graduate medical education training programs. It does not define or limit the scope of the practice of hospital medicine. Rather, the Core Competencies serve as measurable learning objectives that encourage teaching faculty, practicing hospitalists, and administrators to develop individual skill sets and programs to improve patient care contextualized to the needs of an individual, care setting, or institution. To permit this flexibility, individual chapter-specific objectives are intentionally general in nature. Finally, the Core Competencies document is not a set of practice guidelines, nor does it offer any representation of a “standard of care.” Readers are encouraged to explore the article by McKean et al.⁹ to review examples of application of the Core Competencies and suggestions for curricular development.

The purpose of this article is to describe the criteria for inclusion of new chapters in the Core Competencies and the methodology of the review and revision process. It outlines the process of initial review and editing of the existing chapters; needs assessment for new topics; new chapter production; and the process of review and revision of individual chapters to create the complete document. The revised Core Competencies document is available online at http://www.journalofhospitalmedicine.com/jhospmed/issue/134981/journal-hospital-medicine-124-suppl-1.

In 2012, the Society of Hospital Medicine (SHM) Education Committee created a Core Competencies Task Force (CCTF) in response to the SHM Board of Directors’ charge that it review and update the initial Core Competencies document. The CCTF comprised of 5 physician SHM Education Committee members and one SHM staff representative. CCTF membership included hospitalists with an interest and familiarity with the Core Competencies document. The SHM Education Committee nominated the CCTF chair, who determined the optimal size, qualifications, and composition of the task force with approval from the Committee. The CCTF communicated through frequent conference calls and via e-mail correspondence to conduct an initial review of the existing chapters and to perform a needs assessment for new topics.

Individual Chapter Review

The SHM Education Committee provided critical input and approved the chapter review process designed by the CCTF (Figure). The CCTF reviewed each chapter of the Core Competencies document to assess its continuing relevance to the field of hospital medicine with a standardized tool (Appendix 1). The process required that at least 2 CCTF members reviewed each chapter. Preliminary reviewers assessed the current relevance of each chapter, determined whether individual learning objectives required additional investigation or modification, and developed new learning objectives to fill any educational gaps. All CCTF members then discussed assimilated feedback from the initial CCTF review, using consensus decision making to determine chapter changes and modifications. The CCTF found each of the existing chapters to be relevant to the field and identified none for removal.

The CCTF rewrote all chapters. It then disseminated proposed chapter changes to a panel of diverse independent reviewers to solicit suggestions and comments to ensure a multidisciplinary and balanced review process. Independent reviewers included authors of the original Core Competencies chapters, invited content experts, and members of the SHM Education Committee. When appropriate, corresponding SHM Committees reviewed individual chapters for updates and revisions. For example, the SHM Hospital Quality and Patient Safety Committee reviewed the chapters on patient safety and quality improvement, and the SHM Practice Management Committee reviewed the chapter on management practices. Four CCTF section editors managed an independent portfolio of chapters. Each CCTF section editor assimilated the various draft versions, corresponded with individual reviewers when necessary, and compiled the changes into a subsequent draft. This process ensured that the final version of every chapter reflected the thoughtful input from all parties involved in the review. Throughout the process, the CCTF used consensus decision making to adjudicate chapter changes and modifications. The 2006 Core Competencies Editorial team also reviewed the revision and provided critical input. The SHM Education Committee and the SHM Board of Directors reviewed and approved the final version of the Core Competencies document.

Needs Assessment and Selection of New Core Competency Chapters

The CCTF issued a call for new topics to the members of the SHM Education Committee for inclusion in the Core Competencies. Topics were also identified from the following sources: the top 100 adult medical diagnoses at hospital discharge in the Healthcare Cost and Utilization Project database in 2010; topics in hospital medicine textbooks; curricula presented at the 3 most recent SHM annual meetings; and responses from SHM annual meeting surveys. Table 1 lists the topics considered for addition.

Members of the SHM Education Committee rated each of the potential topics considered for inclusion based on the following characteristics: relevance to the field of hospital medicine; intersection of the topic with medical subspecialties; and its appropriateness as a separate, stand-alone chapter. In addition, topics more frequently encountered by hospitalists, those deemed clinically important with a known risk of complications or management inconsistencies, and those with significant opportunities for quality improvement initiatives carried more weight. Syncope and hyponatremia were the only 2 clinical conditions identified that met all of the inclusion criteria. No additional topics met the criteria for new chapter development in the Procedures or Healthcare Systems sections. The SHM Education Committee identified the use of point-of-care ultrasonography as an important advancement in the field. Where appropriate, the individual procedure chapters now include a new competency-based objective highlighting its role. In addition, a separate SHM task force is working to develop a practice guideline for the use of point-of-care ultrasonography by hospitalists.

Contributors

The SHM Education Committee determined authorship for the new chapters (syncope and hyponatremia). It assigned 2 CCTF members with content expertise and familiarity with the Core Competencies to each author one chapter. Given the limited number of new chapters, it made a decision to develop the content internally rather than through an open-call for authorship nominations to practicing SHM members. The authors made an effort to maintain consistency with the educational theory used to develop the initial Core Competencies. Each of the new topics underwent rigorous review as previously described, including additional independent reviews by hospitalists with content expertise in these areas.

Following the same format as the earlier version, the 2017 Core Competencies revision contains 53 chapters, divided into 3 sections—Clinical Conditions, Procedures, and Healthcare Systems (Table 2) —all integral components of the practice of hospital medicine. The design allows individual chapters to stand alone. However, each chapter should be considered in the context of the entire document because a particular concept may be only briefly discussed in one chapter, but described in greater depth in another given the potential overlap across topics.

The chapters maintain the same content structure as the original version. Each chapter begins with an introductory paragraph followed by a list of competency-based objectives grouped in subsections according to the educational theory of learning domains: cognitive (knowledge), psychomotor (skills), and affective (attitudes).¹⁰ In addition, a subsection for System Organization and Improvement is included in the Clinical Conditions and Procedure chapters to emphasize the importance of interprofessional collaboration for optimal patient care. These subsections were not included in the Healthcare Systems chapters, as system organization and improvement is intrinsic to these subjects.

The introductory paragraph provides background information and describes how the chapter remains relevant to the current practice of hospital medicine. Individual competency-based objectives outline a relevant concept and expected level of proficiency as defined by Bloom’s taxonomy.¹⁰ New objectives reflect changes in the healthcare landscape over the past decade or further enhance each chapter’s concepts. Chapter authors made an effort to develop chapter and learning objective concepts that are consistent with external resources such as the ACGME Milestones Project and practice guideline objectives developed by a variety of professional organizations.

The Core Competencies document serves as a resource for hospitalists and hospital medicine programs to evaluate, develop, and improve individual and collective skills and the practice environment. The Core Competencies also provide a framework for medical school clerkship directors and residency and fellowship program directors, as well as course directors of Continuing Medical Education programs, to develop curricula to enhance educational experiences for trainees and hospital medicine providers. The updates in every chapter in this revision to the Core Competencies reflects the changes in the healthcare landscape and hospitalist practice environment over the past decade, and we encourage readers to revisit the entire compendium. Table 3 highlights some of the salient changes in this revision.

Hospital medicine continues to evolve as a specialty. The Core Competencies define hospitalists as agents of change and foster the development of a culture of safe and effective patient care within the hospital environment. Although the CCTF hopes that the Core Competencies will preserve their relevance over time, it recognizes the importance of their periodic reevaluation and adaptation. Additionally, SHM developed the Core Competencies primarily for physicians practicing as hospitalists. As the number of physician assistants and nurse practitioners engaged in the practice of hospital medicine increases, and hospital medicine expands into nontraditional specialties such as surgical comanagement, it may be necessary to consider the development of additional or separate Hospital Medicine Core Competencies tailored to the needs of these subsets of clinicians.

Acknowledgments

The authors and the CCTF are immensely grateful to Nick Marzano for project coordination and Abbie Young for her assistance with medical editing and chapter formatting. We extend our sincerest appreciation and gratitude to the index team of authors and editors whose efforts laid the foundation for this body of work. The initial development and this revision of the Core Competencies would not have been possible without the support and assistance of the SHM staff, the SHM Education Committee, and the scores of contributors and reviewers who participated in its creation (complete list of individuals is available in Appendix 2). We thank everyone for his or her invaluable input and effort.

Disclosures

The Society of Hospital Medicine (SHM) provided administrative support for project coordination. SHM, or any of its representatives, had no role in the development of topic areas, refinement, or vetting of the topic list. No member of the Core Competencies Task Force or the SHM Education Committee received compensation for their participation in revising the Core Competencies. The authors report no conflicts of interest.

In 2006, the Society of Hospital Medicine (SHM) first published The Core Competencies in Hospital Medicine: A Framework for Curricular Development (henceforth described as the Core Competencies) to help define the role and expectations of hospitalists.^1,2 The Core Competencies provided a framework for evaluating clinical skills and professional expertise within a rapidly developing field and highlighted opportunities for growth. Since the initial development and publication of the Core Competencies, changes in the healthcare landscape and hospitalist practice environment have prompted this revision.

Over the past decade, the field of hospital medicine has experienced exponential growth. In 2005, just over 16,000 hospitalists were practicing in the United States. By 2015, that number had increased to an estimated 44,000 hospitalists, accounting for approximately 6% of the physician workforce.³ Hospitalists have expanded the scope of hospital medicine in many ways. In their roles, hospitalists lead and participate in hospital-based care models that emphasize interprofessional collaboration and a focus on the delivery of high-quality and cost-effective care across a variety of clinical domains (eg, the Choosing Wisely initiative).⁴ They are also engaged in patient safety and quality initiatives that are increasingly being used as benchmarks to rate hospitals and as factors for hospital payment (eg, Hospital Inpatient Value-Based Purchasing Program).⁵ In fact, the American Board of Internal Medicine (ABIM) created a Focused Practice in Hospital Medicine Maintenance of Certification program in response to the growing number of internists choosing to concentrate their practice in the hospital setting. This decision by the ABIM underscores the value that hospitalists bring to improving patient care in the hospital setting. The ABIM also recognizes the Core Competencies as a curricular framework for a focused practice in hospital medicine.⁶

Changes within the educational environment have demanded attentive and active participation by many hospitalists. For example, in 2012, the Accreditation Council for Graduate Medical Education (ACGME) introduced the Milestones Project, a new outcomes-based framework designed to more effectively assess learner performance across the 6 core competencies.⁷ These milestones assessments create intentional opportunities to guide the development of physicians during their training, including in the inpatient environments in which hospitalists practice. Where applicable, existing Core Competencies learning objectives were compared with external sources such as the individual ACGME performance milestones for this revision.

The Core Competencies focus on adult hospital medicine. The Pediatric Hospital Medicine Core Competencies are published separately.⁸ Importantly, the Core Competencies document is not intended to define an absolute set of clinical, procedural, or system-based topics described in textbooks or used by graduate medical education training programs. It does not define or limit the scope of the practice of hospital medicine. Rather, the Core Competencies serve as measurable learning objectives that encourage teaching faculty, practicing hospitalists, and administrators to develop individual skill sets and programs to improve patient care contextualized to the needs of an individual, care setting, or institution. To permit this flexibility, individual chapter-specific objectives are intentionally general in nature. Finally, the Core Competencies document is not a set of practice guidelines, nor does it offer any representation of a “standard of care.” Readers are encouraged to explore the article by McKean et al.⁹ to review examples of application of the Core Competencies and suggestions for curricular development.

The purpose of this article is to describe the criteria for inclusion of new chapters in the Core Competencies and the methodology of the review and revision process. It outlines the process of initial review and editing of the existing chapters; needs assessment for new topics; new chapter production; and the process of review and revision of individual chapters to create the complete document. The revised Core Competencies document is available online at http://www.journalofhospitalmedicine.com/jhospmed/issue/134981/journal-hospital-medicine-124-suppl-1.

In 2012, the Society of Hospital Medicine (SHM) Education Committee created a Core Competencies Task Force (CCTF) in response to the SHM Board of Directors’ charge that it review and update the initial Core Competencies document. The CCTF comprised of 5 physician SHM Education Committee members and one SHM staff representative. CCTF membership included hospitalists with an interest and familiarity with the Core Competencies document. The SHM Education Committee nominated the CCTF chair, who determined the optimal size, qualifications, and composition of the task force with approval from the Committee. The CCTF communicated through frequent conference calls and via e-mail correspondence to conduct an initial review of the existing chapters and to perform a needs assessment for new topics.

Individual Chapter Review

The SHM Education Committee provided critical input and approved the chapter review process designed by the CCTF (Figure). The CCTF reviewed each chapter of the Core Competencies document to assess its continuing relevance to the field of hospital medicine with a standardized tool (Appendix 1). The process required that at least 2 CCTF members reviewed each chapter. Preliminary reviewers assessed the current relevance of each chapter, determined whether individual learning objectives required additional investigation or modification, and developed new learning objectives to fill any educational gaps. All CCTF members then discussed assimilated feedback from the initial CCTF review, using consensus decision making to determine chapter changes and modifications. The CCTF found each of the existing chapters to be relevant to the field and identified none for removal.

The CCTF rewrote all chapters. It then disseminated proposed chapter changes to a panel of diverse independent reviewers to solicit suggestions and comments to ensure a multidisciplinary and balanced review process. Independent reviewers included authors of the original Core Competencies chapters, invited content experts, and members of the SHM Education Committee. When appropriate, corresponding SHM Committees reviewed individual chapters for updates and revisions. For example, the SHM Hospital Quality and Patient Safety Committee reviewed the chapters on patient safety and quality improvement, and the SHM Practice Management Committee reviewed the chapter on management practices. Four CCTF section editors managed an independent portfolio of chapters. Each CCTF section editor assimilated the various draft versions, corresponded with individual reviewers when necessary, and compiled the changes into a subsequent draft. This process ensured that the final version of every chapter reflected the thoughtful input from all parties involved in the review. Throughout the process, the CCTF used consensus decision making to adjudicate chapter changes and modifications. The 2006 Core Competencies Editorial team also reviewed the revision and provided critical input. The SHM Education Committee and the SHM Board of Directors reviewed and approved the final version of the Core Competencies document.

Needs Assessment and Selection of New Core Competency Chapters

The CCTF issued a call for new topics to the members of the SHM Education Committee for inclusion in the Core Competencies. Topics were also identified from the following sources: the top 100 adult medical diagnoses at hospital discharge in the Healthcare Cost and Utilization Project database in 2010; topics in hospital medicine textbooks; curricula presented at the 3 most recent SHM annual meetings; and responses from SHM annual meeting surveys. Table 1 lists the topics considered for addition.

Members of the SHM Education Committee rated each of the potential topics considered for inclusion based on the following characteristics: relevance to the field of hospital medicine; intersection of the topic with medical subspecialties; and its appropriateness as a separate, stand-alone chapter. In addition, topics more frequently encountered by hospitalists, those deemed clinically important with a known risk of complications or management inconsistencies, and those with significant opportunities for quality improvement initiatives carried more weight. Syncope and hyponatremia were the only 2 clinical conditions identified that met all of the inclusion criteria. No additional topics met the criteria for new chapter development in the Procedures or Healthcare Systems sections. The SHM Education Committee identified the use of point-of-care ultrasonography as an important advancement in the field. Where appropriate, the individual procedure chapters now include a new competency-based objective highlighting its role. In addition, a separate SHM task force is working to develop a practice guideline for the use of point-of-care ultrasonography by hospitalists.

Contributors

The SHM Education Committee determined authorship for the new chapters (syncope and hyponatremia). It assigned 2 CCTF members with content expertise and familiarity with the Core Competencies to each author one chapter. Given the limited number of new chapters, it made a decision to develop the content internally rather than through an open-call for authorship nominations to practicing SHM members. The authors made an effort to maintain consistency with the educational theory used to develop the initial Core Competencies. Each of the new topics underwent rigorous review as previously described, including additional independent reviews by hospitalists with content expertise in these areas.

Following the same format as the earlier version, the 2017 Core Competencies revision contains 53 chapters, divided into 3 sections—Clinical Conditions, Procedures, and Healthcare Systems (Table 2) —all integral components of the practice of hospital medicine. The design allows individual chapters to stand alone. However, each chapter should be considered in the context of the entire document because a particular concept may be only briefly discussed in one chapter, but described in greater depth in another given the potential overlap across topics.

The chapters maintain the same content structure as the original version. Each chapter begins with an introductory paragraph followed by a list of competency-based objectives grouped in subsections according to the educational theory of learning domains: cognitive (knowledge), psychomotor (skills), and affective (attitudes).¹⁰ In addition, a subsection for System Organization and Improvement is included in the Clinical Conditions and Procedure chapters to emphasize the importance of interprofessional collaboration for optimal patient care. These subsections were not included in the Healthcare Systems chapters, as system organization and improvement is intrinsic to these subjects.

The introductory paragraph provides background information and describes how the chapter remains relevant to the current practice of hospital medicine. Individual competency-based objectives outline a relevant concept and expected level of proficiency as defined by Bloom’s taxonomy.¹⁰ New objectives reflect changes in the healthcare landscape over the past decade or further enhance each chapter’s concepts. Chapter authors made an effort to develop chapter and learning objective concepts that are consistent with external resources such as the ACGME Milestones Project and practice guideline objectives developed by a variety of professional organizations.

The Core Competencies document serves as a resource for hospitalists and hospital medicine programs to evaluate, develop, and improve individual and collective skills and the practice environment. The Core Competencies also provide a framework for medical school clerkship directors and residency and fellowship program directors, as well as course directors of Continuing Medical Education programs, to develop curricula to enhance educational experiences for trainees and hospital medicine providers. The updates in every chapter in this revision to the Core Competencies reflects the changes in the healthcare landscape and hospitalist practice environment over the past decade, and we encourage readers to revisit the entire compendium. Table 3 highlights some of the salient changes in this revision.

Hospital medicine continues to evolve as a specialty. The Core Competencies define hospitalists as agents of change and foster the development of a culture of safe and effective patient care within the hospital environment. Although the CCTF hopes that the Core Competencies will preserve their relevance over time, it recognizes the importance of their periodic reevaluation and adaptation. Additionally, SHM developed the Core Competencies primarily for physicians practicing as hospitalists. As the number of physician assistants and nurse practitioners engaged in the practice of hospital medicine increases, and hospital medicine expands into nontraditional specialties such as surgical comanagement, it may be necessary to consider the development of additional or separate Hospital Medicine Core Competencies tailored to the needs of these subsets of clinicians.

Acknowledgments

The authors and the CCTF are immensely grateful to Nick Marzano for project coordination and Abbie Young for her assistance with medical editing and chapter formatting. We extend our sincerest appreciation and gratitude to the index team of authors and editors whose efforts laid the foundation for this body of work. The initial development and this revision of the Core Competencies would not have been possible without the support and assistance of the SHM staff, the SHM Education Committee, and the scores of contributors and reviewers who participated in its creation (complete list of individuals is available in Appendix 2). We thank everyone for his or her invaluable input and effort.

Disclosures

The Society of Hospital Medicine (SHM) provided administrative support for project coordination. SHM, or any of its representatives, had no role in the development of topic areas, refinement, or vetting of the topic list. No member of the Core Competencies Task Force or the SHM Education Committee received compensation for their participation in revising the Core Competencies. The authors report no conflicts of interest.

In 2006, the Society of Hospital Medicine (SHM) first published The Core Competencies in Hospital Medicine: A Framework for Curricular Development (henceforth described as the Core Competencies) to help define the role and expectations of hospitalists.^1,2 The Core Competencies provided a framework for evaluating clinical skills and professional expertise within a rapidly developing field and highlighted opportunities for growth. Since the initial development and publication of the Core Competencies, changes in the healthcare landscape and hospitalist practice environment have prompted this revision.

Over the past decade, the field of hospital medicine has experienced exponential growth. In 2005, just over 16,000 hospitalists were practicing in the United States. By 2015, that number had increased to an estimated 44,000 hospitalists, accounting for approximately 6% of the physician workforce.³ Hospitalists have expanded the scope of hospital medicine in many ways. In their roles, hospitalists lead and participate in hospital-based care models that emphasize interprofessional collaboration and a focus on the delivery of high-quality and cost-effective care across a variety of clinical domains (eg, the Choosing Wisely initiative).⁴ They are also engaged in patient safety and quality initiatives that are increasingly being used as benchmarks to rate hospitals and as factors for hospital payment (eg, Hospital Inpatient Value-Based Purchasing Program).⁵ In fact, the American Board of Internal Medicine (ABIM) created a Focused Practice in Hospital Medicine Maintenance of Certification program in response to the growing number of internists choosing to concentrate their practice in the hospital setting. This decision by the ABIM underscores the value that hospitalists bring to improving patient care in the hospital setting. The ABIM also recognizes the Core Competencies as a curricular framework for a focused practice in hospital medicine.⁶

Changes within the educational environment have demanded attentive and active participation by many hospitalists. For example, in 2012, the Accreditation Council for Graduate Medical Education (ACGME) introduced the Milestones Project, a new outcomes-based framework designed to more effectively assess learner performance across the 6 core competencies.⁷ These milestones assessments create intentional opportunities to guide the development of physicians during their training, including in the inpatient environments in which hospitalists practice. Where applicable, existing Core Competencies learning objectives were compared with external sources such as the individual ACGME performance milestones for this revision.

The Core Competencies focus on adult hospital medicine. The Pediatric Hospital Medicine Core Competencies are published separately.⁸ Importantly, the Core Competencies document is not intended to define an absolute set of clinical, procedural, or system-based topics described in textbooks or used by graduate medical education training programs. It does not define or limit the scope of the practice of hospital medicine. Rather, the Core Competencies serve as measurable learning objectives that encourage teaching faculty, practicing hospitalists, and administrators to develop individual skill sets and programs to improve patient care contextualized to the needs of an individual, care setting, or institution. To permit this flexibility, individual chapter-specific objectives are intentionally general in nature. Finally, the Core Competencies document is not a set of practice guidelines, nor does it offer any representation of a “standard of care.” Readers are encouraged to explore the article by McKean et al.⁹ to review examples of application of the Core Competencies and suggestions for curricular development.

The purpose of this article is to describe the criteria for inclusion of new chapters in the Core Competencies and the methodology of the review and revision process. It outlines the process of initial review and editing of the existing chapters; needs assessment for new topics; new chapter production; and the process of review and revision of individual chapters to create the complete document. The revised Core Competencies document is available online at http://www.journalofhospitalmedicine.com/jhospmed/issue/134981/journal-hospital-medicine-124-suppl-1.

In 2012, the Society of Hospital Medicine (SHM) Education Committee created a Core Competencies Task Force (CCTF) in response to the SHM Board of Directors’ charge that it review and update the initial Core Competencies document. The CCTF comprised of 5 physician SHM Education Committee members and one SHM staff representative. CCTF membership included hospitalists with an interest and familiarity with the Core Competencies document. The SHM Education Committee nominated the CCTF chair, who determined the optimal size, qualifications, and composition of the task force with approval from the Committee. The CCTF communicated through frequent conference calls and via e-mail correspondence to conduct an initial review of the existing chapters and to perform a needs assessment for new topics.

Individual Chapter Review

The SHM Education Committee provided critical input and approved the chapter review process designed by the CCTF (Figure). The CCTF reviewed each chapter of the Core Competencies document to assess its continuing relevance to the field of hospital medicine with a standardized tool (Appendix 1). The process required that at least 2 CCTF members reviewed each chapter. Preliminary reviewers assessed the current relevance of each chapter, determined whether individual learning objectives required additional investigation or modification, and developed new learning objectives to fill any educational gaps. All CCTF members then discussed assimilated feedback from the initial CCTF review, using consensus decision making to determine chapter changes and modifications. The CCTF found each of the existing chapters to be relevant to the field and identified none for removal.

The CCTF rewrote all chapters. It then disseminated proposed chapter changes to a panel of diverse independent reviewers to solicit suggestions and comments to ensure a multidisciplinary and balanced review process. Independent reviewers included authors of the original Core Competencies chapters, invited content experts, and members of the SHM Education Committee. When appropriate, corresponding SHM Committees reviewed individual chapters for updates and revisions. For example, the SHM Hospital Quality and Patient Safety Committee reviewed the chapters on patient safety and quality improvement, and the SHM Practice Management Committee reviewed the chapter on management practices. Four CCTF section editors managed an independent portfolio of chapters. Each CCTF section editor assimilated the various draft versions, corresponded with individual reviewers when necessary, and compiled the changes into a subsequent draft. This process ensured that the final version of every chapter reflected the thoughtful input from all parties involved in the review. Throughout the process, the CCTF used consensus decision making to adjudicate chapter changes and modifications. The 2006 Core Competencies Editorial team also reviewed the revision and provided critical input. The SHM Education Committee and the SHM Board of Directors reviewed and approved the final version of the Core Competencies document.

Needs Assessment and Selection of New Core Competency Chapters

The CCTF issued a call for new topics to the members of the SHM Education Committee for inclusion in the Core Competencies. Topics were also identified from the following sources: the top 100 adult medical diagnoses at hospital discharge in the Healthcare Cost and Utilization Project database in 2010; topics in hospital medicine textbooks; curricula presented at the 3 most recent SHM annual meetings; and responses from SHM annual meeting surveys. Table 1 lists the topics considered for addition.

Members of the SHM Education Committee rated each of the potential topics considered for inclusion based on the following characteristics: relevance to the field of hospital medicine; intersection of the topic with medical subspecialties; and its appropriateness as a separate, stand-alone chapter. In addition, topics more frequently encountered by hospitalists, those deemed clinically important with a known risk of complications or management inconsistencies, and those with significant opportunities for quality improvement initiatives carried more weight. Syncope and hyponatremia were the only 2 clinical conditions identified that met all of the inclusion criteria. No additional topics met the criteria for new chapter development in the Procedures or Healthcare Systems sections. The SHM Education Committee identified the use of point-of-care ultrasonography as an important advancement in the field. Where appropriate, the individual procedure chapters now include a new competency-based objective highlighting its role. In addition, a separate SHM task force is working to develop a practice guideline for the use of point-of-care ultrasonography by hospitalists.

Contributors

The SHM Education Committee determined authorship for the new chapters (syncope and hyponatremia). It assigned 2 CCTF members with content expertise and familiarity with the Core Competencies to each author one chapter. Given the limited number of new chapters, it made a decision to develop the content internally rather than through an open-call for authorship nominations to practicing SHM members. The authors made an effort to maintain consistency with the educational theory used to develop the initial Core Competencies. Each of the new topics underwent rigorous review as previously described, including additional independent reviews by hospitalists with content expertise in these areas.

Following the same format as the earlier version, the 2017 Core Competencies revision contains 53 chapters, divided into 3 sections—Clinical Conditions, Procedures, and Healthcare Systems (Table 2) —all integral components of the practice of hospital medicine. The design allows individual chapters to stand alone. However, each chapter should be considered in the context of the entire document because a particular concept may be only briefly discussed in one chapter, but described in greater depth in another given the potential overlap across topics.

The chapters maintain the same content structure as the original version. Each chapter begins with an introductory paragraph followed by a list of competency-based objectives grouped in subsections according to the educational theory of learning domains: cognitive (knowledge), psychomotor (skills), and affective (attitudes).¹⁰ In addition, a subsection for System Organization and Improvement is included in the Clinical Conditions and Procedure chapters to emphasize the importance of interprofessional collaboration for optimal patient care. These subsections were not included in the Healthcare Systems chapters, as system organization and improvement is intrinsic to these subjects.

The introductory paragraph provides background information and describes how the chapter remains relevant to the current practice of hospital medicine. Individual competency-based objectives outline a relevant concept and expected level of proficiency as defined by Bloom’s taxonomy.¹⁰ New objectives reflect changes in the healthcare landscape over the past decade or further enhance each chapter’s concepts. Chapter authors made an effort to develop chapter and learning objective concepts that are consistent with external resources such as the ACGME Milestones Project and practice guideline objectives developed by a variety of professional organizations.

The Core Competencies document serves as a resource for hospitalists and hospital medicine programs to evaluate, develop, and improve individual and collective skills and the practice environment. The Core Competencies also provide a framework for medical school clerkship directors and residency and fellowship program directors, as well as course directors of Continuing Medical Education programs, to develop curricula to enhance educational experiences for trainees and hospital medicine providers. The updates in every chapter in this revision to the Core Competencies reflects the changes in the healthcare landscape and hospitalist practice environment over the past decade, and we encourage readers to revisit the entire compendium. Table 3 highlights some of the salient changes in this revision.

Hospital medicine continues to evolve as a specialty. The Core Competencies define hospitalists as agents of change and foster the development of a culture of safe and effective patient care within the hospital environment. Although the CCTF hopes that the Core Competencies will preserve their relevance over time, it recognizes the importance of their periodic reevaluation and adaptation. Additionally, SHM developed the Core Competencies primarily for physicians practicing as hospitalists. As the number of physician assistants and nurse practitioners engaged in the practice of hospital medicine increases, and hospital medicine expands into nontraditional specialties such as surgical comanagement, it may be necessary to consider the development of additional or separate Hospital Medicine Core Competencies tailored to the needs of these subsets of clinicians.

Acknowledgments

The authors and the CCTF are immensely grateful to Nick Marzano for project coordination and Abbie Young for her assistance with medical editing and chapter formatting. We extend our sincerest appreciation and gratitude to the index team of authors and editors whose efforts laid the foundation for this body of work. The initial development and this revision of the Core Competencies would not have been possible without the support and assistance of the SHM staff, the SHM Education Committee, and the scores of contributors and reviewers who participated in its creation (complete list of individuals is available in Appendix 2). We thank everyone for his or her invaluable input and effort.

Disclosures

The Society of Hospital Medicine (SHM) provided administrative support for project coordination. SHM, or any of its representatives, had no role in the development of topic areas, refinement, or vetting of the topic list. No member of the Core Competencies Task Force or the SHM Education Committee received compensation for their participation in revising the Core Competencies. The authors report no conflicts of interest.

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.

—Randy Dotinga

Suggested Reading

Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59-63.

Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology. 2017;88(12):1144-1152.

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.

—Randy Dotinga

Suggested Reading

Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59-63.

Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology. 2017;88(12):1144-1152.

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.

—Randy Dotinga

Suggested Reading

Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59-63.

Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009;72(5):402-409.

Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology. 2017;88(12):1144-1152.

LOS ANGELES—Patisiran, an investigational RNA interference therapy that suppresses the production of transthyretin (TTR) protein, significantly improves polyneuropathy in patients with hereditary TTR-mediated (hATTR) amyloidosis, according to phase III trial results described at the 70th Annual Meeting of the American Academy of Neurology.

After 18 months of treatment with patisiran, patients’ scores on a measure of neuropathy impairment had improved from baseline, whereas scores progressively worsened among patients who received placebo.

“The results are amazing,” said principal investigator David Adams, MD, PhD, Head of the Department of Neurology at Centre Hospitalier Universitaire Bicêtre in Paris. “The hope is to stop the progression of the disease and eventually to reverse it.”

Patients Often Present With Polyneuropathy

Formerly known as familial amyloidotic polyneuropathy, hATTR amyloidosis is a rare, multisystemic, progressive, life-threatening disease caused by mutations in the TTR gene. The mutations may cause misfolded TTR protein to accumulate as amyloid fibrils in the nerves, heart, and gastrointestinal tract. There are more than 120 known TTR mutations, and people with the most common mutation, Val30Met, often present with polyneuropathy. Patients with hATTR amyloidosis also may present with cardiomyopathy or a mixed phenotype. The median age of disease onset is 39.

In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness, and impaired balance). Current treatment options include liver transplantation.

Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.

The APOLLO Trial

To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.

The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.

Assessing Change From Baseline

The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.

At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.

At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.

At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).

“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.

The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.

All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.

In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.

Therapy Is Under FDA Review

There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.

Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).

The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.

Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.

—Jake Remaly

Suggested Reading

Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.

Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.

Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.

Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.

LOS ANGELES—Patisiran, an investigational RNA interference therapy that suppresses the production of transthyretin (TTR) protein, significantly improves polyneuropathy in patients with hereditary TTR-mediated (hATTR) amyloidosis, according to phase III trial results described at the 70th Annual Meeting of the American Academy of Neurology.

After 18 months of treatment with patisiran, patients’ scores on a measure of neuropathy impairment had improved from baseline, whereas scores progressively worsened among patients who received placebo.

“The results are amazing,” said principal investigator David Adams, MD, PhD, Head of the Department of Neurology at Centre Hospitalier Universitaire Bicêtre in Paris. “The hope is to stop the progression of the disease and eventually to reverse it.”

Patients Often Present With Polyneuropathy

Formerly known as familial amyloidotic polyneuropathy, hATTR amyloidosis is a rare, multisystemic, progressive, life-threatening disease caused by mutations in the TTR gene. The mutations may cause misfolded TTR protein to accumulate as amyloid fibrils in the nerves, heart, and gastrointestinal tract. There are more than 120 known TTR mutations, and people with the most common mutation, Val30Met, often present with polyneuropathy. Patients with hATTR amyloidosis also may present with cardiomyopathy or a mixed phenotype. The median age of disease onset is 39.

In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness, and impaired balance). Current treatment options include liver transplantation.

Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.

The APOLLO Trial

To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.

The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.

Assessing Change From Baseline

The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.

At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.

At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.

At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).

“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.

The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.

All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.

In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.

Therapy Is Under FDA Review

There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.

Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).

The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.

Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.

—Jake Remaly

Suggested Reading

Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.

Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.

Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.

Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.

LOS ANGELES—Patisiran, an investigational RNA interference therapy that suppresses the production of transthyretin (TTR) protein, significantly improves polyneuropathy in patients with hereditary TTR-mediated (hATTR) amyloidosis, according to phase III trial results described at the 70th Annual Meeting of the American Academy of Neurology.

After 18 months of treatment with patisiran, patients’ scores on a measure of neuropathy impairment had improved from baseline, whereas scores progressively worsened among patients who received placebo.

“The results are amazing,” said principal investigator David Adams, MD, PhD, Head of the Department of Neurology at Centre Hospitalier Universitaire Bicêtre in Paris. “The hope is to stop the progression of the disease and eventually to reverse it.”

Patients Often Present With Polyneuropathy

Formerly known as familial amyloidotic polyneuropathy, hATTR amyloidosis is a rare, multisystemic, progressive, life-threatening disease caused by mutations in the TTR gene. The mutations may cause misfolded TTR protein to accumulate as amyloid fibrils in the nerves, heart, and gastrointestinal tract. There are more than 120 known TTR mutations, and people with the most common mutation, Val30Met, often present with polyneuropathy. Patients with hATTR amyloidosis also may present with cardiomyopathy or a mixed phenotype. The median age of disease onset is 39.

In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness, and impaired balance). Current treatment options include liver transplantation.

Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.

The APOLLO Trial

To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.

The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.

Assessing Change From Baseline

The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.

At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.

At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.

At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).

“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.

The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.

All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.

In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.

Therapy Is Under FDA Review

There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.

Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).

The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.

Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.

—Jake Remaly

Suggested Reading

Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.

Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.

Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.

Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.

The Food and Drug Administration has approved the Zephyr endobronchial valve system for those with severe emphysema who are experiencing difficulty breathing. The valve is the first minimally invasive device approved in the United States for treating such patients, according to Pulmonx, the device manufacturer.

The FDA previously granted the novel device expedited review, as patients who did not respond to drug treatment had only limited alternative options, including lung volume reduction and lung transplant, Tina Kiang, PhD, of the FDA’s Center for Devices and Radiological Health, said in a press release. “This novel device is a less invasive treatment that expands the options available to patients,” said Dr. Kiang, acting director of the center’s Division of Anesthesiology, General Hospital, Respiratory, Infection Control, and Dental Devices.

[email protected]

The Food and Drug Administration has approved the Zephyr endobronchial valve system for those with severe emphysema who are experiencing difficulty breathing. The valve is the first minimally invasive device approved in the United States for treating such patients, according to Pulmonx, the device manufacturer.

The FDA previously granted the novel device expedited review, as patients who did not respond to drug treatment had only limited alternative options, including lung volume reduction and lung transplant, Tina Kiang, PhD, of the FDA’s Center for Devices and Radiological Health, said in a press release. “This novel device is a less invasive treatment that expands the options available to patients,” said Dr. Kiang, acting director of the center’s Division of Anesthesiology, General Hospital, Respiratory, Infection Control, and Dental Devices.

[email protected]

The Food and Drug Administration has approved the Zephyr endobronchial valve system for those with severe emphysema who are experiencing difficulty breathing. The valve is the first minimally invasive device approved in the United States for treating such patients, according to Pulmonx, the device manufacturer.

The FDA previously granted the novel device expedited review, as patients who did not respond to drug treatment had only limited alternative options, including lung volume reduction and lung transplant, Tina Kiang, PhD, of the FDA’s Center for Devices and Radiological Health, said in a press release. “This novel device is a less invasive treatment that expands the options available to patients,” said Dr. Kiang, acting director of the center’s Division of Anesthesiology, General Hospital, Respiratory, Infection Control, and Dental Devices.

[email protected]

LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.

Initial Therapy: No Benefit to Levodopa Sparing

Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”

In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.

In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”

Other Therapies

Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”

MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.

Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.

Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.

New and Investigational Treatments

Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”

Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”

Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of neurogenic orthostatic hypotension. Its effectiveness was shown in two two-week clinical trials. “It is expensive, costing tens of thousands of dollars per year. Although it is well tolerated, there is evidence of tachyphylaxis, and it may not work for longer than two weeks.”

Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.

Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.

To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.

—Adriene Marshall

Suggested Reading

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.

Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.

LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.

Initial Therapy: No Benefit to Levodopa Sparing

Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”

In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.

In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”

Other Therapies

Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”

MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.

Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.

Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.

New and Investigational Treatments

Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”

Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”

Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of neurogenic orthostatic hypotension. Its effectiveness was shown in two two-week clinical trials. “It is expensive, costing tens of thousands of dollars per year. Although it is well tolerated, there is evidence of tachyphylaxis, and it may not work for longer than two weeks.”

Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.

Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.

To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.

—Adriene Marshall

Suggested Reading

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.

Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.

LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.

Initial Therapy: No Benefit to Levodopa Sparing

Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”

In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.

In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”

Other Therapies

Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”

MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.

Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.

Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.

New and Investigational Treatments

Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”

Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”

Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of neurogenic orthostatic hypotension. Its effectiveness was shown in two two-week clinical trials. “It is expensive, costing tens of thousands of dollars per year. Although it is well tolerated, there is evidence of tachyphylaxis, and it may not work for longer than two weeks.”

Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.

Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.

To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.

—Adriene Marshall

Suggested Reading

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.

Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.

LOS ANGELES—Among patients with chronic migraine, IV infusion of eptinezumab significantly reduces the average number of migraine days per month, compared with placebo, according to phase III trial data presented at the 70th Annual Meeting of the American Academy of Neurology. In addition, one-year data from a trial of eptinezumab in patients with episodic migraine suggest that treatment response may improve with subsequent infusions, researchers said.

Eptinezumab (formerly known as ALD403) is a humanized monoclonal antibody that inhibits calcitonin gene-related peptide (CGRP). It is designed to be administered quarterly via IV infusion. Eptinezumab previously was found to be effective and well tolerated in phase II studies in episodic and chronic migraine and in a phase III trial in episodic migraine. Alder BioPharmaceuticals, based in Bothell, Washington, is developing the therapy.

Treatment-emergent adverse events in phase III studies were similar for eptinezumab and placebo, and the safety profile was consistent with that in prior studies, researchers said.

The PROMISE Clinical Trial Program

The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy (PROMISE) clinical trial program includes phase III, randomized, double-blind, placebo-controlled trials of eptinezumab for chronic migraine prevention (PROMISE-2) and episodic migraine prevention (PROMISE-1).

In the PROMISE-2 trial, 1,072 patients were randomized to receive eptinezumab (300 mg), eptinezumab (100 mg), or placebo administered by IV infusion once every 12 weeks. Eligible patients had at least 15 headache days per month, of which at least eight met criteria for migraine. The primary end point was the mean change from baseline in monthly migraine days over the 12-week treatment period. Secondary end points included reduction in migraine prevalence on Day 1 and the proportion of patients with reductions of at least 50% and 75%.

In the PROMISE-1 trial, 888 patients were randomized to receive eptinezumab (300 mg), eptinezumab (100 mg), eptinezumab (30 mg), or placebo administered by IV infusion once every 12 weeks. Eligible patients had 14 or fewer headache days per month, of which at least four met the criteria for migraine. The primary end point was the mean change from baseline in monthly migraine days over the 12-week treatment period.

PROMISE-2

Patients in PROMISE-2 had an average of about 20 headache days per month, including 16 migraine days, at baseline, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York. Patients’ mean age was about 40, mean BMI was 26, and about 88% were female.

Patients had had migraine for about 18 years on average, and mean duration of chronic migraine was about 12 years.

During the 12 weeks after treatment, the mean change from baseline in monthly migraine days was –7.7 for patients who received the 100-mg dose of eptinezumab and –8.2 for patients who received the 300-mg dose of eptinezumab, compared with –5.6 for patients who received placebo. The difference was statistically significant for both active treatment groups versus placebo.

Secondary end points significantly favored eptinezumab. The percentage of patients with at least a 75% reduction in migraine days was 15.0% for placebo, 26.7% for the 100-mg dose of eptinezumab, and 33.1% for the 300-mg dose of eptinezumab. The percentage of patients with at least a 50% reduction in migraine days was 39.3% for placebo, 57.6% for the 100-mg dose of eptinezumab, and 61.4% for the 300-mg dose of eptinezumab.

On Day 1 post infusion, the percentage of patients with migraine decreased by 51% and 52% in the 100-mg and 300-mg treatment arms, respectively, compared with a decrease of 27% in the placebo arm.

Adverse event rates among eptinezumab-treated subjects were similar to those in placebo-treated subjects. The most commonly reported adverse events for eptinezumab were nasopharyngitis (6.3%), upper respiratory infection (4.0%), and nausea (3.4%).

Treatment-emergent adverse events occurred in approximately 40% of all treatment arms (39% in the placebo group, 38% in the 100-mg group, and 44% in the 300-mg group). Serious adverse events were rare, occurred in approximately equal rates in all treatment arms, and were considered unrelated to study drug.

PROMISE-1

Patients in PROMISE-1 had a mean age of about 40, and about 85% were female. They had about 8.5 migraine days per month on average, said Stephen D. Silberstein, MD, Professor of Neurology and Director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia.

During Weeks 1–12, mean change in monthly migraine days was significantly greater among patients who received eptinezumab (–4.0 with the 30-mg dose, –3.9 with the 100-mg dose, and –4.3 with the 300-mg dose), compared with patients who received placebo (–3.2).

One-year data indicated that the percentage of participants in the trial with 75% and 50% reductions in migraine increased over time. “With each subsequent infusion, there seems to be a cumulative increase in response,” Dr. Silberstein said. At the end of the trial, the proportion of patients in the 300-mg dose group with at least a 75% reduction in migraine days was 52%, whereas the proportion at Month 3 was 37%. The long-term results are encouraging, said Dr. Silberstein.

In PROMISE-1, the most commonly reported adverse events among treated patients were upper respiratory infection (10.3%), nasopharyngitis (6.6%), and sinusitis (3.6%).

—Jake Remaly

LOS ANGELES—Among patients with chronic migraine, IV infusion of eptinezumab significantly reduces the average number of migraine days per month, compared with placebo, according to phase III trial data presented at the 70th Annual Meeting of the American Academy of Neurology. In addition, one-year data from a trial of eptinezumab in patients with episodic migraine suggest that treatment response may improve with subsequent infusions, researchers said.

Eptinezumab (formerly known as ALD403) is a humanized monoclonal antibody that inhibits calcitonin gene-related peptide (CGRP). It is designed to be administered quarterly via IV infusion. Eptinezumab previously was found to be effective and well tolerated in phase II studies in episodic and chronic migraine and in a phase III trial in episodic migraine. Alder BioPharmaceuticals, based in Bothell, Washington, is developing the therapy.

Treatment-emergent adverse events in phase III studies were similar for eptinezumab and placebo, and the safety profile was consistent with that in prior studies, researchers said.

The PROMISE Clinical Trial Program

The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy (PROMISE) clinical trial program includes phase III, randomized, double-blind, placebo-controlled trials of eptinezumab for chronic migraine prevention (PROMISE-2) and episodic migraine prevention (PROMISE-1).

In the PROMISE-2 trial, 1,072 patients were randomized to receive eptinezumab (300 mg), eptinezumab (100 mg), or placebo administered by IV infusion once every 12 weeks. Eligible patients had at least 15 headache days per month, of which at least eight met criteria for migraine. The primary end point was the mean change from baseline in monthly migraine days over the 12-week treatment period. Secondary end points included reduction in migraine prevalence on Day 1 and the proportion of patients with reductions of at least 50% and 75%.

In the PROMISE-1 trial, 888 patients were randomized to receive eptinezumab (300 mg), eptinezumab (100 mg), eptinezumab (30 mg), or placebo administered by IV infusion once every 12 weeks. Eligible patients had 14 or fewer headache days per month, of which at least four met the criteria for migraine. The primary end point was the mean change from baseline in monthly migraine days over the 12-week treatment period.

PROMISE-2

Patients in PROMISE-2 had an average of about 20 headache days per month, including 16 migraine days, at baseline, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York. Patients’ mean age was about 40, mean BMI was 26, and about 88% were female.

Patients had had migraine for about 18 years on average, and mean duration of chronic migraine was about 12 years.

During the 12 weeks after treatment, the mean change from baseline in monthly migraine days was –7.7 for patients who received the 100-mg dose of eptinezumab and –8.2 for patients who received the 300-mg dose of eptinezumab, compared with –5.6 for patients who received placebo. The difference was statistically significant for both active treatment groups versus placebo.

Secondary end points significantly favored eptinezumab. The percentage of patients with at least a 75% reduction in migraine days was 15.0% for placebo, 26.7% for the 100-mg dose of eptinezumab, and 33.1% for the 300-mg dose of eptinezumab. The percentage of patients with at least a 50% reduction in migraine days was 39.3% for placebo, 57.6% for the 100-mg dose of eptinezumab, and 61.4% for the 300-mg dose of eptinezumab.

On Day 1 post infusion, the percentage of patients with migraine decreased by 51% and 52% in the 100-mg and 300-mg treatment arms, respectively, compared with a decrease of 27% in the placebo arm.

Adverse event rates among eptinezumab-treated subjects were similar to those in placebo-treated subjects. The most commonly reported adverse events for eptinezumab were nasopharyngitis (6.3%), upper respiratory infection (4.0%), and nausea (3.4%).

Treatment-emergent adverse events occurred in approximately 40% of all treatment arms (39% in the placebo group, 38% in the 100-mg group, and 44% in the 300-mg group). Serious adverse events were rare, occurred in approximately equal rates in all treatment arms, and were considered unrelated to study drug.

PROMISE-1

Patients in PROMISE-1 had a mean age of about 40, and about 85% were female. They had about 8.5 migraine days per month on average, said Stephen D. Silberstein, MD, Professor of Neurology and Director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia.

During Weeks 1–12, mean change in monthly migraine days was significantly greater among patients who received eptinezumab (–4.0 with the 30-mg dose, –3.9 with the 100-mg dose, and –4.3 with the 300-mg dose), compared with patients who received placebo (–3.2).

One-year data indicated that the percentage of participants in the trial with 75% and 50% reductions in migraine increased over time. “With each subsequent infusion, there seems to be a cumulative increase in response,” Dr. Silberstein said. At the end of the trial, the proportion of patients in the 300-mg dose group with at least a 75% reduction in migraine days was 52%, whereas the proportion at Month 3 was 37%. The long-term results are encouraging, said Dr. Silberstein.

In PROMISE-1, the most commonly reported adverse events among treated patients were upper respiratory infection (10.3%), nasopharyngitis (6.6%), and sinusitis (3.6%).

—Jake Remaly

LOS ANGELES—Among patients with chronic migraine, IV infusion of eptinezumab significantly reduces the average number of migraine days per month, compared with placebo, according to phase III trial data presented at the 70th Annual Meeting of the American Academy of Neurology. In addition, one-year data from a trial of eptinezumab in patients with episodic migraine suggest that treatment response may improve with subsequent infusions, researchers said.

Eptinezumab (formerly known as ALD403) is a humanized monoclonal antibody that inhibits calcitonin gene-related peptide (CGRP). It is designed to be administered quarterly via IV infusion. Eptinezumab previously was found to be effective and well tolerated in phase II studies in episodic and chronic migraine and in a phase III trial in episodic migraine. Alder BioPharmaceuticals, based in Bothell, Washington, is developing the therapy.

Treatment-emergent adverse events in phase III studies were similar for eptinezumab and placebo, and the safety profile was consistent with that in prior studies, researchers said.

The PROMISE Clinical Trial Program

The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy (PROMISE) clinical trial program includes phase III, randomized, double-blind, placebo-controlled trials of eptinezumab for chronic migraine prevention (PROMISE-2) and episodic migraine prevention (PROMISE-1).

In the PROMISE-2 trial, 1,072 patients were randomized to receive eptinezumab (300 mg), eptinezumab (100 mg), or placebo administered by IV infusion once every 12 weeks. Eligible patients had at least 15 headache days per month, of which at least eight met criteria for migraine. The primary end point was the mean change from baseline in monthly migraine days over the 12-week treatment period. Secondary end points included reduction in migraine prevalence on Day 1 and the proportion of patients with reductions of at least 50% and 75%.

In the PROMISE-1 trial, 888 patients were randomized to receive eptinezumab (300 mg), eptinezumab (100 mg), eptinezumab (30 mg), or placebo administered by IV infusion once every 12 weeks. Eligible patients had 14 or fewer headache days per month, of which at least four met the criteria for migraine. The primary end point was the mean change from baseline in monthly migraine days over the 12-week treatment period.

PROMISE-2

Patients in PROMISE-2 had an average of about 20 headache days per month, including 16 migraine days, at baseline, said Richard B. Lipton, MD, Edwin S. Lowe Chair in Neurology at Albert Einstein College of Medicine in New York. Patients’ mean age was about 40, mean BMI was 26, and about 88% were female.

Patients had had migraine for about 18 years on average, and mean duration of chronic migraine was about 12 years.

During the 12 weeks after treatment, the mean change from baseline in monthly migraine days was –7.7 for patients who received the 100-mg dose of eptinezumab and –8.2 for patients who received the 300-mg dose of eptinezumab, compared with –5.6 for patients who received placebo. The difference was statistically significant for both active treatment groups versus placebo.

Secondary end points significantly favored eptinezumab. The percentage of patients with at least a 75% reduction in migraine days was 15.0% for placebo, 26.7% for the 100-mg dose of eptinezumab, and 33.1% for the 300-mg dose of eptinezumab. The percentage of patients with at least a 50% reduction in migraine days was 39.3% for placebo, 57.6% for the 100-mg dose of eptinezumab, and 61.4% for the 300-mg dose of eptinezumab.

On Day 1 post infusion, the percentage of patients with migraine decreased by 51% and 52% in the 100-mg and 300-mg treatment arms, respectively, compared with a decrease of 27% in the placebo arm.

Adverse event rates among eptinezumab-treated subjects were similar to those in placebo-treated subjects. The most commonly reported adverse events for eptinezumab were nasopharyngitis (6.3%), upper respiratory infection (4.0%), and nausea (3.4%).

Treatment-emergent adverse events occurred in approximately 40% of all treatment arms (39% in the placebo group, 38% in the 100-mg group, and 44% in the 300-mg group). Serious adverse events were rare, occurred in approximately equal rates in all treatment arms, and were considered unrelated to study drug.

PROMISE-1

Patients in PROMISE-1 had a mean age of about 40, and about 85% were female. They had about 8.5 migraine days per month on average, said Stephen D. Silberstein, MD, Professor of Neurology and Director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia.

During Weeks 1–12, mean change in monthly migraine days was significantly greater among patients who received eptinezumab (–4.0 with the 30-mg dose, –3.9 with the 100-mg dose, and –4.3 with the 300-mg dose), compared with patients who received placebo (–3.2).

One-year data indicated that the percentage of participants in the trial with 75% and 50% reductions in migraine increased over time. “With each subsequent infusion, there seems to be a cumulative increase in response,” Dr. Silberstein said. At the end of the trial, the proportion of patients in the 300-mg dose group with at least a 75% reduction in migraine days was 52%, whereas the proportion at Month 3 was 37%. The long-term results are encouraging, said Dr. Silberstein.

In PROMISE-1, the most commonly reported adverse events among treated patients were upper respiratory infection (10.3%), nasopharyngitis (6.6%), and sinusitis (3.6%).

—Jake Remaly