CHARLOTTE, N.C. – Among children with brain tumors, prophylaxis with an antiepileptic drug (AED) is associated with a longer time between brain tumor diagnosis and first seizure diagnosis within the first 6 months of follow-up, according to research presented at the annual meeting of the Child Neurology Society. Levetiracetam, oxcarbazepine, and phenytoin are the most common initial prophylactic AEDs administered to children with brain tumors, the researchers said.

The literature indicates that between 20% and 35% of children with brain tumors have seizures, and up to half of these patients have seizure as their presenting symptom. Common practice is to prescribe antiseizure medication after a child has had a first seizure, because the risk for recurrence is high. In 2000, the American Academy of Neurology discouraged prophylactic use of AEDs in children, citing a lack of evidence for efficacy. Most of the data that it reviewed, however, came from adults.

Michelle Yun, a medical student at Weill Cornell Medical College, New York, and colleagues used national Medicaid claims data that had been collected between 2009 and 2012 for children with seizures to conduct a retrospective, observational, case-control study. They included children aged 0-20 years with a diagnosis of brain tumor, a seizure diagnosis within 6 months after brain tumor diagnosis, an AED prescription, and 12 continuous months of Medicaid coverage following brain tumor diagnosis in their analysis. The investigators defined seizure prophylaxis as AED prescription within 30 days after brain tumor diagnosis but before a first seizure diagnosis.

The exposure in the study was AED prescription within 45 days of diagnosis, and the outcome was the time to first seizure. Ms. Yun and colleagues also analyzed the most common initial prophylactic AEDs and the proportion of cases with first seizure diagnosis after prophylactic AED discontinuation, which was defined as a treatment gap longer than 30 days. The study covariates included age, sex, race, ethnicity, and medical comorbidities.

In all, 218 children were included in the study; 40 received AED prophylaxis and 26 received it within 45 days of brain tumor diagnosis. Patients with and without AED prophylaxis were well matched on all covariates.

At 1 year, Ms. Yun and colleagues saw no difference in time to first seizure between the two groups. The median time to first seizure was 75 days in the prophylaxis group and 80 days in the no-prophylaxis group. The researchers observed a transient separation between the two groups, however, in the early months after brain tumor diagnosis. When they examined children who had a seizure during the first 6 months of follow-up, the median time to diagnosis of first seizure was 68 days in children with prophylaxis and 34 days in the no-prophylaxis group. The difference between groups was statistically significant. “When we added all the covariates of interest, we found that there was a protective effect in these children with early seizures,” said Ms. Yun.

Among the study limitations that Ms. Yun acknowledged were its observational, retrospective design and its small sample size. Medicaid data themselves are limited, since states do not report them in a uniform manner, and the data do not include much clinical information. “Something that would be helpful is a prospective clinical study,” Ms. Yun concluded.

The Weill Cornell Clinical and Translational Science Center and the American Academy of Neurology provided funding for the study. The Pediatric Epilepsy Research Foundation provided the Medicaid data. Ms. Yun had no relevant disclosures.
 

[email protected]

SOURCE: Yun M et al. CNS 2019, Abstract PL2-1.

CHARLOTTE, N.C. – Among children with brain tumors, prophylaxis with an antiepileptic drug (AED) is associated with a longer time between brain tumor diagnosis and first seizure diagnosis within the first 6 months of follow-up, according to research presented at the annual meeting of the Child Neurology Society. Levetiracetam, oxcarbazepine, and phenytoin are the most common initial prophylactic AEDs administered to children with brain tumors, the researchers said.

The literature indicates that between 20% and 35% of children with brain tumors have seizures, and up to half of these patients have seizure as their presenting symptom. Common practice is to prescribe antiseizure medication after a child has had a first seizure, because the risk for recurrence is high. In 2000, the American Academy of Neurology discouraged prophylactic use of AEDs in children, citing a lack of evidence for efficacy. Most of the data that it reviewed, however, came from adults.

Michelle Yun, a medical student at Weill Cornell Medical College, New York, and colleagues used national Medicaid claims data that had been collected between 2009 and 2012 for children with seizures to conduct a retrospective, observational, case-control study. They included children aged 0-20 years with a diagnosis of brain tumor, a seizure diagnosis within 6 months after brain tumor diagnosis, an AED prescription, and 12 continuous months of Medicaid coverage following brain tumor diagnosis in their analysis. The investigators defined seizure prophylaxis as AED prescription within 30 days after brain tumor diagnosis but before a first seizure diagnosis.

The exposure in the study was AED prescription within 45 days of diagnosis, and the outcome was the time to first seizure. Ms. Yun and colleagues also analyzed the most common initial prophylactic AEDs and the proportion of cases with first seizure diagnosis after prophylactic AED discontinuation, which was defined as a treatment gap longer than 30 days. The study covariates included age, sex, race, ethnicity, and medical comorbidities.

In all, 218 children were included in the study; 40 received AED prophylaxis and 26 received it within 45 days of brain tumor diagnosis. Patients with and without AED prophylaxis were well matched on all covariates.

At 1 year, Ms. Yun and colleagues saw no difference in time to first seizure between the two groups. The median time to first seizure was 75 days in the prophylaxis group and 80 days in the no-prophylaxis group. The researchers observed a transient separation between the two groups, however, in the early months after brain tumor diagnosis. When they examined children who had a seizure during the first 6 months of follow-up, the median time to diagnosis of first seizure was 68 days in children with prophylaxis and 34 days in the no-prophylaxis group. The difference between groups was statistically significant. “When we added all the covariates of interest, we found that there was a protective effect in these children with early seizures,” said Ms. Yun.

Among the study limitations that Ms. Yun acknowledged were its observational, retrospective design and its small sample size. Medicaid data themselves are limited, since states do not report them in a uniform manner, and the data do not include much clinical information. “Something that would be helpful is a prospective clinical study,” Ms. Yun concluded.

The Weill Cornell Clinical and Translational Science Center and the American Academy of Neurology provided funding for the study. The Pediatric Epilepsy Research Foundation provided the Medicaid data. Ms. Yun had no relevant disclosures.
 

[email protected]

SOURCE: Yun M et al. CNS 2019, Abstract PL2-1.

CHARLOTTE, N.C. – Among children with brain tumors, prophylaxis with an antiepileptic drug (AED) is associated with a longer time between brain tumor diagnosis and first seizure diagnosis within the first 6 months of follow-up, according to research presented at the annual meeting of the Child Neurology Society. Levetiracetam, oxcarbazepine, and phenytoin are the most common initial prophylactic AEDs administered to children with brain tumors, the researchers said.

The literature indicates that between 20% and 35% of children with brain tumors have seizures, and up to half of these patients have seizure as their presenting symptom. Common practice is to prescribe antiseizure medication after a child has had a first seizure, because the risk for recurrence is high. In 2000, the American Academy of Neurology discouraged prophylactic use of AEDs in children, citing a lack of evidence for efficacy. Most of the data that it reviewed, however, came from adults.

Michelle Yun, a medical student at Weill Cornell Medical College, New York, and colleagues used national Medicaid claims data that had been collected between 2009 and 2012 for children with seizures to conduct a retrospective, observational, case-control study. They included children aged 0-20 years with a diagnosis of brain tumor, a seizure diagnosis within 6 months after brain tumor diagnosis, an AED prescription, and 12 continuous months of Medicaid coverage following brain tumor diagnosis in their analysis. The investigators defined seizure prophylaxis as AED prescription within 30 days after brain tumor diagnosis but before a first seizure diagnosis.

The exposure in the study was AED prescription within 45 days of diagnosis, and the outcome was the time to first seizure. Ms. Yun and colleagues also analyzed the most common initial prophylactic AEDs and the proportion of cases with first seizure diagnosis after prophylactic AED discontinuation, which was defined as a treatment gap longer than 30 days. The study covariates included age, sex, race, ethnicity, and medical comorbidities.

In all, 218 children were included in the study; 40 received AED prophylaxis and 26 received it within 45 days of brain tumor diagnosis. Patients with and without AED prophylaxis were well matched on all covariates.

At 1 year, Ms. Yun and colleagues saw no difference in time to first seizure between the two groups. The median time to first seizure was 75 days in the prophylaxis group and 80 days in the no-prophylaxis group. The researchers observed a transient separation between the two groups, however, in the early months after brain tumor diagnosis. When they examined children who had a seizure during the first 6 months of follow-up, the median time to diagnosis of first seizure was 68 days in children with prophylaxis and 34 days in the no-prophylaxis group. The difference between groups was statistically significant. “When we added all the covariates of interest, we found that there was a protective effect in these children with early seizures,” said Ms. Yun.

Among the study limitations that Ms. Yun acknowledged were its observational, retrospective design and its small sample size. Medicaid data themselves are limited, since states do not report them in a uniform manner, and the data do not include much clinical information. “Something that would be helpful is a prospective clinical study,” Ms. Yun concluded.

The Weill Cornell Clinical and Translational Science Center and the American Academy of Neurology provided funding for the study. The Pediatric Epilepsy Research Foundation provided the Medicaid data. Ms. Yun had no relevant disclosures.
 

[email protected]

SOURCE: Yun M et al. CNS 2019, Abstract PL2-1.

A new study has indicated that tailoring dosage of infliximab based on serum levels of tumor necrosis factor–alpha did not increase the sustained remission rate in rheumatoid arthritis patients.

“The results did not support our initial hypothesis that deep remission and subsequent sustained discontinuation of infliximab can be achieved by intensive and finely tuned treatments with appropriate doses of TNF [tumor necrosis factor] inhibitors,” wrote Yoshiya Tanaka, MD, PhD, of the University of Occupational and Environmental Health, Kitakyushu, Japan. The study was published in Annals of the Rheumatic Diseases.

To determine if levels of TNF-alpha should initiate an increase in infliximab dosage, the researchers launched a multicenter, randomized trial of 337 patients with infliximab-naive RA. Patients were assigned to two groups: standard infliximab treatment of 3 mg/kg at weeks 0, 2, 6, and then every 8 weeks (n = 167) or programmed infliximab treatment (n = 170) in which the dose was adjusted at week 14 based on low, intermediate, or high levels of baseline TNF-alpha.

Patients with low levels (below 0.55 pg/mL) continued receiving 3 mg/kg every 8 weeks. Intermediate levels (between 0.55 and 1.65 pg/mL) meant an increase to 6 mg/kg every 8 weeks. High levels (1.65 pg/mL or higher) meant an increase to 6 mg/kg at week 14 and to 10 mg/kg at week 22 and every 8 weeks afterward. The goal was to discontinue infliximab at 54 weeks and reassess 1 year later.

After 54 weeks, 39.4% of patients in the programmed group and 32.3% of patients in the standard group achieved remission, defined as a Simplified Disease Activity Index (SDAI) score of 3.3 or lower. After 106 weeks, 23.5% of the programmed group and 21.6% of the standard group had maintained discontinuation of infliximab (–2.2% difference; 95% confidence interval, –6.6% to 11.0%; P = .631). After analysis, the most significant predictor of sustained discontinuation was a baseline SDAI less than 26.

The authors acknowledged their study’s limitations, including the initial version of the study not being double blinded. In addition, they noted that the short length of treatment and the low dosage overall “might not be intense enough to achieve differences in disease control between the two groups.”

The study was supported by a research grant from the Ministry of Health, Labor and Welfare of Japan. The authors reported numerous potential conflicts of interest, including receiving grants, consulting fees, speaking fees, and/or honoraria from various medical and pharmaceutical companies.

SOURCE: Tanaka Y et al. Ann Rheum Dis. 2019 Oct 19. doi: 10.1136/annrheumdis-2019-216169.

A new study has indicated that tailoring dosage of infliximab based on serum levels of tumor necrosis factor–alpha did not increase the sustained remission rate in rheumatoid arthritis patients.

“The results did not support our initial hypothesis that deep remission and subsequent sustained discontinuation of infliximab can be achieved by intensive and finely tuned treatments with appropriate doses of TNF [tumor necrosis factor] inhibitors,” wrote Yoshiya Tanaka, MD, PhD, of the University of Occupational and Environmental Health, Kitakyushu, Japan. The study was published in Annals of the Rheumatic Diseases.

To determine if levels of TNF-alpha should initiate an increase in infliximab dosage, the researchers launched a multicenter, randomized trial of 337 patients with infliximab-naive RA. Patients were assigned to two groups: standard infliximab treatment of 3 mg/kg at weeks 0, 2, 6, and then every 8 weeks (n = 167) or programmed infliximab treatment (n = 170) in which the dose was adjusted at week 14 based on low, intermediate, or high levels of baseline TNF-alpha.

Patients with low levels (below 0.55 pg/mL) continued receiving 3 mg/kg every 8 weeks. Intermediate levels (between 0.55 and 1.65 pg/mL) meant an increase to 6 mg/kg every 8 weeks. High levels (1.65 pg/mL or higher) meant an increase to 6 mg/kg at week 14 and to 10 mg/kg at week 22 and every 8 weeks afterward. The goal was to discontinue infliximab at 54 weeks and reassess 1 year later.

After 54 weeks, 39.4% of patients in the programmed group and 32.3% of patients in the standard group achieved remission, defined as a Simplified Disease Activity Index (SDAI) score of 3.3 or lower. After 106 weeks, 23.5% of the programmed group and 21.6% of the standard group had maintained discontinuation of infliximab (–2.2% difference; 95% confidence interval, –6.6% to 11.0%; P = .631). After analysis, the most significant predictor of sustained discontinuation was a baseline SDAI less than 26.

The authors acknowledged their study’s limitations, including the initial version of the study not being double blinded. In addition, they noted that the short length of treatment and the low dosage overall “might not be intense enough to achieve differences in disease control between the two groups.”

The study was supported by a research grant from the Ministry of Health, Labor and Welfare of Japan. The authors reported numerous potential conflicts of interest, including receiving grants, consulting fees, speaking fees, and/or honoraria from various medical and pharmaceutical companies.

SOURCE: Tanaka Y et al. Ann Rheum Dis. 2019 Oct 19. doi: 10.1136/annrheumdis-2019-216169.

A new study has indicated that tailoring dosage of infliximab based on serum levels of tumor necrosis factor–alpha did not increase the sustained remission rate in rheumatoid arthritis patients.

“The results did not support our initial hypothesis that deep remission and subsequent sustained discontinuation of infliximab can be achieved by intensive and finely tuned treatments with appropriate doses of TNF [tumor necrosis factor] inhibitors,” wrote Yoshiya Tanaka, MD, PhD, of the University of Occupational and Environmental Health, Kitakyushu, Japan. The study was published in Annals of the Rheumatic Diseases.

To determine if levels of TNF-alpha should initiate an increase in infliximab dosage, the researchers launched a multicenter, randomized trial of 337 patients with infliximab-naive RA. Patients were assigned to two groups: standard infliximab treatment of 3 mg/kg at weeks 0, 2, 6, and then every 8 weeks (n = 167) or programmed infliximab treatment (n = 170) in which the dose was adjusted at week 14 based on low, intermediate, or high levels of baseline TNF-alpha.

Patients with low levels (below 0.55 pg/mL) continued receiving 3 mg/kg every 8 weeks. Intermediate levels (between 0.55 and 1.65 pg/mL) meant an increase to 6 mg/kg every 8 weeks. High levels (1.65 pg/mL or higher) meant an increase to 6 mg/kg at week 14 and to 10 mg/kg at week 22 and every 8 weeks afterward. The goal was to discontinue infliximab at 54 weeks and reassess 1 year later.

After 54 weeks, 39.4% of patients in the programmed group and 32.3% of patients in the standard group achieved remission, defined as a Simplified Disease Activity Index (SDAI) score of 3.3 or lower. After 106 weeks, 23.5% of the programmed group and 21.6% of the standard group had maintained discontinuation of infliximab (–2.2% difference; 95% confidence interval, –6.6% to 11.0%; P = .631). After analysis, the most significant predictor of sustained discontinuation was a baseline SDAI less than 26.

The authors acknowledged their study’s limitations, including the initial version of the study not being double blinded. In addition, they noted that the short length of treatment and the low dosage overall “might not be intense enough to achieve differences in disease control between the two groups.”

The study was supported by a research grant from the Ministry of Health, Labor and Welfare of Japan. The authors reported numerous potential conflicts of interest, including receiving grants, consulting fees, speaking fees, and/or honoraria from various medical and pharmaceutical companies.

SOURCE: Tanaka Y et al. Ann Rheum Dis. 2019 Oct 19. doi: 10.1136/annrheumdis-2019-216169.

In the wake of Biogen and Eisai’s Oct. 22 announcement about plans to apply to the Food and Drug Administration next year for the regulatory approval of the investigational monoclonal antibody aducanumab as a treatment for Alzheimer’s disease, we spoke with Paul Aisen, MD, the founding director of the Alzheimer’s Therapy Research Institute at the University of Southern California, Los Angeles, for his views on the news. He has been a consultant for Biogen and is a member of the aducanumab steering committee.

Q: What was your first reaction when you heard about the plan to submit an application for aducanumab to the FDA?

A: My initial reaction is that this provides terrific support for the amyloid hypothesis, and is consistent with the early aducanumab studies showing significant reductions in brain amyloid with resulting clinical improvement.

My next thought was that these data are going to be very, very challenging to analyze because both of these trials were stopped early, and one was clearly negative. We really need to scrutinize the data, but even at this point I would say this strongly supports targeting amyloid. The scrutiny will begin in detail at the Clinical Trials in Alzheimer’s Disease conference in December, when Biogen will likely release detailed data. A lot of people will analyze it, and I think that’s great. It’s beneficial to bring different perspectives.

We have had a terribly frustrating series of disappointments in the field. After the futility analysis of aducanumab and the multiple failures of BACE [beta-secretase] inhibitors, many were convinced we were barking up the wrong tree. I think these results, although complicated, should resurrect the enthusiasm for targeting amyloid.
 

Q: What is different about aducanumab from other antibodies tested – and rejected – in Alzheimer’s drug development?

A: There are lots of antibodies that have been tested in clinical trials. They all differ in terms of their affinity for amyloid beta. Some target monomers of the protein. Some target dimers. Some target fibrils. Some tie up amyloid and some reduce it. Aducanumab directly attacks brain plaques, reducing the plaque load in the brain. It carries a liability of amyloid-related imaging abnormalities [ARIA], but it also allows us to assess the impact that removing plaques might have on downstream events, including biomarkers. Overall, these data show that aducanumab did remove brain plaques and that removing them had a beneficial effect on cognition and function, and also a favorable effect on downstream biomarkers.

But again, we must be cautious because this is a complex data set taken from a post hoc analysis of two different terminated trials.
 

Q: We see some statistically significant differences in cognitive and functional outcomes. What would that mean for patients on an everyday basis?

A: Well, everyone is different, so that’s hard to say. A 25% slowing of functional decline on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) might mean that, at the end of a year, there’s not a significant change in memory, or that there’s better social function. If both trials had been completed and if people had 18 months of high-dose aducanumab, the slowing of functional decline on the CDR-SB might in fact be greater than reported. Again, we’re having to draw conclusions from interrupted trials.
 

Q: This suggestion you make of a potentially continuous slowing of decline – are you suggesting that aducanumab might slow decline to the point of stopping it altogether? If an elderly patient has little or no progression until death would that, in effect, be considered a “cure?”

A: I don’t think it is possible to cure AD once the disease is clinically evident. These are studies of people with early AD, late mild cognitive impairment, and mild dementia. At that stage, there’s already a loss of synapses that won’t come back, and these studies don’t suggest that aducanumab can cure that. But what if people took it earlier, when the brain is still functioning normally? Some of us have argued for many years that earlier intervention is the way to go. And since we can now identify people [with brain plaques] before they become symptomatic, there is the possibility that if we removed them, we could stop progression.

Q: Are there any plans to study aducanumab as a preventive agent?

A: A grant has been awarded for this, but it was put on hold after the futility analysis. I don’t know when or if that will go forward.

(Editor’s note: The National Institutes of Health previously awarded Banner Health a $32 million, 5-year grant to examine this. The 2-year prevention study of aducanumab is aimed at cognitively unimpaired 65- to 80-year-old patients with PET-confirmed amyloid brain plaques. It was to be a multicenter, double-blind, placebo-controlled trial using Alzheimer’s biomarker endpoints as primary outcomes, along with cognitive and clinical changes, safety, and tolerability. The study was put on hold after Biogen discontinued the aducanumab development program in March. Investigators are considering whether to resurrect plans considering the new data. The study is intended to be a public-private partnership, with additional unspecified funding from Biogen plus $10 million from philanthropic sources. It has three intended goals: To find an approved prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer’s Disease’s goal of an effective prevention strategy by 2025; to advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical Alzheimer’s stages when some treatments may have their greatest benefit; and to help make it possible to conduct prevention trials in at-risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit.)
 

Q: It seems like rolling this out to an enormous population of patients is going to be difficult, if not impossible. Are people really going to be able to commit to what could be a lifetime of monthly intravenous infusions of a medicine that could be expensive, as therapeutic antibodies generally are?

A: I would say, nothing about this disease is easy. It’s devastating and horrible. And if someone is diagnosed at this stage, I would think that individual would embrace any opportunity to treat it. My hope is that we will be able to prescreen people with an effective blood test for amyloid that would be part of a regular testing protocol once they reach a certain age. Those with positive results would be referred for more testing, including amyloid brain imaging.

In the wake of Biogen and Eisai’s Oct. 22 announcement about plans to apply to the Food and Drug Administration next year for the regulatory approval of the investigational monoclonal antibody aducanumab as a treatment for Alzheimer’s disease, we spoke with Paul Aisen, MD, the founding director of the Alzheimer’s Therapy Research Institute at the University of Southern California, Los Angeles, for his views on the news. He has been a consultant for Biogen and is a member of the aducanumab steering committee.

Q: What was your first reaction when you heard about the plan to submit an application for aducanumab to the FDA?

A: My initial reaction is that this provides terrific support for the amyloid hypothesis, and is consistent with the early aducanumab studies showing significant reductions in brain amyloid with resulting clinical improvement.

My next thought was that these data are going to be very, very challenging to analyze because both of these trials were stopped early, and one was clearly negative. We really need to scrutinize the data, but even at this point I would say this strongly supports targeting amyloid. The scrutiny will begin in detail at the Clinical Trials in Alzheimer’s Disease conference in December, when Biogen will likely release detailed data. A lot of people will analyze it, and I think that’s great. It’s beneficial to bring different perspectives.

We have had a terribly frustrating series of disappointments in the field. After the futility analysis of aducanumab and the multiple failures of BACE [beta-secretase] inhibitors, many were convinced we were barking up the wrong tree. I think these results, although complicated, should resurrect the enthusiasm for targeting amyloid.
 

Q: What is different about aducanumab from other antibodies tested – and rejected – in Alzheimer’s drug development?

A: There are lots of antibodies that have been tested in clinical trials. They all differ in terms of their affinity for amyloid beta. Some target monomers of the protein. Some target dimers. Some target fibrils. Some tie up amyloid and some reduce it. Aducanumab directly attacks brain plaques, reducing the plaque load in the brain. It carries a liability of amyloid-related imaging abnormalities [ARIA], but it also allows us to assess the impact that removing plaques might have on downstream events, including biomarkers. Overall, these data show that aducanumab did remove brain plaques and that removing them had a beneficial effect on cognition and function, and also a favorable effect on downstream biomarkers.

But again, we must be cautious because this is a complex data set taken from a post hoc analysis of two different terminated trials.
 

Q: We see some statistically significant differences in cognitive and functional outcomes. What would that mean for patients on an everyday basis?

A: Well, everyone is different, so that’s hard to say. A 25% slowing of functional decline on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) might mean that, at the end of a year, there’s not a significant change in memory, or that there’s better social function. If both trials had been completed and if people had 18 months of high-dose aducanumab, the slowing of functional decline on the CDR-SB might in fact be greater than reported. Again, we’re having to draw conclusions from interrupted trials.
 

Q: This suggestion you make of a potentially continuous slowing of decline – are you suggesting that aducanumab might slow decline to the point of stopping it altogether? If an elderly patient has little or no progression until death would that, in effect, be considered a “cure?”

A: I don’t think it is possible to cure AD once the disease is clinically evident. These are studies of people with early AD, late mild cognitive impairment, and mild dementia. At that stage, there’s already a loss of synapses that won’t come back, and these studies don’t suggest that aducanumab can cure that. But what if people took it earlier, when the brain is still functioning normally? Some of us have argued for many years that earlier intervention is the way to go. And since we can now identify people [with brain plaques] before they become symptomatic, there is the possibility that if we removed them, we could stop progression.

Q: Are there any plans to study aducanumab as a preventive agent?

A: A grant has been awarded for this, but it was put on hold after the futility analysis. I don’t know when or if that will go forward.

(Editor’s note: The National Institutes of Health previously awarded Banner Health a $32 million, 5-year grant to examine this. The 2-year prevention study of aducanumab is aimed at cognitively unimpaired 65- to 80-year-old patients with PET-confirmed amyloid brain plaques. It was to be a multicenter, double-blind, placebo-controlled trial using Alzheimer’s biomarker endpoints as primary outcomes, along with cognitive and clinical changes, safety, and tolerability. The study was put on hold after Biogen discontinued the aducanumab development program in March. Investigators are considering whether to resurrect plans considering the new data. The study is intended to be a public-private partnership, with additional unspecified funding from Biogen plus $10 million from philanthropic sources. It has three intended goals: To find an approved prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer’s Disease’s goal of an effective prevention strategy by 2025; to advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical Alzheimer’s stages when some treatments may have their greatest benefit; and to help make it possible to conduct prevention trials in at-risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit.)
 

Q: It seems like rolling this out to an enormous population of patients is going to be difficult, if not impossible. Are people really going to be able to commit to what could be a lifetime of monthly intravenous infusions of a medicine that could be expensive, as therapeutic antibodies generally are?

A: I would say, nothing about this disease is easy. It’s devastating and horrible. And if someone is diagnosed at this stage, I would think that individual would embrace any opportunity to treat it. My hope is that we will be able to prescreen people with an effective blood test for amyloid that would be part of a regular testing protocol once they reach a certain age. Those with positive results would be referred for more testing, including amyloid brain imaging.

In the wake of Biogen and Eisai’s Oct. 22 announcement about plans to apply to the Food and Drug Administration next year for the regulatory approval of the investigational monoclonal antibody aducanumab as a treatment for Alzheimer’s disease, we spoke with Paul Aisen, MD, the founding director of the Alzheimer’s Therapy Research Institute at the University of Southern California, Los Angeles, for his views on the news. He has been a consultant for Biogen and is a member of the aducanumab steering committee.

Q: What was your first reaction when you heard about the plan to submit an application for aducanumab to the FDA?

A: My initial reaction is that this provides terrific support for the amyloid hypothesis, and is consistent with the early aducanumab studies showing significant reductions in brain amyloid with resulting clinical improvement.

My next thought was that these data are going to be very, very challenging to analyze because both of these trials were stopped early, and one was clearly negative. We really need to scrutinize the data, but even at this point I would say this strongly supports targeting amyloid. The scrutiny will begin in detail at the Clinical Trials in Alzheimer’s Disease conference in December, when Biogen will likely release detailed data. A lot of people will analyze it, and I think that’s great. It’s beneficial to bring different perspectives.

We have had a terribly frustrating series of disappointments in the field. After the futility analysis of aducanumab and the multiple failures of BACE [beta-secretase] inhibitors, many were convinced we were barking up the wrong tree. I think these results, although complicated, should resurrect the enthusiasm for targeting amyloid.
 

Q: What is different about aducanumab from other antibodies tested – and rejected – in Alzheimer’s drug development?

A: There are lots of antibodies that have been tested in clinical trials. They all differ in terms of their affinity for amyloid beta. Some target monomers of the protein. Some target dimers. Some target fibrils. Some tie up amyloid and some reduce it. Aducanumab directly attacks brain plaques, reducing the plaque load in the brain. It carries a liability of amyloid-related imaging abnormalities [ARIA], but it also allows us to assess the impact that removing plaques might have on downstream events, including biomarkers. Overall, these data show that aducanumab did remove brain plaques and that removing them had a beneficial effect on cognition and function, and also a favorable effect on downstream biomarkers.

But again, we must be cautious because this is a complex data set taken from a post hoc analysis of two different terminated trials.
 

Q: We see some statistically significant differences in cognitive and functional outcomes. What would that mean for patients on an everyday basis?

A: Well, everyone is different, so that’s hard to say. A 25% slowing of functional decline on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) might mean that, at the end of a year, there’s not a significant change in memory, or that there’s better social function. If both trials had been completed and if people had 18 months of high-dose aducanumab, the slowing of functional decline on the CDR-SB might in fact be greater than reported. Again, we’re having to draw conclusions from interrupted trials.
 

Q: This suggestion you make of a potentially continuous slowing of decline – are you suggesting that aducanumab might slow decline to the point of stopping it altogether? If an elderly patient has little or no progression until death would that, in effect, be considered a “cure?”

A: I don’t think it is possible to cure AD once the disease is clinically evident. These are studies of people with early AD, late mild cognitive impairment, and mild dementia. At that stage, there’s already a loss of synapses that won’t come back, and these studies don’t suggest that aducanumab can cure that. But what if people took it earlier, when the brain is still functioning normally? Some of us have argued for many years that earlier intervention is the way to go. And since we can now identify people [with brain plaques] before they become symptomatic, there is the possibility that if we removed them, we could stop progression.

Q: Are there any plans to study aducanumab as a preventive agent?

A: A grant has been awarded for this, but it was put on hold after the futility analysis. I don’t know when or if that will go forward.

(Editor’s note: The National Institutes of Health previously awarded Banner Health a $32 million, 5-year grant to examine this. The 2-year prevention study of aducanumab is aimed at cognitively unimpaired 65- to 80-year-old patients with PET-confirmed amyloid brain plaques. It was to be a multicenter, double-blind, placebo-controlled trial using Alzheimer’s biomarker endpoints as primary outcomes, along with cognitive and clinical changes, safety, and tolerability. The study was put on hold after Biogen discontinued the aducanumab development program in March. Investigators are considering whether to resurrect plans considering the new data. The study is intended to be a public-private partnership, with additional unspecified funding from Biogen plus $10 million from philanthropic sources. It has three intended goals: To find an approved prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer’s Disease’s goal of an effective prevention strategy by 2025; to advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical Alzheimer’s stages when some treatments may have their greatest benefit; and to help make it possible to conduct prevention trials in at-risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit.)
 

Q: It seems like rolling this out to an enormous population of patients is going to be difficult, if not impossible. Are people really going to be able to commit to what could be a lifetime of monthly intravenous infusions of a medicine that could be expensive, as therapeutic antibodies generally are?

A: I would say, nothing about this disease is easy. It’s devastating and horrible. And if someone is diagnosed at this stage, I would think that individual would embrace any opportunity to treat it. My hope is that we will be able to prescreen people with an effective blood test for amyloid that would be part of a regular testing protocol once they reach a certain age. Those with positive results would be referred for more testing, including amyloid brain imaging.

MADRID – The interleukin-17A inhibitor ixekizumab met all primary and secondary endpoints in a phase 3 trial in 6- to 18-year-olds with moderate to severe plaque psoriasis, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

The results bode well for an underserved population.

“I think all of us know that there is still a vulnerable population that remains a high-risk population because of the limited number of therapies available for them, and that is children,” said Dr. Papp, a dermatologist and president of Probity Medical Research, Inc., of Waterloo, Ont.

At present, etanercept, one of the earliest biologics to become available, and a relatively less effective one, is the only biologic approved for treatment of pediatric psoriasis. However, Lilly, which sponsored the phase 3 ixekizumab study, has announced that based upon the highly positive findings the company plans to seek Food and Drug Administration approval for an expanded indication for the medication in pediatric psoriasis. The company now markets ixekizumab for the approved indications of treatment of adults with moderate to severe plaque psoriasis, active psoriatic arthritis, or active ankylosing spondylitis.

The 12-week, double-blind, multicenter phase 3 trial known as IXORA-PEDS included 115 pediatric psoriasis patients randomized to weight-based ixekizumab, 30 on weight-based etanercept, and 58 on placebo. At the 12-week mark, everyone was switched to open-label ixekizumab in a long-term extension study. Children weighing less than 25 kg received a 40-mg loading dose of ixekizumab, followed by a maintenance dose of 20 mg by subcutaneous injection every 4 weeks. Patients weighing 25-50 kg got a starting dose of 80 mg, then 40 mg for maintenance therapy. Those who weighed more than 50 kg got the usual adult dosing: a 160-mg loading dose followed by 80 mg every 4 weeks. Etanercept was dosed at 0.8 mg/kg once weekly.

The coprimary endpoints were the proportion of subjects achieving a static Physician’s Global Assessment (sPGA) of 0 or 1 – that is, clear or almost clear skin – at week 12, and the PASI 75 response rate.

An sPGA of 0 or 1 at week 12 was documented in 81% of the ixekizumab group, 11% on placebo, and 40% of etanercept-treated patients, who on average had more severe baseline disease than did the other two groups.

The PASI 75 rate was 89% with ixekizumab, 25% for placebo, and 63% on etanercept. But Dr. Papp indicated that’s too low a bar. “I don’t think PASI 75s are the standard any longer,” he said.

More revealing was the PASI 90 rate: 78% with the IL-17A inhibitor, 5% in placebo-treated controls, and 40% with etanercept.

And then there’s the PASI 100 response rate: 50% with ixekizumab, 2% for placebo, and 17% for etanercept.

“I think this is very telling. I’ll leave it as a tantalizing comment that if one looks at the slope of the curve, it doesn’t yet seem to have reached its plateau at week 12 – and this is very similar to the pattern that we see in the adult population. I don’t have the long-term extension efficacy data, but I am, like you, very interested in seeing where this PASI 100 response rate finally plateaus,” Dr. Papp said.

He did, however, have the combined safety data for the 12-week double-blind phase plus the open-label extension, which he described as essentially the same as the adult experience. Injection-site reactions occurred in 19% of pediatric patients on ixekizumab, but they were generally mild and there were few if any treatment discontinuations for that reason. There was a 2% incidence of Crohn’s disease. Candidiasis and other infections were rare.

Seventy-one percent of the ixekizumab group had at least a 4-point improvement in itch on a 10-point self-rated scale by week 12, as did 20% of placebo-treated controls. A Dermatologic Life Quality Index score of 0 or 1 at week 12, indicative of no or minimal impact of psoriasis on quality of life, was documented in 64% of the ixekizumab group and 23% of controls.

Dr. Papp reported serving as a consultant, investigator, and/or speaker for Lilly and more than three dozen other pharmaceutical companies.

[email protected]

SOURCE: Papp KA. EADV Late breaker.

MADRID – The interleukin-17A inhibitor ixekizumab met all primary and secondary endpoints in a phase 3 trial in 6- to 18-year-olds with moderate to severe plaque psoriasis, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

The results bode well for an underserved population.

“I think all of us know that there is still a vulnerable population that remains a high-risk population because of the limited number of therapies available for them, and that is children,” said Dr. Papp, a dermatologist and president of Probity Medical Research, Inc., of Waterloo, Ont.

At present, etanercept, one of the earliest biologics to become available, and a relatively less effective one, is the only biologic approved for treatment of pediatric psoriasis. However, Lilly, which sponsored the phase 3 ixekizumab study, has announced that based upon the highly positive findings the company plans to seek Food and Drug Administration approval for an expanded indication for the medication in pediatric psoriasis. The company now markets ixekizumab for the approved indications of treatment of adults with moderate to severe plaque psoriasis, active psoriatic arthritis, or active ankylosing spondylitis.

The 12-week, double-blind, multicenter phase 3 trial known as IXORA-PEDS included 115 pediatric psoriasis patients randomized to weight-based ixekizumab, 30 on weight-based etanercept, and 58 on placebo. At the 12-week mark, everyone was switched to open-label ixekizumab in a long-term extension study. Children weighing less than 25 kg received a 40-mg loading dose of ixekizumab, followed by a maintenance dose of 20 mg by subcutaneous injection every 4 weeks. Patients weighing 25-50 kg got a starting dose of 80 mg, then 40 mg for maintenance therapy. Those who weighed more than 50 kg got the usual adult dosing: a 160-mg loading dose followed by 80 mg every 4 weeks. Etanercept was dosed at 0.8 mg/kg once weekly.

The coprimary endpoints were the proportion of subjects achieving a static Physician’s Global Assessment (sPGA) of 0 or 1 – that is, clear or almost clear skin – at week 12, and the PASI 75 response rate.

An sPGA of 0 or 1 at week 12 was documented in 81% of the ixekizumab group, 11% on placebo, and 40% of etanercept-treated patients, who on average had more severe baseline disease than did the other two groups.

The PASI 75 rate was 89% with ixekizumab, 25% for placebo, and 63% on etanercept. But Dr. Papp indicated that’s too low a bar. “I don’t think PASI 75s are the standard any longer,” he said.

More revealing was the PASI 90 rate: 78% with the IL-17A inhibitor, 5% in placebo-treated controls, and 40% with etanercept.

And then there’s the PASI 100 response rate: 50% with ixekizumab, 2% for placebo, and 17% for etanercept.

“I think this is very telling. I’ll leave it as a tantalizing comment that if one looks at the slope of the curve, it doesn’t yet seem to have reached its plateau at week 12 – and this is very similar to the pattern that we see in the adult population. I don’t have the long-term extension efficacy data, but I am, like you, very interested in seeing where this PASI 100 response rate finally plateaus,” Dr. Papp said.

He did, however, have the combined safety data for the 12-week double-blind phase plus the open-label extension, which he described as essentially the same as the adult experience. Injection-site reactions occurred in 19% of pediatric patients on ixekizumab, but they were generally mild and there were few if any treatment discontinuations for that reason. There was a 2% incidence of Crohn’s disease. Candidiasis and other infections were rare.

Seventy-one percent of the ixekizumab group had at least a 4-point improvement in itch on a 10-point self-rated scale by week 12, as did 20% of placebo-treated controls. A Dermatologic Life Quality Index score of 0 or 1 at week 12, indicative of no or minimal impact of psoriasis on quality of life, was documented in 64% of the ixekizumab group and 23% of controls.

Dr. Papp reported serving as a consultant, investigator, and/or speaker for Lilly and more than three dozen other pharmaceutical companies.

[email protected]

SOURCE: Papp KA. EADV Late breaker.

MADRID – The interleukin-17A inhibitor ixekizumab met all primary and secondary endpoints in a phase 3 trial in 6- to 18-year-olds with moderate to severe plaque psoriasis, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

The results bode well for an underserved population.

“I think all of us know that there is still a vulnerable population that remains a high-risk population because of the limited number of therapies available for them, and that is children,” said Dr. Papp, a dermatologist and president of Probity Medical Research, Inc., of Waterloo, Ont.

At present, etanercept, one of the earliest biologics to become available, and a relatively less effective one, is the only biologic approved for treatment of pediatric psoriasis. However, Lilly, which sponsored the phase 3 ixekizumab study, has announced that based upon the highly positive findings the company plans to seek Food and Drug Administration approval for an expanded indication for the medication in pediatric psoriasis. The company now markets ixekizumab for the approved indications of treatment of adults with moderate to severe plaque psoriasis, active psoriatic arthritis, or active ankylosing spondylitis.

The 12-week, double-blind, multicenter phase 3 trial known as IXORA-PEDS included 115 pediatric psoriasis patients randomized to weight-based ixekizumab, 30 on weight-based etanercept, and 58 on placebo. At the 12-week mark, everyone was switched to open-label ixekizumab in a long-term extension study. Children weighing less than 25 kg received a 40-mg loading dose of ixekizumab, followed by a maintenance dose of 20 mg by subcutaneous injection every 4 weeks. Patients weighing 25-50 kg got a starting dose of 80 mg, then 40 mg for maintenance therapy. Those who weighed more than 50 kg got the usual adult dosing: a 160-mg loading dose followed by 80 mg every 4 weeks. Etanercept was dosed at 0.8 mg/kg once weekly.

The coprimary endpoints were the proportion of subjects achieving a static Physician’s Global Assessment (sPGA) of 0 or 1 – that is, clear or almost clear skin – at week 12, and the PASI 75 response rate.

An sPGA of 0 or 1 at week 12 was documented in 81% of the ixekizumab group, 11% on placebo, and 40% of etanercept-treated patients, who on average had more severe baseline disease than did the other two groups.

The PASI 75 rate was 89% with ixekizumab, 25% for placebo, and 63% on etanercept. But Dr. Papp indicated that’s too low a bar. “I don’t think PASI 75s are the standard any longer,” he said.

More revealing was the PASI 90 rate: 78% with the IL-17A inhibitor, 5% in placebo-treated controls, and 40% with etanercept.

And then there’s the PASI 100 response rate: 50% with ixekizumab, 2% for placebo, and 17% for etanercept.

“I think this is very telling. I’ll leave it as a tantalizing comment that if one looks at the slope of the curve, it doesn’t yet seem to have reached its plateau at week 12 – and this is very similar to the pattern that we see in the adult population. I don’t have the long-term extension efficacy data, but I am, like you, very interested in seeing where this PASI 100 response rate finally plateaus,” Dr. Papp said.

He did, however, have the combined safety data for the 12-week double-blind phase plus the open-label extension, which he described as essentially the same as the adult experience. Injection-site reactions occurred in 19% of pediatric patients on ixekizumab, but they were generally mild and there were few if any treatment discontinuations for that reason. There was a 2% incidence of Crohn’s disease. Candidiasis and other infections were rare.

Seventy-one percent of the ixekizumab group had at least a 4-point improvement in itch on a 10-point self-rated scale by week 12, as did 20% of placebo-treated controls. A Dermatologic Life Quality Index score of 0 or 1 at week 12, indicative of no or minimal impact of psoriasis on quality of life, was documented in 64% of the ixekizumab group and 23% of controls.

Dr. Papp reported serving as a consultant, investigator, and/or speaker for Lilly and more than three dozen other pharmaceutical companies.

[email protected]

SOURCE: Papp KA. EADV Late breaker.

NEW ORLEANS – A new analysis suggests omalizumab reduces exacerbations in patients with severe, uncontrolled asthma, regardless of fixed airflow obstruction (FAO). However, exacerbation reductions were greatest in patients with high reversibility, and omalizumab only improved lung function significantly in FAO-negative patients with high reversibility.

Nicola Hanania, MD, of Baylor College of Medicine, Houston, presented these findings at the annual meeting of the American College of Chest Physicians.

The findings are from a post hoc analysis of the phase 3 EXTRA study (NCT00314574). This 48-week study enrolled patients who had inadequately controlled, severe asthma despite receiving high-dose inhaled corticosteroids and long-acting beta-agonists.

The patients were randomized to receive omalizumab (n = 427) or placebo (n = 421). Baseline characteristics were similar between the treatment arms.

FAO presence was defined as a postbronchodilator FEV₁/FVC (forced expiratory volume in 1 second/forced vital capacity) ratio less than 70%. High reversibility was defined as an increase in FEV1 of 12% or greater after albuterol administration.Omalizumab reduced exacerbations regardless of FAO, but the exacerbation relative rate reductions were greatest in FAO-positive and -negative subgroups with high reversibility.

The exacerbation relative rate reductions with omalizumab versus placebo were as follows:

• 24.8% in the overall population.
• 6.0% in FAO-positive patients with low reversibility.
• 59.8% in FAO-positive patients with high reversibility.
• 17.4% in FAO-negative patients with low reversibility.
• 44.3% in FAO-negative patients with high reversibility.

“So bronchodilator reversibility at baseline was … a correlate of more significant exacerbation reduction than … low reversibility,” Dr. Hanania said. “But the fixed airflow obstruction, whether it was present or not, did not really matter.”

As for lung function improvement, omalizumab conferred a marginal benefit for the overall population, but the improvement was “much more significant” in the FAO-negative patients with high reversibility, according to Dr. Hanania.

At week 48, the least-square mean treatment difference (omalizumab vs. placebo) for absolute FEV₁ change from baseline was:

• 68 mL in the overall population.
• 17 mL in FAO-positive patients with low reversibility.
• 2 mL in FAO-positive patients with high reversibility.
• 34 mL in FAO-negative patients with low reversibility.
• 104 mL in FAO-negative patients with high reversibility.

“As lung function improvement by omalizumab appeared to be driven by reversibility, asthma with lower reversibility and fixed airflow obstruction may represent a different phenotype,” Dr. Hanania said. “I think this needs to be looked at.”

This research was funded by Genentech and Novartis. Dr. Hanania disclosed relationships with Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, GSK, Regeneron, and Sanofi.

[email protected]

SOURCE: Hanania N et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.869.

NEW ORLEANS – A new analysis suggests omalizumab reduces exacerbations in patients with severe, uncontrolled asthma, regardless of fixed airflow obstruction (FAO). However, exacerbation reductions were greatest in patients with high reversibility, and omalizumab only improved lung function significantly in FAO-negative patients with high reversibility.

Nicola Hanania, MD, of Baylor College of Medicine, Houston, presented these findings at the annual meeting of the American College of Chest Physicians.

The findings are from a post hoc analysis of the phase 3 EXTRA study (NCT00314574). This 48-week study enrolled patients who had inadequately controlled, severe asthma despite receiving high-dose inhaled corticosteroids and long-acting beta-agonists.

The patients were randomized to receive omalizumab (n = 427) or placebo (n = 421). Baseline characteristics were similar between the treatment arms.

FAO presence was defined as a postbronchodilator FEV₁/FVC (forced expiratory volume in 1 second/forced vital capacity) ratio less than 70%. High reversibility was defined as an increase in FEV1 of 12% or greater after albuterol administration.Omalizumab reduced exacerbations regardless of FAO, but the exacerbation relative rate reductions were greatest in FAO-positive and -negative subgroups with high reversibility.

The exacerbation relative rate reductions with omalizumab versus placebo were as follows:

• 24.8% in the overall population.
• 6.0% in FAO-positive patients with low reversibility.
• 59.8% in FAO-positive patients with high reversibility.
• 17.4% in FAO-negative patients with low reversibility.
• 44.3% in FAO-negative patients with high reversibility.

“So bronchodilator reversibility at baseline was … a correlate of more significant exacerbation reduction than … low reversibility,” Dr. Hanania said. “But the fixed airflow obstruction, whether it was present or not, did not really matter.”

As for lung function improvement, omalizumab conferred a marginal benefit for the overall population, but the improvement was “much more significant” in the FAO-negative patients with high reversibility, according to Dr. Hanania.

At week 48, the least-square mean treatment difference (omalizumab vs. placebo) for absolute FEV₁ change from baseline was:

• 68 mL in the overall population.
• 17 mL in FAO-positive patients with low reversibility.
• 2 mL in FAO-positive patients with high reversibility.
• 34 mL in FAO-negative patients with low reversibility.
• 104 mL in FAO-negative patients with high reversibility.

“As lung function improvement by omalizumab appeared to be driven by reversibility, asthma with lower reversibility and fixed airflow obstruction may represent a different phenotype,” Dr. Hanania said. “I think this needs to be looked at.”

This research was funded by Genentech and Novartis. Dr. Hanania disclosed relationships with Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, GSK, Regeneron, and Sanofi.

[email protected]

SOURCE: Hanania N et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.869.

NEW ORLEANS – A new analysis suggests omalizumab reduces exacerbations in patients with severe, uncontrolled asthma, regardless of fixed airflow obstruction (FAO). However, exacerbation reductions were greatest in patients with high reversibility, and omalizumab only improved lung function significantly in FAO-negative patients with high reversibility.

Nicola Hanania, MD, of Baylor College of Medicine, Houston, presented these findings at the annual meeting of the American College of Chest Physicians.

The findings are from a post hoc analysis of the phase 3 EXTRA study (NCT00314574). This 48-week study enrolled patients who had inadequately controlled, severe asthma despite receiving high-dose inhaled corticosteroids and long-acting beta-agonists.

The patients were randomized to receive omalizumab (n = 427) or placebo (n = 421). Baseline characteristics were similar between the treatment arms.

FAO presence was defined as a postbronchodilator FEV₁/FVC (forced expiratory volume in 1 second/forced vital capacity) ratio less than 70%. High reversibility was defined as an increase in FEV1 of 12% or greater after albuterol administration.Omalizumab reduced exacerbations regardless of FAO, but the exacerbation relative rate reductions were greatest in FAO-positive and -negative subgroups with high reversibility.

The exacerbation relative rate reductions with omalizumab versus placebo were as follows:

• 24.8% in the overall population.
• 6.0% in FAO-positive patients with low reversibility.
• 59.8% in FAO-positive patients with high reversibility.
• 17.4% in FAO-negative patients with low reversibility.
• 44.3% in FAO-negative patients with high reversibility.

“So bronchodilator reversibility at baseline was … a correlate of more significant exacerbation reduction than … low reversibility,” Dr. Hanania said. “But the fixed airflow obstruction, whether it was present or not, did not really matter.”

As for lung function improvement, omalizumab conferred a marginal benefit for the overall population, but the improvement was “much more significant” in the FAO-negative patients with high reversibility, according to Dr. Hanania.

At week 48, the least-square mean treatment difference (omalizumab vs. placebo) for absolute FEV₁ change from baseline was:

• 68 mL in the overall population.
• 17 mL in FAO-positive patients with low reversibility.
• 2 mL in FAO-positive patients with high reversibility.
• 34 mL in FAO-negative patients with low reversibility.
• 104 mL in FAO-negative patients with high reversibility.

“As lung function improvement by omalizumab appeared to be driven by reversibility, asthma with lower reversibility and fixed airflow obstruction may represent a different phenotype,” Dr. Hanania said. “I think this needs to be looked at.”

This research was funded by Genentech and Novartis. Dr. Hanania disclosed relationships with Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, GSK, Regeneron, and Sanofi.

[email protected]

SOURCE: Hanania N et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.869.

Despite an increasingly diverse workforce, a new study has found that many patients remain biased toward certain physicians, which can produce substantial negative – and occasionally positive – effects.

“Addressing demeaning behavior from patients will require a concerted effort from medical schools and hospital leadership to create an environment that respects the diversity of patients and physicians alike,” wrote Margaret Wheeler, MD, of the University of California, San Francisco (UCSF) and her coauthors. The study was published in JAMA Internal Medicine.

To determine the perspectives of physicians and trainees in regard to patient bias, along with potential barriers to responding effectively, the researchers led 13 focus groups attended by internal 11 medicine hospitalist physicians, 26 internal medicine residents, and 13 medical students affiliated with the UCSF School of Medicine. In terms of gender, 26 participants identified as women, 22 as men, and 2 as gender nonconforming. In terms of racial and ethnic diversity, 26 were white, 8 were Latinx, 7 were Asian, 3 were South Asian, 1 was Middle Eastern, and 5 were black.

In describing biased and demeaning patient behavior, the participants recalled remarks that ranged from refusal of care and questioning the clinician’s role to ethnic jokes, questions as to their ethnic backgrounds, inappropriate flirtations or compliments. The effects of these behaviors on the participants included negative responses like carrying an emotional burden and withdrawing from work, along with positive responses like an increased desire for self-growth and to pursue leadership opportunities.

Barriers to addressing these behaviors included a lack of support, uncertainty as to the appropriate response, and a fear of being perceived as unprofessional. Deciding how to respond – or to respond at all – was often dictated by the level of support from colleagues, a professional responsibility to peers, and the presence of a positive role model who would’ve done the same.

The authors acknowledged their study’s limitations, including only knowing the views of those who were interviewed. In addition, all participants came from a medical school located in a diverse city that embraces different cultures, meaning their findings “may not reflect the experiences of physicians in other geographic regions.”

The study was supported by the Greenwall Foundation. The authors reported no conflicts of interest.

SOURCE: Wheeler M et al. JAMA Intern Med. 2019 Oct 28. doi: 10.1001/jamainternmed.2019.4122.

Despite an increasingly diverse workforce, a new study has found that many patients remain biased toward certain physicians, which can produce substantial negative – and occasionally positive – effects.

“Addressing demeaning behavior from patients will require a concerted effort from medical schools and hospital leadership to create an environment that respects the diversity of patients and physicians alike,” wrote Margaret Wheeler, MD, of the University of California, San Francisco (UCSF) and her coauthors. The study was published in JAMA Internal Medicine.

To determine the perspectives of physicians and trainees in regard to patient bias, along with potential barriers to responding effectively, the researchers led 13 focus groups attended by internal 11 medicine hospitalist physicians, 26 internal medicine residents, and 13 medical students affiliated with the UCSF School of Medicine. In terms of gender, 26 participants identified as women, 22 as men, and 2 as gender nonconforming. In terms of racial and ethnic diversity, 26 were white, 8 were Latinx, 7 were Asian, 3 were South Asian, 1 was Middle Eastern, and 5 were black.

In describing biased and demeaning patient behavior, the participants recalled remarks that ranged from refusal of care and questioning the clinician’s role to ethnic jokes, questions as to their ethnic backgrounds, inappropriate flirtations or compliments. The effects of these behaviors on the participants included negative responses like carrying an emotional burden and withdrawing from work, along with positive responses like an increased desire for self-growth and to pursue leadership opportunities.

Barriers to addressing these behaviors included a lack of support, uncertainty as to the appropriate response, and a fear of being perceived as unprofessional. Deciding how to respond – or to respond at all – was often dictated by the level of support from colleagues, a professional responsibility to peers, and the presence of a positive role model who would’ve done the same.

The authors acknowledged their study’s limitations, including only knowing the views of those who were interviewed. In addition, all participants came from a medical school located in a diverse city that embraces different cultures, meaning their findings “may not reflect the experiences of physicians in other geographic regions.”

The study was supported by the Greenwall Foundation. The authors reported no conflicts of interest.

SOURCE: Wheeler M et al. JAMA Intern Med. 2019 Oct 28. doi: 10.1001/jamainternmed.2019.4122.

Despite an increasingly diverse workforce, a new study has found that many patients remain biased toward certain physicians, which can produce substantial negative – and occasionally positive – effects.

“Addressing demeaning behavior from patients will require a concerted effort from medical schools and hospital leadership to create an environment that respects the diversity of patients and physicians alike,” wrote Margaret Wheeler, MD, of the University of California, San Francisco (UCSF) and her coauthors. The study was published in JAMA Internal Medicine.

To determine the perspectives of physicians and trainees in regard to patient bias, along with potential barriers to responding effectively, the researchers led 13 focus groups attended by internal 11 medicine hospitalist physicians, 26 internal medicine residents, and 13 medical students affiliated with the UCSF School of Medicine. In terms of gender, 26 participants identified as women, 22 as men, and 2 as gender nonconforming. In terms of racial and ethnic diversity, 26 were white, 8 were Latinx, 7 were Asian, 3 were South Asian, 1 was Middle Eastern, and 5 were black.

In describing biased and demeaning patient behavior, the participants recalled remarks that ranged from refusal of care and questioning the clinician’s role to ethnic jokes, questions as to their ethnic backgrounds, inappropriate flirtations or compliments. The effects of these behaviors on the participants included negative responses like carrying an emotional burden and withdrawing from work, along with positive responses like an increased desire for self-growth and to pursue leadership opportunities.

Barriers to addressing these behaviors included a lack of support, uncertainty as to the appropriate response, and a fear of being perceived as unprofessional. Deciding how to respond – or to respond at all – was often dictated by the level of support from colleagues, a professional responsibility to peers, and the presence of a positive role model who would’ve done the same.

The authors acknowledged their study’s limitations, including only knowing the views of those who were interviewed. In addition, all participants came from a medical school located in a diverse city that embraces different cultures, meaning their findings “may not reflect the experiences of physicians in other geographic regions.”

The study was supported by the Greenwall Foundation. The authors reported no conflicts of interest.

SOURCE: Wheeler M et al. JAMA Intern Med. 2019 Oct 28. doi: 10.1001/jamainternmed.2019.4122.

Cannabidiol is a derivative of marijuana that is sold everywhere from medical marijuana stores to health food markets to gas stations. While this chemical is derived from marijuana plants, it can be sold in many states as a supplement and is largely unregulated. The ubiquity of cannabidiol (CBD) and its potential benefits means that doctors need to be able to counsel patients about what we know, what we don’t, and how to use it safely. For conditions such as chronic pain and addiction, where we have few safe and effective alternatives, CBD may be reasonable to recommend.

To find out what physicians need to know about CBD, Elisabeth Poorman, MD, a general internist at a University of Washington neighborhood clinic in Kent and member of the editorial advisory board of Internal Medicine News, interviewed Peter Grinspoon, MD, who provides free consultation to primary care patients on the benefits and risks of using various forms of cannabis, including CBD. Dr. Grinspoon is an internist at Massachusetts General Hospital Chelsea Healthcare Center and is an instructor at Harvard Medical School, Boston. He has contributed to the Harvard Health Blog on the topic of medical marijuana, delivered grand rounds on cannabis at Massachusetts General Hospital, and lectured at the American College of Physicians. Dr. Grinspoon is also medical director for Galenas, a medical marijuana company.

Dr. Grinspoon is the son of Lester Grinspoon, MD, associate professor emeritus of psychiatry at Harvard Medical School, who researched the medicinal legitimacy of marijuana prohibition and has authored books on the medical benefits of marijuana.

Dr. Poorman queried Dr. Peter Grinspoon about his experiences treating patients with CBD and his knowledge of CBD’s efficacy for various medical conditions. Below are excerpts from that conversation.


Dr. Poorman: How do you explain the difference between THC and CBD to patients?

Dr. Grinspoon: Cannabis contains at least a hundred different chemicals called cannabinoids, of which tetrahydrocannabinol (THC) and CBD are the most prevalent. THC is the one that gets you high and can be used recreationally and medically. The CBD molecule is not intoxicating, and people use it for a variety of medical purposes, most commonly to treat anxiety, insomnia, and pain.

Dr. Poorman: There are a lot of gaps in what we now about CBD’s potential benefits. Why don’t we know more?

Dr. Grinspoon: CBD has no abuse liability according to the World Health Organization, but because it is a cannabinoid, it is still technically a schedule I substance under the Controlled Substances Act, and that makes it difficult to study.


Dr. Poorman: What kinds of conditions can CBD treat?

Dr. Grinspoon: In anxiety, the enthusiasm has outpaced the science; there’s no question about that. And most of the studies have done in animals. That said, some studies have shown that CBD helps treat components of anxiety, like public speaking. Unlike THC, it is nonintoxicating and non–habit forming. But we don’t have the wealth of randomized controlled trials that we have for official psychiatric medications.

CBD’s benefits have been most extensively studied in pediatric epilepsy. The one Food and Drug Administration–approved drug derived from cannabis is Epidiolex, used to treat rare forms of childhood epilepsy. There is some evidence that as an adjunct, it can be used for glioblastoma multiforme in patients receiving other appropriate therapy. There is also some preliminary evidence that it can be used for addiction, including to opioids, cannabis, tobacco, and stimulants.

Most of the evidence for using CBD in chronic pain comes from animal studies, including a study published in the European Journal of Pain in 2016. Among my patients to whom I have suggested CBD for chronic pain, a few have noticed great benefit, a few have noticed some benefit, and a lot have noticed no benefit. For those who have said they noticed benefit it is unclear whether that benefit was just the placebo effect.

In insomnia, I usually have them take CBD under the tongue half an hour time before bedtime, or if it’s an edible, an hour before bedtime. I start with a lower dose and slowly try higher doses. I also encourage them to do the other sleep hygiene things, like no screens, increasing exercise, and decreasing caffeine. It seems that CBD helps them fall asleep, though it’s hard to know if it’s the CBD or the fact that they have started taking something, and have simultaneously made various lifestyle changes.


Dr. Poorman: Can CBD interfere with your normal sleep architecture, the way benzodiazepines and Benadryl can?

Dr. Grinspoon: We know that THC affects your sleep architecture and affects what percentage of REM sleep you have. But I don’t know if the effects of CBD on sleep architecture have been studied.


Dr. Poorman: What harms do you counsel patients about when discussing CBD?

Dr. Grinspoon: There are four main harms. The first is the price. It’s overpriced, and the doses are very low. In most animal studies, the doses are about 20 milligrams per kilogram of weight. And you go to the market, and it’s like a dollar for a hundredth of that.

Number two is that it’s not regulated; it’s a supplement. A few years ago, the government tested a bunch of samples of CBD, and some didn’t actually contain CBD, some didn’t have the right amount; and worse, some contained THC that had not been disclosed in the packaging. So you can’t just go to a roadside gas station and assume that if you buy CBD, it’s actually that. You want a place that has a certificate of assurance. Make sure third-party testing was done, including testing for pesticides and other heavy metals.

The third thing is drug interactions. It affects the body like grapefruit and inhibits the cytochrome P450 system. The medications doctors should be most concerned about are blood thinners like Coumadin. And if you’re on blood thinners, you definitely want to tell your doctor that you are on CBD and he or she might want to check your blood levels more frequently than they usually do.

The fourth concern is liver inflammation. In the childhood epilepsy studies, a bump in some liver enzymes was seen, although I haven’t heard of any clinically significant cases of chemical hepatitis related to CBD. But if someone has liver disease you want to keep an eye on their liver enzymes.

Dr. Poorman: What methods of ingestion do you recommend or not recommend?

Dr. Grinspoon: It’s basically trial and error, but I usually recommend oral form. If people feel comfortable taking a gummy bear, or a pill, I’m not particular about that. If the product being taken contains less than 0.3% THC, it won’t get you high.

The topical form probably works better for treating chronic pain if it contains some THC, suggests a review article published in the Cleveland Clinic Journal of Medicine. Topical THC is nonintoxicating, unless you managed to sit in a bathtub for 8 hours after applying it.

I don’t recommend smoking CBD, and right now, I don’t recommend vaping anything.

If people have severe pain, like moderately severe arthritis, CBD may not be enough, whereas medical cannabis with THC could help, a report suggests.


Dr. Poorman: Do you ever encourage patients to stop using CBD products?

Dr. Grinspoon: I work in a low-income area, and my patients don’t have a ton of disposable income. If it’s not working, I worry about the expense.


Dr. Poorman: The CBD industry is growing quickly. What changes are you seeing in what products are out there, and what changes would you like to see?

Dr. Grinspoon: CBD is being put in everything, and it’s comical. On the one hand, you can say if people want to waste their money on a CBD emitting pillowcase, that’s fine. On the other hand, you can say that certainly seems like misleading advertising, because a CBD emitting pillowcase isn’t going to help you sleep any better.

I think the purported benefits are far beyond what we can say scientifically. We do know that CBD has anti-inflammatory characteristics. But that doesn’t mean that putting CBD in all skin products is good for your skin. It’s bad for your pocketbook, though. I would like there to be less of a gap between the claims and the science.
 

Dr. Elisabeth Poorman has no conflicts to disclose.

Cannabidiol is a derivative of marijuana that is sold everywhere from medical marijuana stores to health food markets to gas stations. While this chemical is derived from marijuana plants, it can be sold in many states as a supplement and is largely unregulated. The ubiquity of cannabidiol (CBD) and its potential benefits means that doctors need to be able to counsel patients about what we know, what we don’t, and how to use it safely. For conditions such as chronic pain and addiction, where we have few safe and effective alternatives, CBD may be reasonable to recommend.

To find out what physicians need to know about CBD, Elisabeth Poorman, MD, a general internist at a University of Washington neighborhood clinic in Kent and member of the editorial advisory board of Internal Medicine News, interviewed Peter Grinspoon, MD, who provides free consultation to primary care patients on the benefits and risks of using various forms of cannabis, including CBD. Dr. Grinspoon is an internist at Massachusetts General Hospital Chelsea Healthcare Center and is an instructor at Harvard Medical School, Boston. He has contributed to the Harvard Health Blog on the topic of medical marijuana, delivered grand rounds on cannabis at Massachusetts General Hospital, and lectured at the American College of Physicians. Dr. Grinspoon is also medical director for Galenas, a medical marijuana company.

Dr. Grinspoon is the son of Lester Grinspoon, MD, associate professor emeritus of psychiatry at Harvard Medical School, who researched the medicinal legitimacy of marijuana prohibition and has authored books on the medical benefits of marijuana.

Dr. Poorman queried Dr. Peter Grinspoon about his experiences treating patients with CBD and his knowledge of CBD’s efficacy for various medical conditions. Below are excerpts from that conversation.


Dr. Poorman: How do you explain the difference between THC and CBD to patients?

Dr. Grinspoon: Cannabis contains at least a hundred different chemicals called cannabinoids, of which tetrahydrocannabinol (THC) and CBD are the most prevalent. THC is the one that gets you high and can be used recreationally and medically. The CBD molecule is not intoxicating, and people use it for a variety of medical purposes, most commonly to treat anxiety, insomnia, and pain.

Dr. Poorman: There are a lot of gaps in what we now about CBD’s potential benefits. Why don’t we know more?

Dr. Grinspoon: CBD has no abuse liability according to the World Health Organization, but because it is a cannabinoid, it is still technically a schedule I substance under the Controlled Substances Act, and that makes it difficult to study.


Dr. Poorman: What kinds of conditions can CBD treat?

Dr. Grinspoon: In anxiety, the enthusiasm has outpaced the science; there’s no question about that. And most of the studies have done in animals. That said, some studies have shown that CBD helps treat components of anxiety, like public speaking. Unlike THC, it is nonintoxicating and non–habit forming. But we don’t have the wealth of randomized controlled trials that we have for official psychiatric medications.

CBD’s benefits have been most extensively studied in pediatric epilepsy. The one Food and Drug Administration–approved drug derived from cannabis is Epidiolex, used to treat rare forms of childhood epilepsy. There is some evidence that as an adjunct, it can be used for glioblastoma multiforme in patients receiving other appropriate therapy. There is also some preliminary evidence that it can be used for addiction, including to opioids, cannabis, tobacco, and stimulants.

Most of the evidence for using CBD in chronic pain comes from animal studies, including a study published in the European Journal of Pain in 2016. Among my patients to whom I have suggested CBD for chronic pain, a few have noticed great benefit, a few have noticed some benefit, and a lot have noticed no benefit. For those who have said they noticed benefit it is unclear whether that benefit was just the placebo effect.

In insomnia, I usually have them take CBD under the tongue half an hour time before bedtime, or if it’s an edible, an hour before bedtime. I start with a lower dose and slowly try higher doses. I also encourage them to do the other sleep hygiene things, like no screens, increasing exercise, and decreasing caffeine. It seems that CBD helps them fall asleep, though it’s hard to know if it’s the CBD or the fact that they have started taking something, and have simultaneously made various lifestyle changes.


Dr. Poorman: Can CBD interfere with your normal sleep architecture, the way benzodiazepines and Benadryl can?

Dr. Grinspoon: We know that THC affects your sleep architecture and affects what percentage of REM sleep you have. But I don’t know if the effects of CBD on sleep architecture have been studied.


Dr. Poorman: What harms do you counsel patients about when discussing CBD?

Dr. Grinspoon: There are four main harms. The first is the price. It’s overpriced, and the doses are very low. In most animal studies, the doses are about 20 milligrams per kilogram of weight. And you go to the market, and it’s like a dollar for a hundredth of that.

Number two is that it’s not regulated; it’s a supplement. A few years ago, the government tested a bunch of samples of CBD, and some didn’t actually contain CBD, some didn’t have the right amount; and worse, some contained THC that had not been disclosed in the packaging. So you can’t just go to a roadside gas station and assume that if you buy CBD, it’s actually that. You want a place that has a certificate of assurance. Make sure third-party testing was done, including testing for pesticides and other heavy metals.

The third thing is drug interactions. It affects the body like grapefruit and inhibits the cytochrome P450 system. The medications doctors should be most concerned about are blood thinners like Coumadin. And if you’re on blood thinners, you definitely want to tell your doctor that you are on CBD and he or she might want to check your blood levels more frequently than they usually do.

The fourth concern is liver inflammation. In the childhood epilepsy studies, a bump in some liver enzymes was seen, although I haven’t heard of any clinically significant cases of chemical hepatitis related to CBD. But if someone has liver disease you want to keep an eye on their liver enzymes.

Dr. Poorman: What methods of ingestion do you recommend or not recommend?

Dr. Grinspoon: It’s basically trial and error, but I usually recommend oral form. If people feel comfortable taking a gummy bear, or a pill, I’m not particular about that. If the product being taken contains less than 0.3% THC, it won’t get you high.

The topical form probably works better for treating chronic pain if it contains some THC, suggests a review article published in the Cleveland Clinic Journal of Medicine. Topical THC is nonintoxicating, unless you managed to sit in a bathtub for 8 hours after applying it.

I don’t recommend smoking CBD, and right now, I don’t recommend vaping anything.

If people have severe pain, like moderately severe arthritis, CBD may not be enough, whereas medical cannabis with THC could help, a report suggests.


Dr. Poorman: Do you ever encourage patients to stop using CBD products?

Dr. Grinspoon: I work in a low-income area, and my patients don’t have a ton of disposable income. If it’s not working, I worry about the expense.


Dr. Poorman: The CBD industry is growing quickly. What changes are you seeing in what products are out there, and what changes would you like to see?

Dr. Grinspoon: CBD is being put in everything, and it’s comical. On the one hand, you can say if people want to waste their money on a CBD emitting pillowcase, that’s fine. On the other hand, you can say that certainly seems like misleading advertising, because a CBD emitting pillowcase isn’t going to help you sleep any better.

I think the purported benefits are far beyond what we can say scientifically. We do know that CBD has anti-inflammatory characteristics. But that doesn’t mean that putting CBD in all skin products is good for your skin. It’s bad for your pocketbook, though. I would like there to be less of a gap between the claims and the science.
 

Dr. Elisabeth Poorman has no conflicts to disclose.

Cannabidiol is a derivative of marijuana that is sold everywhere from medical marijuana stores to health food markets to gas stations. While this chemical is derived from marijuana plants, it can be sold in many states as a supplement and is largely unregulated. The ubiquity of cannabidiol (CBD) and its potential benefits means that doctors need to be able to counsel patients about what we know, what we don’t, and how to use it safely. For conditions such as chronic pain and addiction, where we have few safe and effective alternatives, CBD may be reasonable to recommend.

To find out what physicians need to know about CBD, Elisabeth Poorman, MD, a general internist at a University of Washington neighborhood clinic in Kent and member of the editorial advisory board of Internal Medicine News, interviewed Peter Grinspoon, MD, who provides free consultation to primary care patients on the benefits and risks of using various forms of cannabis, including CBD. Dr. Grinspoon is an internist at Massachusetts General Hospital Chelsea Healthcare Center and is an instructor at Harvard Medical School, Boston. He has contributed to the Harvard Health Blog on the topic of medical marijuana, delivered grand rounds on cannabis at Massachusetts General Hospital, and lectured at the American College of Physicians. Dr. Grinspoon is also medical director for Galenas, a medical marijuana company.

Dr. Grinspoon is the son of Lester Grinspoon, MD, associate professor emeritus of psychiatry at Harvard Medical School, who researched the medicinal legitimacy of marijuana prohibition and has authored books on the medical benefits of marijuana.

Dr. Poorman queried Dr. Peter Grinspoon about his experiences treating patients with CBD and his knowledge of CBD’s efficacy for various medical conditions. Below are excerpts from that conversation.


Dr. Poorman: How do you explain the difference between THC and CBD to patients?

Dr. Grinspoon: Cannabis contains at least a hundred different chemicals called cannabinoids, of which tetrahydrocannabinol (THC) and CBD are the most prevalent. THC is the one that gets you high and can be used recreationally and medically. The CBD molecule is not intoxicating, and people use it for a variety of medical purposes, most commonly to treat anxiety, insomnia, and pain.

Dr. Poorman: There are a lot of gaps in what we now about CBD’s potential benefits. Why don’t we know more?

Dr. Grinspoon: CBD has no abuse liability according to the World Health Organization, but because it is a cannabinoid, it is still technically a schedule I substance under the Controlled Substances Act, and that makes it difficult to study.


Dr. Poorman: What kinds of conditions can CBD treat?

Dr. Grinspoon: In anxiety, the enthusiasm has outpaced the science; there’s no question about that. And most of the studies have done in animals. That said, some studies have shown that CBD helps treat components of anxiety, like public speaking. Unlike THC, it is nonintoxicating and non–habit forming. But we don’t have the wealth of randomized controlled trials that we have for official psychiatric medications.

CBD’s benefits have been most extensively studied in pediatric epilepsy. The one Food and Drug Administration–approved drug derived from cannabis is Epidiolex, used to treat rare forms of childhood epilepsy. There is some evidence that as an adjunct, it can be used for glioblastoma multiforme in patients receiving other appropriate therapy. There is also some preliminary evidence that it can be used for addiction, including to opioids, cannabis, tobacco, and stimulants.

Most of the evidence for using CBD in chronic pain comes from animal studies, including a study published in the European Journal of Pain in 2016. Among my patients to whom I have suggested CBD for chronic pain, a few have noticed great benefit, a few have noticed some benefit, and a lot have noticed no benefit. For those who have said they noticed benefit it is unclear whether that benefit was just the placebo effect.

In insomnia, I usually have them take CBD under the tongue half an hour time before bedtime, or if it’s an edible, an hour before bedtime. I start with a lower dose and slowly try higher doses. I also encourage them to do the other sleep hygiene things, like no screens, increasing exercise, and decreasing caffeine. It seems that CBD helps them fall asleep, though it’s hard to know if it’s the CBD or the fact that they have started taking something, and have simultaneously made various lifestyle changes.


Dr. Poorman: Can CBD interfere with your normal sleep architecture, the way benzodiazepines and Benadryl can?

Dr. Grinspoon: We know that THC affects your sleep architecture and affects what percentage of REM sleep you have. But I don’t know if the effects of CBD on sleep architecture have been studied.


Dr. Poorman: What harms do you counsel patients about when discussing CBD?

Dr. Grinspoon: There are four main harms. The first is the price. It’s overpriced, and the doses are very low. In most animal studies, the doses are about 20 milligrams per kilogram of weight. And you go to the market, and it’s like a dollar for a hundredth of that.

Number two is that it’s not regulated; it’s a supplement. A few years ago, the government tested a bunch of samples of CBD, and some didn’t actually contain CBD, some didn’t have the right amount; and worse, some contained THC that had not been disclosed in the packaging. So you can’t just go to a roadside gas station and assume that if you buy CBD, it’s actually that. You want a place that has a certificate of assurance. Make sure third-party testing was done, including testing for pesticides and other heavy metals.

The third thing is drug interactions. It affects the body like grapefruit and inhibits the cytochrome P450 system. The medications doctors should be most concerned about are blood thinners like Coumadin. And if you’re on blood thinners, you definitely want to tell your doctor that you are on CBD and he or she might want to check your blood levels more frequently than they usually do.

The fourth concern is liver inflammation. In the childhood epilepsy studies, a bump in some liver enzymes was seen, although I haven’t heard of any clinically significant cases of chemical hepatitis related to CBD. But if someone has liver disease you want to keep an eye on their liver enzymes.

Dr. Poorman: What methods of ingestion do you recommend or not recommend?

Dr. Grinspoon: It’s basically trial and error, but I usually recommend oral form. If people feel comfortable taking a gummy bear, or a pill, I’m not particular about that. If the product being taken contains less than 0.3% THC, it won’t get you high.

The topical form probably works better for treating chronic pain if it contains some THC, suggests a review article published in the Cleveland Clinic Journal of Medicine. Topical THC is nonintoxicating, unless you managed to sit in a bathtub for 8 hours after applying it.

I don’t recommend smoking CBD, and right now, I don’t recommend vaping anything.

If people have severe pain, like moderately severe arthritis, CBD may not be enough, whereas medical cannabis with THC could help, a report suggests.


Dr. Poorman: Do you ever encourage patients to stop using CBD products?

Dr. Grinspoon: I work in a low-income area, and my patients don’t have a ton of disposable income. If it’s not working, I worry about the expense.


Dr. Poorman: The CBD industry is growing quickly. What changes are you seeing in what products are out there, and what changes would you like to see?

Dr. Grinspoon: CBD is being put in everything, and it’s comical. On the one hand, you can say if people want to waste their money on a CBD emitting pillowcase, that’s fine. On the other hand, you can say that certainly seems like misleading advertising, because a CBD emitting pillowcase isn’t going to help you sleep any better.

I think the purported benefits are far beyond what we can say scientifically. We do know that CBD has anti-inflammatory characteristics. But that doesn’t mean that putting CBD in all skin products is good for your skin. It’s bad for your pocketbook, though. I would like there to be less of a gap between the claims and the science.
 

Dr. Elisabeth Poorman has no conflicts to disclose.

SAN FRANCISCO – Nearly one in three surgical residents report experiencing gender-based discrimination, and one in six report racial discrimination, with mistreatment linked to burnout and suicidal thoughts, according to data presented at the annual clinical congress of the American College of Surgeons.

Published simultaneously in the New England Journal of Medicine, the cross-sectional national survey of 7,409 residents across all 262 surgical residency programs investigated the impact of mistreatment on burnout rates and suicidal thoughts. The sample included 99.3% of all eligible U.S. trainees.

The survey found that 31.9% of all respondents – 65.1% of women and 10% of men – said they had experienced discrimination because of their self-reported gender, and 16.6% had experienced racial discrimination. In the case of both gender-based and racial discrimination, nearly half of respondents who had experienced these identified patients and patients’ families as the source.

One-third of female respondents (33%) had been on the receiving end of verbal emotional abuse, as had 28.3% of male respondents. Most of the abuse came from other surgeons.

Around 1 in 10 residents – 19.9% of women and 3.9% of men – had experienced sexual harassment. In around one-third of cases, the source was other surgeons, and in one-third the source was patients and their families.

Nearly half of all the residents said they had experienced some form of mistreatment, 19% said they experienced it a few times a month, and 30.9% said it happened a few times a year.

The survey found that 38.5% of residents experienced the symptoms of burnout – such as emotional exhaustion and depersonalization – at least once a week. The incidence was higher in women than in men (42.4% vs. 35.9%), with women reporting a higher prevalence of emotional exhaustion than men. Nearly 1 in 20 (4.5%) reported having suicidal thoughts (5.3% of women and 3.9% of men).

Researchers found that the more mistreatment a resident experienced, the greater the frequency of burnout symptoms. Those who reported experiencing mistreatment a few times a year had a twofold greater odds of burnout, compared with those who had not experienced any mistreatment. Those who experienced mistreatment a few times a month or more had nearly threefold higher odds of burnout. Similarly, increasing exposure to mistreatment was also associated with stepwise increases in the odds of suicidal thoughts.

“Mistreatment is a frequent experience for general surgery residents in the United States, and is associated with burnout and suicidal thoughts,” wrote Yue-Yung Hu, MD, from the Surgical Outcomes and Quality Improvement Center at Northwestern University, Chicago, and coauthors. “Our results provide initial insights on how we may build safer, more equitable and more effective education environments for trainees.”

The study was supported by the American College of Surgeons, the Accreditation Council for Graduate Medical Education, and the American Board of Surgery. Two authors were supported by grants from the Agency for Healthcare Research and Quality, and one by a grant from the National Institutes of Health. One author was an employee of the Accreditation Council for Graduate Medical Education.

SOURCE: Hu Y-Y et al. N Engl J Med. 2019 Oct 28. doi: 10.1056/NEJMsa1903759.

SAN FRANCISCO – Nearly one in three surgical residents report experiencing gender-based discrimination, and one in six report racial discrimination, with mistreatment linked to burnout and suicidal thoughts, according to data presented at the annual clinical congress of the American College of Surgeons.

Published simultaneously in the New England Journal of Medicine, the cross-sectional national survey of 7,409 residents across all 262 surgical residency programs investigated the impact of mistreatment on burnout rates and suicidal thoughts. The sample included 99.3% of all eligible U.S. trainees.

The survey found that 31.9% of all respondents – 65.1% of women and 10% of men – said they had experienced discrimination because of their self-reported gender, and 16.6% had experienced racial discrimination. In the case of both gender-based and racial discrimination, nearly half of respondents who had experienced these identified patients and patients’ families as the source.

One-third of female respondents (33%) had been on the receiving end of verbal emotional abuse, as had 28.3% of male respondents. Most of the abuse came from other surgeons.

Around 1 in 10 residents – 19.9% of women and 3.9% of men – had experienced sexual harassment. In around one-third of cases, the source was other surgeons, and in one-third the source was patients and their families.

Nearly half of all the residents said they had experienced some form of mistreatment, 19% said they experienced it a few times a month, and 30.9% said it happened a few times a year.

The survey found that 38.5% of residents experienced the symptoms of burnout – such as emotional exhaustion and depersonalization – at least once a week. The incidence was higher in women than in men (42.4% vs. 35.9%), with women reporting a higher prevalence of emotional exhaustion than men. Nearly 1 in 20 (4.5%) reported having suicidal thoughts (5.3% of women and 3.9% of men).

Researchers found that the more mistreatment a resident experienced, the greater the frequency of burnout symptoms. Those who reported experiencing mistreatment a few times a year had a twofold greater odds of burnout, compared with those who had not experienced any mistreatment. Those who experienced mistreatment a few times a month or more had nearly threefold higher odds of burnout. Similarly, increasing exposure to mistreatment was also associated with stepwise increases in the odds of suicidal thoughts.

“Mistreatment is a frequent experience for general surgery residents in the United States, and is associated with burnout and suicidal thoughts,” wrote Yue-Yung Hu, MD, from the Surgical Outcomes and Quality Improvement Center at Northwestern University, Chicago, and coauthors. “Our results provide initial insights on how we may build safer, more equitable and more effective education environments for trainees.”

The study was supported by the American College of Surgeons, the Accreditation Council for Graduate Medical Education, and the American Board of Surgery. Two authors were supported by grants from the Agency for Healthcare Research and Quality, and one by a grant from the National Institutes of Health. One author was an employee of the Accreditation Council for Graduate Medical Education.

SOURCE: Hu Y-Y et al. N Engl J Med. 2019 Oct 28. doi: 10.1056/NEJMsa1903759.

SAN FRANCISCO – Nearly one in three surgical residents report experiencing gender-based discrimination, and one in six report racial discrimination, with mistreatment linked to burnout and suicidal thoughts, according to data presented at the annual clinical congress of the American College of Surgeons.

Published simultaneously in the New England Journal of Medicine, the cross-sectional national survey of 7,409 residents across all 262 surgical residency programs investigated the impact of mistreatment on burnout rates and suicidal thoughts. The sample included 99.3% of all eligible U.S. trainees.

The survey found that 31.9% of all respondents – 65.1% of women and 10% of men – said they had experienced discrimination because of their self-reported gender, and 16.6% had experienced racial discrimination. In the case of both gender-based and racial discrimination, nearly half of respondents who had experienced these identified patients and patients’ families as the source.

One-third of female respondents (33%) had been on the receiving end of verbal emotional abuse, as had 28.3% of male respondents. Most of the abuse came from other surgeons.

Around 1 in 10 residents – 19.9% of women and 3.9% of men – had experienced sexual harassment. In around one-third of cases, the source was other surgeons, and in one-third the source was patients and their families.

Nearly half of all the residents said they had experienced some form of mistreatment, 19% said they experienced it a few times a month, and 30.9% said it happened a few times a year.

The survey found that 38.5% of residents experienced the symptoms of burnout – such as emotional exhaustion and depersonalization – at least once a week. The incidence was higher in women than in men (42.4% vs. 35.9%), with women reporting a higher prevalence of emotional exhaustion than men. Nearly 1 in 20 (4.5%) reported having suicidal thoughts (5.3% of women and 3.9% of men).

Researchers found that the more mistreatment a resident experienced, the greater the frequency of burnout symptoms. Those who reported experiencing mistreatment a few times a year had a twofold greater odds of burnout, compared with those who had not experienced any mistreatment. Those who experienced mistreatment a few times a month or more had nearly threefold higher odds of burnout. Similarly, increasing exposure to mistreatment was also associated with stepwise increases in the odds of suicidal thoughts.

“Mistreatment is a frequent experience for general surgery residents in the United States, and is associated with burnout and suicidal thoughts,” wrote Yue-Yung Hu, MD, from the Surgical Outcomes and Quality Improvement Center at Northwestern University, Chicago, and coauthors. “Our results provide initial insights on how we may build safer, more equitable and more effective education environments for trainees.”

The study was supported by the American College of Surgeons, the Accreditation Council for Graduate Medical Education, and the American Board of Surgery. Two authors were supported by grants from the Agency for Healthcare Research and Quality, and one by a grant from the National Institutes of Health. One author was an employee of the Accreditation Council for Graduate Medical Education.

SOURCE: Hu Y-Y et al. N Engl J Med. 2019 Oct 28. doi: 10.1056/NEJMsa1903759.

The Society for Vascular Surgery (SVS), in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), is launching an exciting new program meant to provide a meaningful leadership development experience for a select group of mid-career vascular surgeons. This highly interactive and unique program will begin in 2020 and be implemented over a six-month period. The aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. Learn more here.

The Society for Vascular Surgery (SVS), in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), is launching an exciting new program meant to provide a meaningful leadership development experience for a select group of mid-career vascular surgeons. This highly interactive and unique program will begin in 2020 and be implemented over a six-month period. The aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. Learn more here.

The Society for Vascular Surgery (SVS), in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), is launching an exciting new program meant to provide a meaningful leadership development experience for a select group of mid-career vascular surgeons. This highly interactive and unique program will begin in 2020 and be implemented over a six-month period. The aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. Learn more here.