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VIDEO: Encouraging results reported for novel Huntington’s disease therapy
LOS ANGELES – Results from the first-in-human trial of the investigational antisense oligonucleotide therapy IONIS-HTTRx showed strong dose-dependent reductions in the toxic huntingtin protein in Huntington’s disease patients’ cerebrospinal fluid when compared with placebo.
An exploratory analysis also showed signals of clinical improvement among patients receiving the therapy, the study’s lead author, Sarah Tabrizi, MD, PhD, of University College London, reported at the annual meeting of the American Academy of Neurology.
The findings represent a potential breakthrough in the way Huntington’s – and possibly other neurodegenerative diseases – are treated, said Dr. Tabrizi of University College London. The intrathecally-delivered drug binds to mutant huntingtin protein mRNA to reduce the level of the toxic protein being made.
In the phase 1/2a trial, Dr. Tabrizi and her colleagues enrolled 46 patients with early-stage Huntington’s disease and randomized them to four doses of IONIS-HTTRx or placebo. Patients received four monthly injections of the study drug into the cerebrospinal fluid followed by a 4-month untreated follow-up period. IONIS-HTTRx was delivered in five ascending-dose cohorts.
IONIS-HTTRx was safe and well tolerated and all patients completed the study, Dr. Tabrizi reported. “Our results show that we had significant lowering of the toxic mutant huntingtin protein in the spinal fluid of the patients,” she said, noting that patients receiving the highest doses saw 40%-60% lowering of the protein, which preclinical work suggests correlates to reductions of the protein in the brain.
Dr. Tabrizi stressed that the main outcome measures in the study were reduction of the mutant protein in the CSF and safety and tolerance of the study drug. The investigators did not expect to see clinical measures to change in such a short, small study, she said.
“But then when we looked more carefully at the data with exploratory analysis we found a link between lowering of CSF mutant huntingtin and improvement in total motor score, which is a measure of neurological function, and also, improvement in the Symbol Digit Modalities Test.”
The clinical results are exploratory and require confirmation in larger studies, Dr. Tabrizi stressed.
The study was supported by Ionis Pharmaceuticals. Roche will develop the drug in further clinical trials.
SOURCE: Tabrizi S et al. AAN 2018 abstract CT.002.
LOS ANGELES – Results from the first-in-human trial of the investigational antisense oligonucleotide therapy IONIS-HTTRx showed strong dose-dependent reductions in the toxic huntingtin protein in Huntington’s disease patients’ cerebrospinal fluid when compared with placebo.
An exploratory analysis also showed signals of clinical improvement among patients receiving the therapy, the study’s lead author, Sarah Tabrizi, MD, PhD, of University College London, reported at the annual meeting of the American Academy of Neurology.
The findings represent a potential breakthrough in the way Huntington’s – and possibly other neurodegenerative diseases – are treated, said Dr. Tabrizi of University College London. The intrathecally-delivered drug binds to mutant huntingtin protein mRNA to reduce the level of the toxic protein being made.
In the phase 1/2a trial, Dr. Tabrizi and her colleagues enrolled 46 patients with early-stage Huntington’s disease and randomized them to four doses of IONIS-HTTRx or placebo. Patients received four monthly injections of the study drug into the cerebrospinal fluid followed by a 4-month untreated follow-up period. IONIS-HTTRx was delivered in five ascending-dose cohorts.
IONIS-HTTRx was safe and well tolerated and all patients completed the study, Dr. Tabrizi reported. “Our results show that we had significant lowering of the toxic mutant huntingtin protein in the spinal fluid of the patients,” she said, noting that patients receiving the highest doses saw 40%-60% lowering of the protein, which preclinical work suggests correlates to reductions of the protein in the brain.
Dr. Tabrizi stressed that the main outcome measures in the study were reduction of the mutant protein in the CSF and safety and tolerance of the study drug. The investigators did not expect to see clinical measures to change in such a short, small study, she said.
“But then when we looked more carefully at the data with exploratory analysis we found a link between lowering of CSF mutant huntingtin and improvement in total motor score, which is a measure of neurological function, and also, improvement in the Symbol Digit Modalities Test.”
The clinical results are exploratory and require confirmation in larger studies, Dr. Tabrizi stressed.
The study was supported by Ionis Pharmaceuticals. Roche will develop the drug in further clinical trials.
SOURCE: Tabrizi S et al. AAN 2018 abstract CT.002.
LOS ANGELES – Results from the first-in-human trial of the investigational antisense oligonucleotide therapy IONIS-HTTRx showed strong dose-dependent reductions in the toxic huntingtin protein in Huntington’s disease patients’ cerebrospinal fluid when compared with placebo.
An exploratory analysis also showed signals of clinical improvement among patients receiving the therapy, the study’s lead author, Sarah Tabrizi, MD, PhD, of University College London, reported at the annual meeting of the American Academy of Neurology.
The findings represent a potential breakthrough in the way Huntington’s – and possibly other neurodegenerative diseases – are treated, said Dr. Tabrizi of University College London. The intrathecally-delivered drug binds to mutant huntingtin protein mRNA to reduce the level of the toxic protein being made.
In the phase 1/2a trial, Dr. Tabrizi and her colleagues enrolled 46 patients with early-stage Huntington’s disease and randomized them to four doses of IONIS-HTTRx or placebo. Patients received four monthly injections of the study drug into the cerebrospinal fluid followed by a 4-month untreated follow-up period. IONIS-HTTRx was delivered in five ascending-dose cohorts.
IONIS-HTTRx was safe and well tolerated and all patients completed the study, Dr. Tabrizi reported. “Our results show that we had significant lowering of the toxic mutant huntingtin protein in the spinal fluid of the patients,” she said, noting that patients receiving the highest doses saw 40%-60% lowering of the protein, which preclinical work suggests correlates to reductions of the protein in the brain.
Dr. Tabrizi stressed that the main outcome measures in the study were reduction of the mutant protein in the CSF and safety and tolerance of the study drug. The investigators did not expect to see clinical measures to change in such a short, small study, she said.
“But then when we looked more carefully at the data with exploratory analysis we found a link between lowering of CSF mutant huntingtin and improvement in total motor score, which is a measure of neurological function, and also, improvement in the Symbol Digit Modalities Test.”
The clinical results are exploratory and require confirmation in larger studies, Dr. Tabrizi stressed.
The study was supported by Ionis Pharmaceuticals. Roche will develop the drug in further clinical trials.
SOURCE: Tabrizi S et al. AAN 2018 abstract CT.002.
REPORTING FROM AAN 2018
VIDEO: Ubrogepant reduced pain, related symptoms of a migraine attack
LOS ANGELES – The investigational oral calcitonin gene-related peptide (CGRP) blocker ubrogepant proved superior to placebo in treating a single, acute, moderate to severe migraine attack in the phase 3 ACHIEVE I trial.
Blocking the function of CGRP when it is pathologically released during a migraine attack is the mechanism of a bevy of antagonists under development for treating migraine, and the ACHIEVE I trial results are the first to be reported from a phase 3 trial of an oral small molecule to treat single migraine attacks rather than prevent attacks with monoclonal antibodies targeting CGRP or its receptor, according to the lead author of ACHIEVE I, Joel M. Trugman, MD, director of clinical development for Allergan.
Dr. Trugman and his colleagues recruited 1,672 adult patients (88% female, mean age 41) with a history of migraine with or without aura, and randomized them to placebo, ubrogepant 50 mg, or ubrogepant 100 mg. Patients were instructed to treat a single migraine attack of moderate to severe pain intensity and record symptoms, such as pain, light sensitivity, and sound sensitivity, before and after taking the medication.
“The paradigm for this type of trial is to treat a single, well characterized migraine attack in a large population of patients,” Dr. Trugman said in a press conference at the annual meeting of the American Academy of Neurology.
At 2 hours after dosing, the percentage of ubrogepant-treated patients achieving freedom from pain was significantly greater than the percentage of those treated with placebo (50 mg: 19.2%, P = .0023; 100 mg: 21.2%, P = .0003; placebo: 11.8%).
The percentage of ubrogepant-treated patients achieving absence of their most bothersome symptom was also significantly greater than that of placebo (50 mg: 38.6%, P = .0023; 100 mg: 37.7%, P = .0023; placebo: 27.8%).
Adverse events in the ubrogepant groups were similar to those of placebo, the most reported to be nausea, somnolence, and dry mouth.
Several authors are employees of Allergan, which sponsored the study.
SOURCE: Trugman J et al. AAN 2018 emerging science abstract 008.
LOS ANGELES – The investigational oral calcitonin gene-related peptide (CGRP) blocker ubrogepant proved superior to placebo in treating a single, acute, moderate to severe migraine attack in the phase 3 ACHIEVE I trial.
Blocking the function of CGRP when it is pathologically released during a migraine attack is the mechanism of a bevy of antagonists under development for treating migraine, and the ACHIEVE I trial results are the first to be reported from a phase 3 trial of an oral small molecule to treat single migraine attacks rather than prevent attacks with monoclonal antibodies targeting CGRP or its receptor, according to the lead author of ACHIEVE I, Joel M. Trugman, MD, director of clinical development for Allergan.
Dr. Trugman and his colleagues recruited 1,672 adult patients (88% female, mean age 41) with a history of migraine with or without aura, and randomized them to placebo, ubrogepant 50 mg, or ubrogepant 100 mg. Patients were instructed to treat a single migraine attack of moderate to severe pain intensity and record symptoms, such as pain, light sensitivity, and sound sensitivity, before and after taking the medication.
“The paradigm for this type of trial is to treat a single, well characterized migraine attack in a large population of patients,” Dr. Trugman said in a press conference at the annual meeting of the American Academy of Neurology.
At 2 hours after dosing, the percentage of ubrogepant-treated patients achieving freedom from pain was significantly greater than the percentage of those treated with placebo (50 mg: 19.2%, P = .0023; 100 mg: 21.2%, P = .0003; placebo: 11.8%).
The percentage of ubrogepant-treated patients achieving absence of their most bothersome symptom was also significantly greater than that of placebo (50 mg: 38.6%, P = .0023; 100 mg: 37.7%, P = .0023; placebo: 27.8%).
Adverse events in the ubrogepant groups were similar to those of placebo, the most reported to be nausea, somnolence, and dry mouth.
Several authors are employees of Allergan, which sponsored the study.
SOURCE: Trugman J et al. AAN 2018 emerging science abstract 008.
LOS ANGELES – The investigational oral calcitonin gene-related peptide (CGRP) blocker ubrogepant proved superior to placebo in treating a single, acute, moderate to severe migraine attack in the phase 3 ACHIEVE I trial.
Blocking the function of CGRP when it is pathologically released during a migraine attack is the mechanism of a bevy of antagonists under development for treating migraine, and the ACHIEVE I trial results are the first to be reported from a phase 3 trial of an oral small molecule to treat single migraine attacks rather than prevent attacks with monoclonal antibodies targeting CGRP or its receptor, according to the lead author of ACHIEVE I, Joel M. Trugman, MD, director of clinical development for Allergan.
Dr. Trugman and his colleagues recruited 1,672 adult patients (88% female, mean age 41) with a history of migraine with or without aura, and randomized them to placebo, ubrogepant 50 mg, or ubrogepant 100 mg. Patients were instructed to treat a single migraine attack of moderate to severe pain intensity and record symptoms, such as pain, light sensitivity, and sound sensitivity, before and after taking the medication.
“The paradigm for this type of trial is to treat a single, well characterized migraine attack in a large population of patients,” Dr. Trugman said in a press conference at the annual meeting of the American Academy of Neurology.
At 2 hours after dosing, the percentage of ubrogepant-treated patients achieving freedom from pain was significantly greater than the percentage of those treated with placebo (50 mg: 19.2%, P = .0023; 100 mg: 21.2%, P = .0003; placebo: 11.8%).
The percentage of ubrogepant-treated patients achieving absence of their most bothersome symptom was also significantly greater than that of placebo (50 mg: 38.6%, P = .0023; 100 mg: 37.7%, P = .0023; placebo: 27.8%).
Adverse events in the ubrogepant groups were similar to those of placebo, the most reported to be nausea, somnolence, and dry mouth.
Several authors are employees of Allergan, which sponsored the study.
SOURCE: Trugman J et al. AAN 2018 emerging science abstract 008.
REPORTING FROM AAN 2018
Art education benefits blood cancer patients
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
New research suggests a bedside visual art intervention (BVAI) can reduce pain and anxiety in inpatients with hematologic malignancies, including those undergoing transplant.
The BVAI involved an educator teaching patients art technique one-on-one for approximately 30 minutes.
After a single session, patients had significant improvements in positive mood and pain scores, as well as decreases in negative mood and anxiety.
Alexandra P. Wolanskyj, MD, of Mayo Clinic in Rochester, Minnesota, and her colleagues reported these results in the European Journal of Cancer Care.
The study included 21 patients, 19 of them female. Their median age was 53.5 (range, 19-75). Six patients were undergoing hematopoietic stem cell transplant.
The patients had multiple myeloma (n=5), acute myeloid leukemia (n=5), non-Hodgkin lymphoma (n=3), Hodgkin lymphoma (n=2), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=1), amyloidosis (n=1), Gardner-Diamond syndrome (n=1), myelodysplastic syndrome (n=1), and Waldenstrom’s macroglobulinemia (n=1).
Nearly half of patients had relapsed disease (47.6%), 23.8% had active and new disease, 19.0% had active disease with primary resistance on chemotherapy, and 9.5% of patients were in remission.
Intervention
The researchers recruited an educator from a community art center to teach art at the patients’ bedsides. Sessions were intended to be about 30 minutes. However, patients could stop at any time or continue beyond 30 minutes.
Patients and their families could make art or just observe. Materials used included watercolors, oil pastels, colored pencils, and clay (all non-toxic and odorless). The materials were left with patients so they could continue to use them after the sessions.
Results
The researchers assessed patients’ pain, anxiety, and mood at baseline and after the patients had a session with the art educator.
After the BVAI, patients had a significant decrease in pain, according to the Visual Analog Scale (VAS). The 14 patients who reported any pain at baseline had a mean reduction in VAS score of 1.5, or a 35.1% reduction in pain (P=0.017).
Patients had a 21.6% reduction in anxiety after the BVAI. Among the 20 patients who completed this assessment, there was a mean 9.2-point decrease in State-Trait Anxiety Inventory (STAI) score (P=0.001).
In addition, patients had a significant increase in positive mood and a significant decrease in negative mood after the BVAI. Mood was assessed in 20 patients using the Positive and Negative Affect Schedule (PANAS) scale.
Positive mood increased 14.6% (P=0.003), and negative mood decreased 18.0% (P=0.015) after the BVAI. Patients’ mean PANAS scores increased 4.6 points for positive mood and decreased 3.3 points for negative mood.
All 21 patients completed a questionnaire on the BVAI. All but 1 patient (95%) said the intervention was positive overall, and 85% of patients (n=18) said they would be interested in participating in future art-based interventions.
The researchers said these results suggest experiences provided by artists in the community may be an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain.
E-cigarette use in teens increases risk of cannabis use
, reported Hongying Dai, PhD, of Children’s Mercy Kansas City (Mo.), and her associates.
In an analysis of data from the Population Assessment of Tobacco and Health (PATH) survey, 11,996 participants aged 12-17 years completed both the wave 1 and wave 2 surveys. Researchers found one in four adolescents (26.6%) who used e-cigarettes at wave 1 reported marijuana use at wave 2, compared with 7.7% of adolescents who never used e-cigarettes at wave 1 (P less than .05). E-cigarette users at wave 1 were more likely to report marijuana use in the past 12 months at wave 2 (adjusted odds ratio = 1.9). In addition, 2.8% of participants who had never used marijuana at wave 1 reported heavy use of marijuana at wave 2.
“Our study revealed that e-cigarette use was associated with an increased risk of subsequent marijuana use among youth, with a stronger temporal association among younger adolescents,” the researchers concluded. “With these findings, we suggest that the widespread use of e-cigarettes among youth may have implications for the uptake of other drugs of abuse beyond nicotine and tobacco products.”
SOURCE: Dai H et al. Pediatrics. 2018;141(5):e20173787.
, reported Hongying Dai, PhD, of Children’s Mercy Kansas City (Mo.), and her associates.
In an analysis of data from the Population Assessment of Tobacco and Health (PATH) survey, 11,996 participants aged 12-17 years completed both the wave 1 and wave 2 surveys. Researchers found one in four adolescents (26.6%) who used e-cigarettes at wave 1 reported marijuana use at wave 2, compared with 7.7% of adolescents who never used e-cigarettes at wave 1 (P less than .05). E-cigarette users at wave 1 were more likely to report marijuana use in the past 12 months at wave 2 (adjusted odds ratio = 1.9). In addition, 2.8% of participants who had never used marijuana at wave 1 reported heavy use of marijuana at wave 2.
“Our study revealed that e-cigarette use was associated with an increased risk of subsequent marijuana use among youth, with a stronger temporal association among younger adolescents,” the researchers concluded. “With these findings, we suggest that the widespread use of e-cigarettes among youth may have implications for the uptake of other drugs of abuse beyond nicotine and tobacco products.”
SOURCE: Dai H et al. Pediatrics. 2018;141(5):e20173787.
, reported Hongying Dai, PhD, of Children’s Mercy Kansas City (Mo.), and her associates.
In an analysis of data from the Population Assessment of Tobacco and Health (PATH) survey, 11,996 participants aged 12-17 years completed both the wave 1 and wave 2 surveys. Researchers found one in four adolescents (26.6%) who used e-cigarettes at wave 1 reported marijuana use at wave 2, compared with 7.7% of adolescents who never used e-cigarettes at wave 1 (P less than .05). E-cigarette users at wave 1 were more likely to report marijuana use in the past 12 months at wave 2 (adjusted odds ratio = 1.9). In addition, 2.8% of participants who had never used marijuana at wave 1 reported heavy use of marijuana at wave 2.
“Our study revealed that e-cigarette use was associated with an increased risk of subsequent marijuana use among youth, with a stronger temporal association among younger adolescents,” the researchers concluded. “With these findings, we suggest that the widespread use of e-cigarettes among youth may have implications for the uptake of other drugs of abuse beyond nicotine and tobacco products.”
SOURCE: Dai H et al. Pediatrics. 2018;141(5):e20173787.
FROM PEDIATRICS
Nonopioids as effective as opioids in reducing acute pain in the ED
Clinical question: What is the most effective analgesic combination, opioid vs. nonopioid, for treating acute extremity pain in the emergency department?
Background: Patients often are prescribed opioids for acute pain in the ED while awaiting work-up. With the current opioid epidemic in the United States, it is important to examine the appropriate use of opioids and look for alternative medications for acute pain.
Setting: Two urban New York City emergency departments from July 2015 to August 2016.
Synopsis: 411 patients aged 21-65 years were randomized to four groups for treatment of acute extremity pain. Each received one oral analgesic combination: ibuprofen 400 mg and acetaminophen 1,000 mg; oxycodone 5 mg and acetaminophen 325 mg; hydrocodone 5 mg and acetaminophen 300 mg; or codeine 30 mg and acetaminophen 300 mg. Their pain was scored on presentation using a standard 0-10 numerical rating scale (NRS) and then at 2 hours after medication. The primary outcome was difference in NRS among groups. All patients had improvement in pain scores. Pain score improved by 4.4 in the oxycodone group, 4.3 in the ibuprofen group, 3.5 in the hydrocodone group, and 3.9 in the codeine group. There were no statistically significant differences among groups. Limitations to the study included short follow-up time, no reported data on adverse effects, and lack of uniform acetaminophen doses in each group.
Bottom line: There was no statistically significant difference in pain control among patients given a combination of acetaminophen and ibuprofen vs. three different opioids with acetaminophen when treating acute extremity pain in the ED.
Citation: Chang AK et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
Dr. Mathew is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: What is the most effective analgesic combination, opioid vs. nonopioid, for treating acute extremity pain in the emergency department?
Background: Patients often are prescribed opioids for acute pain in the ED while awaiting work-up. With the current opioid epidemic in the United States, it is important to examine the appropriate use of opioids and look for alternative medications for acute pain.
Setting: Two urban New York City emergency departments from July 2015 to August 2016.
Synopsis: 411 patients aged 21-65 years were randomized to four groups for treatment of acute extremity pain. Each received one oral analgesic combination: ibuprofen 400 mg and acetaminophen 1,000 mg; oxycodone 5 mg and acetaminophen 325 mg; hydrocodone 5 mg and acetaminophen 300 mg; or codeine 30 mg and acetaminophen 300 mg. Their pain was scored on presentation using a standard 0-10 numerical rating scale (NRS) and then at 2 hours after medication. The primary outcome was difference in NRS among groups. All patients had improvement in pain scores. Pain score improved by 4.4 in the oxycodone group, 4.3 in the ibuprofen group, 3.5 in the hydrocodone group, and 3.9 in the codeine group. There were no statistically significant differences among groups. Limitations to the study included short follow-up time, no reported data on adverse effects, and lack of uniform acetaminophen doses in each group.
Bottom line: There was no statistically significant difference in pain control among patients given a combination of acetaminophen and ibuprofen vs. three different opioids with acetaminophen when treating acute extremity pain in the ED.
Citation: Chang AK et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
Dr. Mathew is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: What is the most effective analgesic combination, opioid vs. nonopioid, for treating acute extremity pain in the emergency department?
Background: Patients often are prescribed opioids for acute pain in the ED while awaiting work-up. With the current opioid epidemic in the United States, it is important to examine the appropriate use of opioids and look for alternative medications for acute pain.
Setting: Two urban New York City emergency departments from July 2015 to August 2016.
Synopsis: 411 patients aged 21-65 years were randomized to four groups for treatment of acute extremity pain. Each received one oral analgesic combination: ibuprofen 400 mg and acetaminophen 1,000 mg; oxycodone 5 mg and acetaminophen 325 mg; hydrocodone 5 mg and acetaminophen 300 mg; or codeine 30 mg and acetaminophen 300 mg. Their pain was scored on presentation using a standard 0-10 numerical rating scale (NRS) and then at 2 hours after medication. The primary outcome was difference in NRS among groups. All patients had improvement in pain scores. Pain score improved by 4.4 in the oxycodone group, 4.3 in the ibuprofen group, 3.5 in the hydrocodone group, and 3.9 in the codeine group. There were no statistically significant differences among groups. Limitations to the study included short follow-up time, no reported data on adverse effects, and lack of uniform acetaminophen doses in each group.
Bottom line: There was no statistically significant difference in pain control among patients given a combination of acetaminophen and ibuprofen vs. three different opioids with acetaminophen when treating acute extremity pain in the ED.
Citation: Chang AK et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
Dr. Mathew is assistant professor of medicine, division of hospital medicine, University of Virginia.
Therapy targets ICU ‘teachable moment’ of suicide-attempt survivors
WASHINGTON – in a pair of controlled pilot studies with a total of 87 patients.
In the more recent study, the 32 patients who received this “teachable moment brief intervention” (TMBI) plus usual care tallied an overall satisfaction score of 3.88 on a 1-4 scale and showed a trend to higher motivation scores than patients managed with usual care alone, Stephen S. O’Connor, PhD, said at the annual conference of the American Association of Suicidology.
The TMBI was designed to help suicide-attempt survivors “wrap their head around what happened in a nonshaming way at a sensitive time. We try to help the patient understand what was the purpose of their attempt and what moving forward will look like,” Dr. O’Connor said in an interview.
The TMBI usually lasts about 30-45 minutes, and Dr. O’Connor described the general outline of the conversation: After the therapist establishes a rapport with the patient, the discussion moves to a functional analysis of what drove the patient to this action and why the suicide attempt seemed to make sense at the time. The therapist asks the patient what he or she sees as having been gained and lost by the event, and what the patient has gleaned from the experience. The goal is to help the patient understand what happened and its purpose, and also to discuss issues that need to be addressed going forward. “In a respectful, nonshaming way we get the patient to talk about what happened and how they got there,” he said.
The TMBI is a “drop in the ocean” of talk therapy that the patient will eventually receive, he said, but it is “all about the context.” In usual care, although the suicide attempter in the ICU may see a therapist, the conversation is generally about risk management and discharge planning.
In the initial test of the efficacy of this approach, Dr. O’Connor randomized 30 suicide survivors in the ICU to usual care or usual care plus the TMBI. The results showed a high level of patient satisfaction with the intervention and statistically significant improvements in readiness to change and in reasons for living, compared with controls (Gen Hosp Psychiatry. 2015 Sept-Oct;37[5]:427-33).
In a second pilot study that has not yet been published, Dr. O’Connor and his associates at Vanderbilt University in Nashville treated 32 patients with the TMBI and usual care and 25 with usual care only, with the study primarily designed to assess feasibility and acceptability to patients. Once again, patients who received the TMBI reported a high level of satisfaction with the encounter, including an average 3.96 rating (1-4 scale) of how likely they were to return to the service for future needs. Patients who received the extra intervention also showed trends toward a higher level of motivation after 3 months and less suicide ideation.
Further small-scale studies of the TMBI are now underway at two U.S. centers, and Dr. O’Connor said that a larger-scale test of the approach is now appropriate. One of the current limiting factors in dissemination is the training needed to perform a TMBI. One way to better leverage trained therapists might be to have the intervention occur remotely through telemedicine, with the patient encounter happening on a hand-held device.
The evidence collected so far on the TMBI has not yet proven its efficacy, Dr. O’Connor stressed. “We need to see to what degree this makes a difference. But there is clearly need for more engagement” with patients when they are in the ICU immediately after a suicide attempt. “Maybe it’s not the intervention, but just having someone being kind to the patient and sitting with them,” he suggested.
SOURCE: O’Connor S et al. American Association of Suicidology annual conference.
WASHINGTON – in a pair of controlled pilot studies with a total of 87 patients.
In the more recent study, the 32 patients who received this “teachable moment brief intervention” (TMBI) plus usual care tallied an overall satisfaction score of 3.88 on a 1-4 scale and showed a trend to higher motivation scores than patients managed with usual care alone, Stephen S. O’Connor, PhD, said at the annual conference of the American Association of Suicidology.
The TMBI was designed to help suicide-attempt survivors “wrap their head around what happened in a nonshaming way at a sensitive time. We try to help the patient understand what was the purpose of their attempt and what moving forward will look like,” Dr. O’Connor said in an interview.
The TMBI usually lasts about 30-45 minutes, and Dr. O’Connor described the general outline of the conversation: After the therapist establishes a rapport with the patient, the discussion moves to a functional analysis of what drove the patient to this action and why the suicide attempt seemed to make sense at the time. The therapist asks the patient what he or she sees as having been gained and lost by the event, and what the patient has gleaned from the experience. The goal is to help the patient understand what happened and its purpose, and also to discuss issues that need to be addressed going forward. “In a respectful, nonshaming way we get the patient to talk about what happened and how they got there,” he said.
The TMBI is a “drop in the ocean” of talk therapy that the patient will eventually receive, he said, but it is “all about the context.” In usual care, although the suicide attempter in the ICU may see a therapist, the conversation is generally about risk management and discharge planning.
In the initial test of the efficacy of this approach, Dr. O’Connor randomized 30 suicide survivors in the ICU to usual care or usual care plus the TMBI. The results showed a high level of patient satisfaction with the intervention and statistically significant improvements in readiness to change and in reasons for living, compared with controls (Gen Hosp Psychiatry. 2015 Sept-Oct;37[5]:427-33).
In a second pilot study that has not yet been published, Dr. O’Connor and his associates at Vanderbilt University in Nashville treated 32 patients with the TMBI and usual care and 25 with usual care only, with the study primarily designed to assess feasibility and acceptability to patients. Once again, patients who received the TMBI reported a high level of satisfaction with the encounter, including an average 3.96 rating (1-4 scale) of how likely they were to return to the service for future needs. Patients who received the extra intervention also showed trends toward a higher level of motivation after 3 months and less suicide ideation.
Further small-scale studies of the TMBI are now underway at two U.S. centers, and Dr. O’Connor said that a larger-scale test of the approach is now appropriate. One of the current limiting factors in dissemination is the training needed to perform a TMBI. One way to better leverage trained therapists might be to have the intervention occur remotely through telemedicine, with the patient encounter happening on a hand-held device.
The evidence collected so far on the TMBI has not yet proven its efficacy, Dr. O’Connor stressed. “We need to see to what degree this makes a difference. But there is clearly need for more engagement” with patients when they are in the ICU immediately after a suicide attempt. “Maybe it’s not the intervention, but just having someone being kind to the patient and sitting with them,” he suggested.
SOURCE: O’Connor S et al. American Association of Suicidology annual conference.
WASHINGTON – in a pair of controlled pilot studies with a total of 87 patients.
In the more recent study, the 32 patients who received this “teachable moment brief intervention” (TMBI) plus usual care tallied an overall satisfaction score of 3.88 on a 1-4 scale and showed a trend to higher motivation scores than patients managed with usual care alone, Stephen S. O’Connor, PhD, said at the annual conference of the American Association of Suicidology.
The TMBI was designed to help suicide-attempt survivors “wrap their head around what happened in a nonshaming way at a sensitive time. We try to help the patient understand what was the purpose of their attempt and what moving forward will look like,” Dr. O’Connor said in an interview.
The TMBI usually lasts about 30-45 minutes, and Dr. O’Connor described the general outline of the conversation: After the therapist establishes a rapport with the patient, the discussion moves to a functional analysis of what drove the patient to this action and why the suicide attempt seemed to make sense at the time. The therapist asks the patient what he or she sees as having been gained and lost by the event, and what the patient has gleaned from the experience. The goal is to help the patient understand what happened and its purpose, and also to discuss issues that need to be addressed going forward. “In a respectful, nonshaming way we get the patient to talk about what happened and how they got there,” he said.
The TMBI is a “drop in the ocean” of talk therapy that the patient will eventually receive, he said, but it is “all about the context.” In usual care, although the suicide attempter in the ICU may see a therapist, the conversation is generally about risk management and discharge planning.
In the initial test of the efficacy of this approach, Dr. O’Connor randomized 30 suicide survivors in the ICU to usual care or usual care plus the TMBI. The results showed a high level of patient satisfaction with the intervention and statistically significant improvements in readiness to change and in reasons for living, compared with controls (Gen Hosp Psychiatry. 2015 Sept-Oct;37[5]:427-33).
In a second pilot study that has not yet been published, Dr. O’Connor and his associates at Vanderbilt University in Nashville treated 32 patients with the TMBI and usual care and 25 with usual care only, with the study primarily designed to assess feasibility and acceptability to patients. Once again, patients who received the TMBI reported a high level of satisfaction with the encounter, including an average 3.96 rating (1-4 scale) of how likely they were to return to the service for future needs. Patients who received the extra intervention also showed trends toward a higher level of motivation after 3 months and less suicide ideation.
Further small-scale studies of the TMBI are now underway at two U.S. centers, and Dr. O’Connor said that a larger-scale test of the approach is now appropriate. One of the current limiting factors in dissemination is the training needed to perform a TMBI. One way to better leverage trained therapists might be to have the intervention occur remotely through telemedicine, with the patient encounter happening on a hand-held device.
The evidence collected so far on the TMBI has not yet proven its efficacy, Dr. O’Connor stressed. “We need to see to what degree this makes a difference. But there is clearly need for more engagement” with patients when they are in the ICU immediately after a suicide attempt. “Maybe it’s not the intervention, but just having someone being kind to the patient and sitting with them,” he suggested.
SOURCE: O’Connor S et al. American Association of Suicidology annual conference.
REPORTING FROM THE AAS ANNUAL CONFERENCE
Key clinical point: A 30- to 45-minute conversation was feasible and acceptable to suicide-attempt survivors in the ICU.
Major finding: Overall patient satisfaction with the intervention was rated 3.88 on a 1-4 scale.
Study details: Single-center randomized study with 57 patients.
Disclosures: Dr. O’Connor had no disclosures.
Source: O’Connor S et al. American Association of Suicidology annual conference.
Don’t discount rare pityriasis rosea for kids with persistent itch
Persistent cases of small erythematous lesions could be the rare condition of relapsing pityriasis rosea, based on data from a case report of an 11-year-old girl.
Unlike standard pityriasis rosea (PR), relapsing cases tend to present with fewer, smaller lesions, Ilka Engelmann, MD, of the Centre P Boulanger Hôpital A Calmette in Lille, France, and colleagues wrote in Pediatrics.
“A viral etiology of PR is strongly suspected because human herpesvirus 7 (HHV-7) DNA is frequently detected in blood and saliva of patients with PR,” they said. Infection with the HHV-7 virus generally occurs in childhood and remains a lifelong latent condition with the potential for multiple recurrences, they added.
The authors described the case of an 11-year-old white girl who presented with pruritic, erythematous, oval-shaped lesions that began on the right side of her trunk and spread across the trunk over the next few days. The patient had no other symptoms or physical abnormalities on examination and was not taking any medications, although she reported some trouble sleeping.
The treating clinicians identified HHV-7 in a blood sample and diagnosed PR. The lesions resolved in approximately 2 months with no treatment, but, 2 years after the initial presentation, the patient developed similar lesions on her legs, which also resolved without treatment. Over the next 5 years, she presented with similar lesions in different locations approximately three times per year, and these episodes were usually associated with times of stress, such as school examinations. Some saliva specimens taken during the episodes tested positive for HHV-7. The lesions persisted for 4-8 weeks and resolved without treatment, but they were reduced in size and number after the third recurrence. The change in size and location are characteristic of relapsing PR, the authors said, but more than three relapses is rare. “To our knowledge, this is the first report of a case with frequently relapsing PR for 7 years, with several episodes per year,” they said.
The occurrence of the relapses during stressful periods “is consistent with the hypothesis of viral reactivation because stress has been described as a stimulus inducing the reactivation of Herpesviridae from latency,” they noted.
A differential diagnosis of PR includes other infectious diseases and medication-induced skin reactions, but a medication history and virologic tests can help make or rule out a relapsing PR diagnosis, the authors said.
The authors had no financial conflicts to disclose.
SOURCE: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
Persistent cases of small erythematous lesions could be the rare condition of relapsing pityriasis rosea, based on data from a case report of an 11-year-old girl.
Unlike standard pityriasis rosea (PR), relapsing cases tend to present with fewer, smaller lesions, Ilka Engelmann, MD, of the Centre P Boulanger Hôpital A Calmette in Lille, France, and colleagues wrote in Pediatrics.
“A viral etiology of PR is strongly suspected because human herpesvirus 7 (HHV-7) DNA is frequently detected in blood and saliva of patients with PR,” they said. Infection with the HHV-7 virus generally occurs in childhood and remains a lifelong latent condition with the potential for multiple recurrences, they added.
The authors described the case of an 11-year-old white girl who presented with pruritic, erythematous, oval-shaped lesions that began on the right side of her trunk and spread across the trunk over the next few days. The patient had no other symptoms or physical abnormalities on examination and was not taking any medications, although she reported some trouble sleeping.
The treating clinicians identified HHV-7 in a blood sample and diagnosed PR. The lesions resolved in approximately 2 months with no treatment, but, 2 years after the initial presentation, the patient developed similar lesions on her legs, which also resolved without treatment. Over the next 5 years, she presented with similar lesions in different locations approximately three times per year, and these episodes were usually associated with times of stress, such as school examinations. Some saliva specimens taken during the episodes tested positive for HHV-7. The lesions persisted for 4-8 weeks and resolved without treatment, but they were reduced in size and number after the third recurrence. The change in size and location are characteristic of relapsing PR, the authors said, but more than three relapses is rare. “To our knowledge, this is the first report of a case with frequently relapsing PR for 7 years, with several episodes per year,” they said.
The occurrence of the relapses during stressful periods “is consistent with the hypothesis of viral reactivation because stress has been described as a stimulus inducing the reactivation of Herpesviridae from latency,” they noted.
A differential diagnosis of PR includes other infectious diseases and medication-induced skin reactions, but a medication history and virologic tests can help make or rule out a relapsing PR diagnosis, the authors said.
The authors had no financial conflicts to disclose.
SOURCE: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
Persistent cases of small erythematous lesions could be the rare condition of relapsing pityriasis rosea, based on data from a case report of an 11-year-old girl.
Unlike standard pityriasis rosea (PR), relapsing cases tend to present with fewer, smaller lesions, Ilka Engelmann, MD, of the Centre P Boulanger Hôpital A Calmette in Lille, France, and colleagues wrote in Pediatrics.
“A viral etiology of PR is strongly suspected because human herpesvirus 7 (HHV-7) DNA is frequently detected in blood and saliva of patients with PR,” they said. Infection with the HHV-7 virus generally occurs in childhood and remains a lifelong latent condition with the potential for multiple recurrences, they added.
The authors described the case of an 11-year-old white girl who presented with pruritic, erythematous, oval-shaped lesions that began on the right side of her trunk and spread across the trunk over the next few days. The patient had no other symptoms or physical abnormalities on examination and was not taking any medications, although she reported some trouble sleeping.
The treating clinicians identified HHV-7 in a blood sample and diagnosed PR. The lesions resolved in approximately 2 months with no treatment, but, 2 years after the initial presentation, the patient developed similar lesions on her legs, which also resolved without treatment. Over the next 5 years, she presented with similar lesions in different locations approximately three times per year, and these episodes were usually associated with times of stress, such as school examinations. Some saliva specimens taken during the episodes tested positive for HHV-7. The lesions persisted for 4-8 weeks and resolved without treatment, but they were reduced in size and number after the third recurrence. The change in size and location are characteristic of relapsing PR, the authors said, but more than three relapses is rare. “To our knowledge, this is the first report of a case with frequently relapsing PR for 7 years, with several episodes per year,” they said.
The occurrence of the relapses during stressful periods “is consistent with the hypothesis of viral reactivation because stress has been described as a stimulus inducing the reactivation of Herpesviridae from latency,” they noted.
A differential diagnosis of PR includes other infectious diseases and medication-induced skin reactions, but a medication history and virologic tests can help make or rule out a relapsing PR diagnosis, the authors said.
The authors had no financial conflicts to disclose.
SOURCE: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
FROM PEDIATRICS
Key clinical point: Check children with persistent erythematous lesions for human herpesvirus and possible pityriasis rosea.
Major finding: A presentation of erythematous lesions in an 11-year-old girl recurred over 7 years.
Study details: The data come from a case report of rare relapsing pityriasis rosea.
Disclosures: The authors presenting the case had no financial conflicts to disclose.
Source: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
Artificial pancreas treatment improves glycemic control in T1DM: Meta-analysis
Use of artificial pancreas devices added nearly 2.5 hours of time in near normoglycemia over 24 hours in patients with type 1 diabetes, a meta-analysis of randomized clinical trials showed.
The improvement versus control subjects was primarily because of the favorable effect of the closed loop glucose control systems in the overnight period, authors of the meta-analysis reported in the BMJ.
Both single and dual hormone systems had robust results in the meta-anaysis, said lead researcher Eleni Bekiari, MD, PhD, of Aristotle University of Thessaloniki, Greece, and her coinvestigators.
Results were likewise robust for an analysis restricted to trials conducted under normal living conditions and no remote monitoring, supporting the convenience and ease of use of these systems, according to Dr. Bekiari and her colleagues.
“Overall, our results reflect the progress made over recent decades of extensive research and development in artificial pancreas use,” they wrote.
Despite the findings, more research needs to be done, they added, since the individual clinical trials supporting use of closed-loop systems in type 1 diabetes have included relatively few patients and have had short follow-up durations.
The systematic review and meta-analysis by Dr. Bekiari and her colleagues was based on 40 randomized controlled trials involving a total of 1,027 participants. The primary outcome of the analysis was proportion of time that sensor glucose level was in the normoglycemic range of 3.9-10 mmol/L.
Overall, use of the systems was associated with 140 additional minutes in near normoglycemia over 24 hours, with a 9.62% mean weighted difference (95% confidence interval, 7.54%-11.7%), reported data show.
The favorable effect was even more evident on overnight measures, the investigators said, with a weighted mean difference of 15.15% (95% CI, 12.21%-18.09%).
Results were similar even when the analysis was limited to studies that had a low risk of bias, and also when the analysis was limited to studies of unsupervised patients in normal living conditions, according to Dr. Bekiari and her associates.
Artificial pancreas use also had favorable impacts on time in hyperglycemia over the entire day. Compared with controls, time with glucose concentrations less than 10 mmol/L were shortened by about 2 hours, the investigators said.
Likewise, mean levels of sensor blood glucose over 24 hours fell by 0.48 mmol/L compared with control treatment (95% CI, 0.3-0.66 mmol/L), they reported.
Taken together, these findings suggest artificial pancreas systems are efficacious and safe for patients with type 1 diabetes, the investigators concluded.
“Further research with rigorous studies, cooperation of research groups in terms of outcome reporting, and cost-effectiveness data are required to verify these findings and support adoption of artificial pancreas systems in clinical practice,” they wrote.
Dr. Bekiari reported no disclosures. Her coauthors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim and others outside of the submitted work.
SOURCE: Bekiai E et al. BMJ 2018;361:k1310.
Closed-loop glucose control systems have much to offer patients, but better evidence will likely be needed to convince policy makers who have increasing demands and scarce resources, Dr. Norman Waugh and his coauthors said in an editorial.
Users of closed-loop systems did spend approximately 10% more time near normoglycemia when compared with control subjects in the present systematic review and meta-analysis of randomized clinical trials by Dr. Bekiari and colleagues.
The overall base of evidence is weak, however, and many studies in the review were low quality, according to Dr. Waugh and his coauthors. Moreover, the trials were short, with the majority lasting 7 days or less, they noted.
The current review does demonstrate that closed-loop systems improve control overnight and reduce the burden of self-management during the day, but it’s unknown if the systems can reduce long-term diabetes complications, according to the editorial authors, and evidence to date is insufficient for policy makers to perform cost-effectiveness analyses.
“We need longer and larger trials, in both adults and children, to compare closed-loop systems with self-management using continuous glucose monitoring,” Dr. Waugh and his colleagues wrote. “These trials should measure HbA1c for modeling the effects on complications, blood glucose variability, hypoglycemia, quality of life, and cost effectiveness.”
Norman Waugh is professor of public health medicine and health technology assessment at the University of Warwick, England. These comments are derived from an editorial by Dr. Waugh and his coauthors BMJ. 2018;361:k1613. doi: 10.1136/bmj.k1613 . They reported advising Roche and Novo Nordisk on matters not related to the topic of this editorial.
Closed-loop glucose control systems have much to offer patients, but better evidence will likely be needed to convince policy makers who have increasing demands and scarce resources, Dr. Norman Waugh and his coauthors said in an editorial.
Users of closed-loop systems did spend approximately 10% more time near normoglycemia when compared with control subjects in the present systematic review and meta-analysis of randomized clinical trials by Dr. Bekiari and colleagues.
The overall base of evidence is weak, however, and many studies in the review were low quality, according to Dr. Waugh and his coauthors. Moreover, the trials were short, with the majority lasting 7 days or less, they noted.
The current review does demonstrate that closed-loop systems improve control overnight and reduce the burden of self-management during the day, but it’s unknown if the systems can reduce long-term diabetes complications, according to the editorial authors, and evidence to date is insufficient for policy makers to perform cost-effectiveness analyses.
“We need longer and larger trials, in both adults and children, to compare closed-loop systems with self-management using continuous glucose monitoring,” Dr. Waugh and his colleagues wrote. “These trials should measure HbA1c for modeling the effects on complications, blood glucose variability, hypoglycemia, quality of life, and cost effectiveness.”
Norman Waugh is professor of public health medicine and health technology assessment at the University of Warwick, England. These comments are derived from an editorial by Dr. Waugh and his coauthors BMJ. 2018;361:k1613. doi: 10.1136/bmj.k1613 . They reported advising Roche and Novo Nordisk on matters not related to the topic of this editorial.
Closed-loop glucose control systems have much to offer patients, but better evidence will likely be needed to convince policy makers who have increasing demands and scarce resources, Dr. Norman Waugh and his coauthors said in an editorial.
Users of closed-loop systems did spend approximately 10% more time near normoglycemia when compared with control subjects in the present systematic review and meta-analysis of randomized clinical trials by Dr. Bekiari and colleagues.
The overall base of evidence is weak, however, and many studies in the review were low quality, according to Dr. Waugh and his coauthors. Moreover, the trials were short, with the majority lasting 7 days or less, they noted.
The current review does demonstrate that closed-loop systems improve control overnight and reduce the burden of self-management during the day, but it’s unknown if the systems can reduce long-term diabetes complications, according to the editorial authors, and evidence to date is insufficient for policy makers to perform cost-effectiveness analyses.
“We need longer and larger trials, in both adults and children, to compare closed-loop systems with self-management using continuous glucose monitoring,” Dr. Waugh and his colleagues wrote. “These trials should measure HbA1c for modeling the effects on complications, blood glucose variability, hypoglycemia, quality of life, and cost effectiveness.”
Norman Waugh is professor of public health medicine and health technology assessment at the University of Warwick, England. These comments are derived from an editorial by Dr. Waugh and his coauthors BMJ. 2018;361:k1613. doi: 10.1136/bmj.k1613 . They reported advising Roche and Novo Nordisk on matters not related to the topic of this editorial.
Use of artificial pancreas devices added nearly 2.5 hours of time in near normoglycemia over 24 hours in patients with type 1 diabetes, a meta-analysis of randomized clinical trials showed.
The improvement versus control subjects was primarily because of the favorable effect of the closed loop glucose control systems in the overnight period, authors of the meta-analysis reported in the BMJ.
Both single and dual hormone systems had robust results in the meta-anaysis, said lead researcher Eleni Bekiari, MD, PhD, of Aristotle University of Thessaloniki, Greece, and her coinvestigators.
Results were likewise robust for an analysis restricted to trials conducted under normal living conditions and no remote monitoring, supporting the convenience and ease of use of these systems, according to Dr. Bekiari and her colleagues.
“Overall, our results reflect the progress made over recent decades of extensive research and development in artificial pancreas use,” they wrote.
Despite the findings, more research needs to be done, they added, since the individual clinical trials supporting use of closed-loop systems in type 1 diabetes have included relatively few patients and have had short follow-up durations.
The systematic review and meta-analysis by Dr. Bekiari and her colleagues was based on 40 randomized controlled trials involving a total of 1,027 participants. The primary outcome of the analysis was proportion of time that sensor glucose level was in the normoglycemic range of 3.9-10 mmol/L.
Overall, use of the systems was associated with 140 additional minutes in near normoglycemia over 24 hours, with a 9.62% mean weighted difference (95% confidence interval, 7.54%-11.7%), reported data show.
The favorable effect was even more evident on overnight measures, the investigators said, with a weighted mean difference of 15.15% (95% CI, 12.21%-18.09%).
Results were similar even when the analysis was limited to studies that had a low risk of bias, and also when the analysis was limited to studies of unsupervised patients in normal living conditions, according to Dr. Bekiari and her associates.
Artificial pancreas use also had favorable impacts on time in hyperglycemia over the entire day. Compared with controls, time with glucose concentrations less than 10 mmol/L were shortened by about 2 hours, the investigators said.
Likewise, mean levels of sensor blood glucose over 24 hours fell by 0.48 mmol/L compared with control treatment (95% CI, 0.3-0.66 mmol/L), they reported.
Taken together, these findings suggest artificial pancreas systems are efficacious and safe for patients with type 1 diabetes, the investigators concluded.
“Further research with rigorous studies, cooperation of research groups in terms of outcome reporting, and cost-effectiveness data are required to verify these findings and support adoption of artificial pancreas systems in clinical practice,” they wrote.
Dr. Bekiari reported no disclosures. Her coauthors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim and others outside of the submitted work.
SOURCE: Bekiai E et al. BMJ 2018;361:k1310.
Use of artificial pancreas devices added nearly 2.5 hours of time in near normoglycemia over 24 hours in patients with type 1 diabetes, a meta-analysis of randomized clinical trials showed.
The improvement versus control subjects was primarily because of the favorable effect of the closed loop glucose control systems in the overnight period, authors of the meta-analysis reported in the BMJ.
Both single and dual hormone systems had robust results in the meta-anaysis, said lead researcher Eleni Bekiari, MD, PhD, of Aristotle University of Thessaloniki, Greece, and her coinvestigators.
Results were likewise robust for an analysis restricted to trials conducted under normal living conditions and no remote monitoring, supporting the convenience and ease of use of these systems, according to Dr. Bekiari and her colleagues.
“Overall, our results reflect the progress made over recent decades of extensive research and development in artificial pancreas use,” they wrote.
Despite the findings, more research needs to be done, they added, since the individual clinical trials supporting use of closed-loop systems in type 1 diabetes have included relatively few patients and have had short follow-up durations.
The systematic review and meta-analysis by Dr. Bekiari and her colleagues was based on 40 randomized controlled trials involving a total of 1,027 participants. The primary outcome of the analysis was proportion of time that sensor glucose level was in the normoglycemic range of 3.9-10 mmol/L.
Overall, use of the systems was associated with 140 additional minutes in near normoglycemia over 24 hours, with a 9.62% mean weighted difference (95% confidence interval, 7.54%-11.7%), reported data show.
The favorable effect was even more evident on overnight measures, the investigators said, with a weighted mean difference of 15.15% (95% CI, 12.21%-18.09%).
Results were similar even when the analysis was limited to studies that had a low risk of bias, and also when the analysis was limited to studies of unsupervised patients in normal living conditions, according to Dr. Bekiari and her associates.
Artificial pancreas use also had favorable impacts on time in hyperglycemia over the entire day. Compared with controls, time with glucose concentrations less than 10 mmol/L were shortened by about 2 hours, the investigators said.
Likewise, mean levels of sensor blood glucose over 24 hours fell by 0.48 mmol/L compared with control treatment (95% CI, 0.3-0.66 mmol/L), they reported.
Taken together, these findings suggest artificial pancreas systems are efficacious and safe for patients with type 1 diabetes, the investigators concluded.
“Further research with rigorous studies, cooperation of research groups in terms of outcome reporting, and cost-effectiveness data are required to verify these findings and support adoption of artificial pancreas systems in clinical practice,” they wrote.
Dr. Bekiari reported no disclosures. Her coauthors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim and others outside of the submitted work.
SOURCE: Bekiai E et al. BMJ 2018;361:k1310.
FROM THE BMJ
Key clinical point: In patients with type 1 diabetes, artificial pancreas systems were effective in increasing the amount of time patients spent in the near normoglycemic range.
Major finding: The proportion of time in the near-normoglycemic range was significantly higher both overnight (15.15% mean weighted difference) and over 24 hours (9.62% mean weighted difference) for artificial pancreas versus controls.
Study details: A systematic review and meta-analysis of 40 randomized controlled trials including 1,027 participants.
Disclosures: Authors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim, and others outside of the submitted work.
Source: Bekiari E et al. BMJ 2018;361:k1310.
VTE risk after bariatric surgery should be assessed
SEATTLE – Preop thromboelastometry can identify patients who need extra according to a prospective investigation of 40 patients at Conemaugh Memorial Medical Center in Johnstown, Pa.
Enoxaparin 40 mg twice daily just wasn’t enough for people who were hypercoagulable before surgery. The goal of the study was to find the best way to prevent venous thromboembolism (VTE) after weight loss surgery. At present, there’s no consensus on prophylaxis dosing, timing, duration, or even what agent to use for these patients. Conemaugh uses postop enoxaparin, a low-molecular-weight heparin. Among many other options, some hospitals opt for preop dosing with traditional heparin, which is less expensive.
The Conemaugh team turned to thromboelastometry (TEM) to look at the question of VTE risk in bariatric surgery patients. The test gauges coagulation status by measuring elasticity as a small blood sample clots over a few minutes. The investigators found that patients who were hypercoagulable before surgery were likely to be hypercoagulable afterwards. The finding argues for baseline TEM testing to guide postop anticoagulation.
The problem is that bariatric services don’t often have access to TEM equipment, and insurance doesn’t cover the $60 test. In this instance, the Lake Erie College of Osteopathic Medicine in Erie, Pa., had the equipment and covered the testing for the study.
The patients had TEM at baseline and then received 40 mg of enoxaparin about 4 hours after surgery – mostly laparoscopic gastric bypasses – and a second dose about 12 hours after the first. TEM was repeated about 2 hours after the second dose.
At baseline, 2 (5%) of the patients were hypocoagulable, 15 (37.5%) were normal, and 23 (57.5%) were hypercoagulable. On postop TEM, 17 patients (42.5%) were normal and 23 (57.5%) were hypercoagulable: “These 23 were inadequately anticoagulated,” said lead investigator Daniel Urias, MD, a general surgery resident at the medical center.
“There was an association between being normal at baseline and being normal postop, and being hypercoagulable at baseline and hypercoagulable postop. We didn’t anticipate finding such similarity between the numbers. Our suspicion that baseline status plays a major role is holding true,” Dr. Urias said at the World Congress of Endoscopic Surgery hosted by SAGES & CAGS.
When patients test hypercoagulable at baseline, “we are [now] leaning towards [enoxaparin] 60 mg twice daily,” he said.
Ultimately, anticoagulation TEM could be used to titrate patients into the normal range. For best outcomes, it’s likely that “obese patients require goal-directed therapy instead of weight-based or fixed dosing,” he said, but nothing is going to happen until insurance steps up.
The patients did not have underlying coagulopathies, and 33 (82.5%) were women; the average age was 44 years and average body mass index was 43.6 kg/m2. The mean preop Caprini score was 4, indicating moderate VTE risk. Surgery lasted about 200 minutes. Patients were out of bed and walking on postop day 0.
The investigators had no relevant disclosures.
SOURCE: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
SEATTLE – Preop thromboelastometry can identify patients who need extra according to a prospective investigation of 40 patients at Conemaugh Memorial Medical Center in Johnstown, Pa.
Enoxaparin 40 mg twice daily just wasn’t enough for people who were hypercoagulable before surgery. The goal of the study was to find the best way to prevent venous thromboembolism (VTE) after weight loss surgery. At present, there’s no consensus on prophylaxis dosing, timing, duration, or even what agent to use for these patients. Conemaugh uses postop enoxaparin, a low-molecular-weight heparin. Among many other options, some hospitals opt for preop dosing with traditional heparin, which is less expensive.
The Conemaugh team turned to thromboelastometry (TEM) to look at the question of VTE risk in bariatric surgery patients. The test gauges coagulation status by measuring elasticity as a small blood sample clots over a few minutes. The investigators found that patients who were hypercoagulable before surgery were likely to be hypercoagulable afterwards. The finding argues for baseline TEM testing to guide postop anticoagulation.
The problem is that bariatric services don’t often have access to TEM equipment, and insurance doesn’t cover the $60 test. In this instance, the Lake Erie College of Osteopathic Medicine in Erie, Pa., had the equipment and covered the testing for the study.
The patients had TEM at baseline and then received 40 mg of enoxaparin about 4 hours after surgery – mostly laparoscopic gastric bypasses – and a second dose about 12 hours after the first. TEM was repeated about 2 hours after the second dose.
At baseline, 2 (5%) of the patients were hypocoagulable, 15 (37.5%) were normal, and 23 (57.5%) were hypercoagulable. On postop TEM, 17 patients (42.5%) were normal and 23 (57.5%) were hypercoagulable: “These 23 were inadequately anticoagulated,” said lead investigator Daniel Urias, MD, a general surgery resident at the medical center.
“There was an association between being normal at baseline and being normal postop, and being hypercoagulable at baseline and hypercoagulable postop. We didn’t anticipate finding such similarity between the numbers. Our suspicion that baseline status plays a major role is holding true,” Dr. Urias said at the World Congress of Endoscopic Surgery hosted by SAGES & CAGS.
When patients test hypercoagulable at baseline, “we are [now] leaning towards [enoxaparin] 60 mg twice daily,” he said.
Ultimately, anticoagulation TEM could be used to titrate patients into the normal range. For best outcomes, it’s likely that “obese patients require goal-directed therapy instead of weight-based or fixed dosing,” he said, but nothing is going to happen until insurance steps up.
The patients did not have underlying coagulopathies, and 33 (82.5%) were women; the average age was 44 years and average body mass index was 43.6 kg/m2. The mean preop Caprini score was 4, indicating moderate VTE risk. Surgery lasted about 200 minutes. Patients were out of bed and walking on postop day 0.
The investigators had no relevant disclosures.
SOURCE: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
SEATTLE – Preop thromboelastometry can identify patients who need extra according to a prospective investigation of 40 patients at Conemaugh Memorial Medical Center in Johnstown, Pa.
Enoxaparin 40 mg twice daily just wasn’t enough for people who were hypercoagulable before surgery. The goal of the study was to find the best way to prevent venous thromboembolism (VTE) after weight loss surgery. At present, there’s no consensus on prophylaxis dosing, timing, duration, or even what agent to use for these patients. Conemaugh uses postop enoxaparin, a low-molecular-weight heparin. Among many other options, some hospitals opt for preop dosing with traditional heparin, which is less expensive.
The Conemaugh team turned to thromboelastometry (TEM) to look at the question of VTE risk in bariatric surgery patients. The test gauges coagulation status by measuring elasticity as a small blood sample clots over a few minutes. The investigators found that patients who were hypercoagulable before surgery were likely to be hypercoagulable afterwards. The finding argues for baseline TEM testing to guide postop anticoagulation.
The problem is that bariatric services don’t often have access to TEM equipment, and insurance doesn’t cover the $60 test. In this instance, the Lake Erie College of Osteopathic Medicine in Erie, Pa., had the equipment and covered the testing for the study.
The patients had TEM at baseline and then received 40 mg of enoxaparin about 4 hours after surgery – mostly laparoscopic gastric bypasses – and a second dose about 12 hours after the first. TEM was repeated about 2 hours after the second dose.
At baseline, 2 (5%) of the patients were hypocoagulable, 15 (37.5%) were normal, and 23 (57.5%) were hypercoagulable. On postop TEM, 17 patients (42.5%) were normal and 23 (57.5%) were hypercoagulable: “These 23 were inadequately anticoagulated,” said lead investigator Daniel Urias, MD, a general surgery resident at the medical center.
“There was an association between being normal at baseline and being normal postop, and being hypercoagulable at baseline and hypercoagulable postop. We didn’t anticipate finding such similarity between the numbers. Our suspicion that baseline status plays a major role is holding true,” Dr. Urias said at the World Congress of Endoscopic Surgery hosted by SAGES & CAGS.
When patients test hypercoagulable at baseline, “we are [now] leaning towards [enoxaparin] 60 mg twice daily,” he said.
Ultimately, anticoagulation TEM could be used to titrate patients into the normal range. For best outcomes, it’s likely that “obese patients require goal-directed therapy instead of weight-based or fixed dosing,” he said, but nothing is going to happen until insurance steps up.
The patients did not have underlying coagulopathies, and 33 (82.5%) were women; the average age was 44 years and average body mass index was 43.6 kg/m2. The mean preop Caprini score was 4, indicating moderate VTE risk. Surgery lasted about 200 minutes. Patients were out of bed and walking on postop day 0.
The investigators had no relevant disclosures.
SOURCE: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
REPORTING FROM SAGES 2018
Key clinical point: Preoperative thromboelastometry identifies patients who need extra anticoagulation against venous thromboembolism following bariatric surgery.
Major finding: Baseline and postop coagulation were similar: 37.5% vs. 42.5% were normal and 57.5% vs 57.5% were hypercoagulable.
Study details: Prospective study of 40 bariatric surgery patients.
Disclosures: The investigators did not have any relevant disclosures. The Lake Erie College of Osteopathic Medicine paid for the testing.
Source: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
Therapy shows early promise in phase 1 MM trial
CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.
CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.
CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.