Jim Kling

SAN DIEGO — In the phase 3 ALLEVIATE study, eptinezumab (Vyepti, Lundbeck) failed to achieve a statistically significant improvement in the primary outcome of reducing the number of weekly attacks from week 1 to week 2 in patients with episodic cluster headache. However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.

Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society

Tepper_Stewart_J_NH_web.jpg

Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
 

Are We Looking at the Wrong Endpoint?

Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.

He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.

Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.

The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.

The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
 

Thoughts on Redesigning Cluster Headache Clinical Trials

During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.

Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.

Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.

SAN DIEGO — In the phase 3 ALLEVIATE study, eptinezumab (Vyepti, Lundbeck) failed to achieve a statistically significant improvement in the primary outcome of reducing the number of weekly attacks from week 1 to week 2 in patients with episodic cluster headache. However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.

Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society

Tepper_Stewart_J_NH_web.jpg

Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
 

Are We Looking at the Wrong Endpoint?

Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.

He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.

Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.

The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.

The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
 

Thoughts on Redesigning Cluster Headache Clinical Trials

During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.

Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.

Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.

SAN DIEGO — In the phase 3 ALLEVIATE study, eptinezumab (Vyepti, Lundbeck) failed to achieve a statistically significant improvement in the primary outcome of reducing the number of weekly attacks from week 1 to week 2 in patients with episodic cluster headache. However, the drug met secondary outcomes of reduction in weekly attacks, mean change in baseline pain, and Patient Global Impression of Change (PGIC) score.

Eptinezumab is the latest of multiple anti–calcitonin gene-related peptide (CGRP) therapies to fail in the clinic against episodic cluster headache, all using weekly attacks as a primary endpoint, though therapies also scored positive results for secondary endpoints, according to Stewart Tepper, MD, who presented the study results at the annual meeting of the American Headache Society

Tepper_Stewart_J_NH_web.jpg

Eptinezumab is already approved for migraine, and is fully bioavailable by the end of an infusion. “That was why we thought this might be a really interesting treatment for prevention of cluster headache,” said Dr. Tepper, who is VP of external research at the New England Institute for Neurology and Headache in Stamford, Connecticut.
 

Are We Looking at the Wrong Endpoint?

Secondary endpoints offered more encouragement. “For each week, the eptinezumab looked either numerically higher than the placebo or nominal statistical significance was achieved. By week 4, two-thirds of the patients had at least a 50% reduction in their number of weekly cluster attacks. Then the average pain intensity for the day and the patient global impression of change were all in favor of eptinezumab. That made us interested in whether we’re missing something, whether this is maybe not the correct endpoint to be looking at,” said Dr. Tepper.

He suggested that it may be time for the Food and Drug Administration (FDA) to reconsider the endpoints used in clinical trials for cluster headaches.

Study criteria included cluster periods that lasted at least 6 weeks, and at least 1 year since the diagnosis of episodic cluster headache. The study enrolled patients who were out of their cluster period, who underwent a second screening of 7-14 days after they entered a new cycle. After that, they were randomized to an injection of placebo or 400 mg eptinezumab, and followed for 4 weeks. After 4 weeks, all patients received an injection of 400 mg eptinezumab and placebo patients were crossed over to eptinezumab and followed out to 24 weeks.

The study population included 231 patients (78% male; mean age, 44 years), with a mean of 2.7 cluster headache attacks per day an average duration of 62 minutes per attack. The worst pain was reported as excruciating in 59% of participants.

The mean change in number of weekly attacks in weeks 1 and 2, compared with baseline, was not statistically significant (–4.6 with eptinezumab, –4.6 with placebo; P = .5048). More patients in the eptinezumab group had a 50% or greater reduction in attack frequency in weeks 3 (50.9% vs 37.3%; P < .05), week 3 (62.5% vs 43.8%; P < .01), and week 4 (66.7% vs 50.5%; P < .01). The difference in mean change in pain from baseline became statistically significant at week 3 and 4 (P < .01). There were also statistically significant differences in PGIC score at weeks 1, 2, and 4. The frequency of any treatment-emergent adverse event was similar in the eptinezumab and placebo groups (25.0% vs 26.5%), and only one led to treatment withdrawal in the eptinezumab group (0.9%).
 

Thoughts on Redesigning Cluster Headache Clinical Trials

During the Q&A session, Andrea Harriott, MD, PhD, a neurologist at Massachusetts General Hospital, Boston, and the session’s moderator, asked Dr. Tepper for his thoughts on how to design a good cluster headache trial. “I think we should go to the regulators and say we’re looking at the wrong outcome measure, and that we should use responder rate as the primary endpoint. That’s my guess. I think after four failed cluster studies for anti-CGRP therapies in terms of primary endpoint, all of which suggest some benefit, I think maybe we are looking at the wrong endpoint,” said Dr. Tepper.

Dr. Tepper was also asked about the potential for comparative efficacy trials testing anti-CGRP versus usual therapy, or usual therapy combined with antibodies against usual therapy. He noted that he had coauthored a recent commentary that responded to International Headache Society 2022 guidelines for randomized, placebo-controlled trials in cluster headache. “We actually did suggest comparative effectiveness [trials], both for recruitment and for compassion, but one of the problems is that verapamil is not even FDA approved for cluster headache in the US, and galcanezumab (Emgality, Eli Lilly) [is not approved] in the EU, so it becomes difficult from a regulatory standpoint to set that up, and you have to have buy in from regulatory authorities,” said Dr. Tepper.

Dr. Tepper has financial relationships with many pharmaceutical companies, including consulting for/advising Lundbeck, which funded the study. Dr. Harriott has served on the scientific advisory board of Theranica and has an authorship agreement with AbbVie.

SAN DIEGO — Migraine may be associated with a greater risk of cardiovascular disease, ischemic stroke, and transient ischemic attack (TIA), but also a reduction in risk of hemorrhagic stroke in men, according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.

Gender Matters

The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.

The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.

Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.

The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.

Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).

While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
 

Another Piece of the Puzzle

The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.

The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.

Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Migraine may be associated with a greater risk of cardiovascular disease, ischemic stroke, and transient ischemic attack (TIA), but also a reduction in risk of hemorrhagic stroke in men, according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.

Gender Matters

The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.

The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.

Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.

The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.

Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).

While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
 

Another Piece of the Puzzle

The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.

The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.

Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Migraine may be associated with a greater risk of cardiovascular disease, ischemic stroke, and transient ischemic attack (TIA), but also a reduction in risk of hemorrhagic stroke in men, according to results from a retrospective analysis of Veterans Health Administration (VHA) data. Migraine was also linked to greater risk of cardiovascular disease, and the researchers found similar risk among both genders, with the exceptions of a larger stroke risk among women and larger risk of TIA among men.

Gender Matters

The research complements other studies, such as an analysis drawn from the Women’s Health Study, according to Alexandra Schwartz, a doctoral student at Yeshiva University, who presented the research at the annual meeting of the American Headache Society. That study found a 53% increased risk of stroke (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.02-2.31) among 17,531 female subjects between the ages of 25 and 42. Another, smaller study in 1,400 men drawn from the Physicians Health study found an increased risk of major cardiovascular events of 1.24 (P = .008). Previous studies have shown that around two-thirds of VHA patients with migraine are male. “Our population gives us this really unique opportunity to look at men with migraine,” Ms. Schwartz said in an interview.

The differential risk factors among men and women are tantalizing. “Gender likely matters in terms of how migraine and stroke are related, and a number of other cardiovascular diseases,” said Ms. Schwartz.

Migraine has long been considered a disease of women, but 6% of men experience the condition, making it important to understand how migraine might affect cardiovascular result in men. “We would expect that there could be different underlying mechanisms in this kind of relationship ... it is absolutely worth understanding the extent to which this disease might impact their risk of cardiovascular events,” senior author Elizabeth Seng, PhD, said in an interview. She is a professor at Yeshiva University and a research associate at Albert Einstein School of Medicine.

The researchers examined data from 2,006,905 veterans between 2008 and 2021, including 681,784 migraineurs (492,234 men; 189,430 women) and 1,325,121 controls (983,154 men; 341,967 women) that were matched based on age within a 5-year band, gender, race, ethnicity, and VHA site of care.

Among individuals diagnosed with migraine, there was an increased risk of ischemic stroke (odds ratio [OR], 2.7; 95% CI, 2.6-2.7), TIA (OR, 7.3; 95% CI, 6.8-7.7), cardiovascular disease (OR, 3.6; 95% CI, 3.5-3.6), acute myocardial infarction (OR, 1.7; 95% CI, 1.6-1.8), heart failure (OR, 1.3; 95% CI, 1.3-1.4), and unstable angina (OR, 2.7; 95% CI, 2.5-2.8). There was an association between migraine and a lower risk of hemorrhagic stroke (OR, 0.4; 95% CI, 0.4-0.5), but only in men. When the findings were analyzed by gender, the findings were generally similar with the exception of a statistically significant, larger risk of ischemic stroke in women (OR, 3.0 versus 2.6), and a trend toward greater risk of TIA in men (OR, 7.3 versus 6.5).

While the study lends unique insight due to the high proportion of men, it also comes with the limitation that the participants were veterans, and may therefore differ from the general population with respect to general health status and other characteristics, said Ms. Schwartz.
 

Another Piece of the Puzzle

The large number of men in the study is important, according to session moderator Laine Green, MD, who was asked for comment. “The biggest population that was studied with respect to cardiovascular risk was the Women’s Health Study, which was predominantly White nurses over time, and it is one of our biggest important pieces of information when it comes to cardiovascular risk, specifically looking at those with migraine who seem to have this doubling of their underlying stroke risk. Trying to get the same type of information from different populations is exquisitely helpful, because it’s long been thought that the risk for stroke and cardiovascular events seems to lie with females with aura. Knowing that there may be risk in other groups is important and part of the overall counseling that we do with patients,” said Dr. Green, assistant professor of neurology at Mayo Clinic Arizona.

The findings could hint at causal mechanisms, according to Dr. Seng. Preliminary analyses, not yet reported, suggest that age also plays a role in the relationship between migraine and cardiovascular risks. “I think that it’s important to [determine] to what extent migraine might back up the curve on the age-related timing of these events. Migraine peaks in the 40s, and that’s well before most of these cardiovascular events peak. We want to understand not just the cross-sectional relationships, which were large, but also the extent to which migraine may be having a differential impact on risk in different age bands,” said Dr. Seng.

Ms. Schwartz, Dr. Seng, and Dr. Green have no relevant financial disclosures.

SAN DIEGO — A new analysis of patients with new daily persistent headache (NDPH) lends insight into the condition and provides some hints as to some of the more effective treatments, including some calcitonin gene-related peptide (CGRP) inhibitors.

“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.

There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.

The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.

Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
 

Additional Information on a Rare, Hard-to-Treat Condition

Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.

He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.

The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
 

‘A Good Data Set’

The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.

The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
 

Insights Into Treatment Efficacy

Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’

“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.

There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.

Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.

SAN DIEGO — A new analysis of patients with new daily persistent headache (NDPH) lends insight into the condition and provides some hints as to some of the more effective treatments, including some calcitonin gene-related peptide (CGRP) inhibitors.

“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.

There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.

The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.

Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
 

Additional Information on a Rare, Hard-to-Treat Condition

Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.

He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.

The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
 

‘A Good Data Set’

The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.

The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
 

Insights Into Treatment Efficacy

Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’

“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.

There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.

Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.

SAN DIEGO — A new analysis of patients with new daily persistent headache (NDPH) lends insight into the condition and provides some hints as to some of the more effective treatments, including some calcitonin gene-related peptide (CGRP) inhibitors.

“There’s just not a lot [of information] about these patients,” Mark Burish, MD, PhD, associate professor of neurology at UT Houston, said in an interview. He presented the results of the survey at the annual meeting of the American Headache Society.

There have been some retrospective analyses of patient data, but that has a lot of potential for bias. “It’s only the patients who can afford to be there, and who needed those treatments, and so we want to do more of a general survey,” said Dr. Burish.

The results weren’t particularly surprising, and tended to reaffirm what was known anecdotally, including symptoms similar to those of migraine, but it gave some insight into treatments. “Some of the CGRP inhibitors and the onabotulinum toxin seem to be some of the more effective treatments, according to our survey, so those are probably worth looking into for these patients if you can get them approved by insurance, and if you can get patients to accept the idea they might have to give themselves an injection of some sort,” said Dr. Burish.

Despite having some promise, there was variation among CGRP inhibitors. Eptinezumab, rimegepant, and atogepant were commonly reported as effective, but others, such as erenumab and galcanezumab, were less often reported. “None of them were incredibly effective. These were just the best things we have at this time,” said Dr. Burish.
 

Additional Information on a Rare, Hard-to-Treat Condition

Jason Sico, MD, who moderated the session, was asked for comment. “I’m so appreciative that the team has looked at a new daily persistent headache. It’s a rare type of headache disorder. It’s also one that is notoriously difficult to treat and something that we that we really need to know more about. It is difficult to really get good, robust in-depth information on these patients, and the team did a really nice job with that,” said Dr. Sico, associate professor of neurology and internal medicine at Yale School of Medicine and national director of the Headache Centers of Excellence Program within the Veterans Health Administration.

He noted that the researchers found that opioids were the most commonly used acute treatment. That’s not surprising, but “it would be interesting to see what was tried before someone had gotten to opioids,” he said.

The findings also gave some unexpected insight into the condition. “I really found it striking that an overwhelming majority of patients reported brain fog. Given the context that it is daily persistent headache, one could surmise that they have brain fog a lot of the time,” said Dr. Sico.
 

‘A Good Data Set’

The researchers analyzed data from 337 international patients who responded to a survey. They also randomly selected 34 patients for an interview, and 32 of those were deemed likely to have NDPH. “So we really spent some effort making sure this was a good data set,” said Dr. Burish. The participant population was 72% female, 83.7% White, and 70.7% were based in the United States, though other countries included Canada, the United Kingdom, Australia, Ireland, Germany, Sweden, and Switzerland. The mean age was 41.2 years. The peak ages of onset were between 11 and 40 years, though there were a few cases in the 0-5 age range and over 70. Possible triggers that occurred in the 3 months before onset included psychological stressors (34%), infection or inflammation (32%, COVID infection (5%), injury or surgery (8%), or a change in medications (4%). No clear trigger was identified by 22% of respondents.

The survey included information on associated features, and frequently reported issues included brain fog (approximate 75%), sound sensitivity (about 62%), light sensitivity (57%), nausea (39%), smell sensitivity (32%), visual disturbances (28%), vomiting (13%), and chills (9%).
 

Insights Into Treatment Efficacy

Dr. Burish showed a slide of responses to questions about acute treatments that respondents had tried at least once and viewed as ‘completely effective,’ ‘mostly effective,’ or ‘somewhat effective.’

“No medicine was completely effective, which I think a lot of people know from NDPH. It is notoriously difficult to treat. The things on the top of the list are mostly opioids. There’s one (non-opioid), the DHE (dihydroergotamine) injection. All the way on the other side, you have diphenhydramine. The NSAIDs and triptans are mostly in the middle. We did ask about some of the wearable devices, and we had extra questions about, are you using it appropriately? Those are kind of in the middle or towards the bottom [in frequency],” said Dr. Burish.

There was a similar question regarding effective preventive medications that had been tried for at least 2 months or 3 months in the cause of onabotulinum toxin or CGRP medications. “This one had a little bit more of a pattern to it: A lot of the CGRP medications are up toward the top. It’s not perfect. Erenumab and galcanezumab are closer to the bottom, but it was interesting that a lot of the CGRP medicines were toward the top. Onabotulinum toxin was also somewhat toward the top. We looked at a few different anti-inflammatories. Methylprednisolone is kind of toward the upper half at least, whereas prednisone and montelukast are at the absolute bottom. And the prednisone is a pretty good dose, 50 milligrams or higher. There are some people thinking that this is an inflammation or infectious etiology, (but) it wasn’t that all of the anti-inflammatories were necessarily toward the top of the list,” said Dr. Burish.

Dr. Burish has received funding from Lundbeck. Dr. Sico has no relevant financial disclosures.

SAN DIEGO — In a randomized, controlled trial, lidocaine injections to the greater occipital nerve were effective in controlling migraine symptoms among adolescents. The treatment has long been used in adults, and frequently in children on the strength of observational evidence.

Prior Research

Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.

Szperka_Christina_Phila_web.jpg

Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.

“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.

The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”

She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
 

A Randomized, Controlled Trial

In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.

There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.

After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.

Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
 

Important Research in an Understudied Population

Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.

Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.

SAN DIEGO — In a randomized, controlled trial, lidocaine injections to the greater occipital nerve were effective in controlling migraine symptoms among adolescents. The treatment has long been used in adults, and frequently in children on the strength of observational evidence.

Prior Research

Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.

Szperka_Christina_Phila_web.jpg

Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.

“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.

The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”

She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
 

A Randomized, Controlled Trial

In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.

There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.

After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.

Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
 

Important Research in an Understudied Population

Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.

Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.

SAN DIEGO — In a randomized, controlled trial, lidocaine injections to the greater occipital nerve were effective in controlling migraine symptoms among adolescents. The treatment has long been used in adults, and frequently in children on the strength of observational evidence.

Prior Research

Most of the studies have been conducted in adults, and these were often in specific settings like the emergency department for status migrainosus, while outpatient studies were generally conducted in chronic migraine, according to presenting author Christina Szperka, MD. “The assumptions were a little bit different,” Dr. Szperka, director of the pediatric headache program at Children’s Hospital of Philadelphia, said in an interview.

Szperka_Christina_Phila_web.jpg

Retrospective studies are also fraught with bias. “We’ve tried to look at retrospective data. People don’t necessarily report how they’re doing unless they come back, and so you lose a huge portion of kids,” said Dr. Szperka, who presented the research at the annual meeting of the American Headache Society.

“From a clinical perspective, I think it gives us additional evidence that what we’re doing makes a difference, and I think that will help us in terms of insurance coverage, because that’s really been a major barrier,” said Dr. Szperka.

The study also opens other avenues for research. “Just doing the greater occipital nerves only reduces the pain so much. So what’s the next step? Do I study additional injections? Do I do a study where I compare different medications?”

She previously conducted a study of how providers were using lidocaine injections, and “there was a large amount of variability, both in terms of what nerves are being injected, what medications they were using, the patient population, et cetera,” said Dr. Szperka. Previous observational studies have suggested efficacy in pediatric populations for transition and prevention of migraine, new daily persistent headache, posttraumatic headache, and post-shunt occipital neuralgia.
 

A Randomized, Controlled Trial

In the new study, 58 adolescents aged 7 to 21 (mean age, 16.0 years; 44 female) were initially treated with lidocaine cream. The patients were “relatively refractory,” said Dr. Szperka, with 25 having received intravenous medications and 6 having been inpatients. After 30 minutes, if they still had pain and consented to further treatment, Dr. Szperka performed bilateral greater occipital nerve injections with lidocaine or a saline placebo, and did additional injections after 30 minutes if there wasn’t sufficient improvement.

There was no significant change in pain after the lidocaine cream treatment, and all patients proceeded to be randomized to lidocaine or placebo injections. The primary outcome of 30-minute reduction in pain score ranked 0-10 favored the lidocaine group (2.3 vs 1.1; P = .013). There was a 2-point reduction in pain scores in 69% of the lidocaine group and 34% of the saline group (P = .009) and a higher frequency of pain relief from moderate/severe to no pain or mild (52% versus 24%; P = .03). There was no significant difference in pain freedom.

After 24 hours, the treatment group was more likely to experience pain relief from moderate/severe to no pain or mild (24% vs 3%; P = .05) and to be free from associated symptoms (48% vs 21%; P = .027). Pain at the injection site was significantly higher in the placebo group (5.4 vs 3.2), prompting a change in plans for future trials. “I don’t think I would do saline again, because I think it hurt them, and I don’t want to cause them harm,” said Dr. Szperka.

Adverse events were common, with all but one patient in the study experiencing at least one. “I think this is a couple of things: One, kids don’t like needles in their head. Nerve blocks hurt. And so it was not surprising in some ways that we had a very high rate of adverse events. We also consented them, and that had a long wait period, and there’s a lot of anxiety in the room. However, most of the adverse events were mild,” said Dr. Szperka.
 

Important Research in an Understudied Population

Laine Greene, MD, who moderated the session, was asked for comment. “I think it’s an important study. Occipital nerve blocks have been used for a long period of time in management of migraine and other headache disorders. The quality of the evidence has always been brought into question, especially from payers, but also a very important aspect to this is that a lot of clinical trials over time have not specifically been done in children or adolescents, so any work that is done in that age category is significantly helpful to advancing therapeutics,” said Dr. Greene, associate professor of neurology at Mayo Clinic Arizona.

Dr. Szperka has consulted for AbbVie and Teva, and serves on data safety and monitoring boards for Eli Lilly and Upsher-Smith. She has been a principal investigator in trials sponsored by Abbvie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Greene has no relevant financial disclosures.

SAN DIEGO — Susceptibility to post-traumatic headache could be linked to mutations in ion channel and ion transporter genes, according to results from a preliminary study.

Post-traumatic headache is a common symptom of traumatic brain injury (TBI).

There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.

The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.

“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.

The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.

The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.

After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.

In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.

In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.

Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).

“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.

During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.

Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”

Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.

He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.

Dr. Griffiths and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Susceptibility to post-traumatic headache could be linked to mutations in ion channel and ion transporter genes, according to results from a preliminary study.

Post-traumatic headache is a common symptom of traumatic brain injury (TBI).

There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.

The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.

“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.

The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.

The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.

After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.

In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.

In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.

Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).

“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.

During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.

Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”

Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.

He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.

Dr. Griffiths and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Susceptibility to post-traumatic headache could be linked to mutations in ion channel and ion transporter genes, according to results from a preliminary study.

Post-traumatic headache is a common symptom of traumatic brain injury (TBI).

There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.

The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.

“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.

The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.

The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.

After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.

In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.

In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.

Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).

“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.

During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.

Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”

Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.

He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.

Dr. Griffiths and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Cognitive impairment, or “brain fog,” is a well-known effect of active migraines, but evidence is mounting that it is also common during interictal periods.

In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.

Lipton_Richard_NY_web2.JPG

He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.

One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.

However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.

He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.

Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.

“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.

Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.

Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.

The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.

He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.

“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.

The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.

He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.

The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.

Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.

SAN DIEGO — Cognitive impairment, or “brain fog,” is a well-known effect of active migraines, but evidence is mounting that it is also common during interictal periods.

In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.

Lipton_Richard_NY_web2.JPG

He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.

One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.

However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.

He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.

Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.

“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.

Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.

Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.

The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.

He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.

“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.

The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.

He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.

The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.

Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.

SAN DIEGO — Cognitive impairment, or “brain fog,” is a well-known effect of active migraines, but evidence is mounting that it is also common during interictal periods.

In fact, these effects may appear in the prodromal phase and carry through the headache and into the post-headache period, according to Richard Lipton, MD, who spoke about cognition and migraine at the annual meeting of the American Headache Society.

Lipton_Richard_NY_web2.JPG

He pointed out existing evidence that migraine patients have cognitive impairment relative to the general population even during the interictal period. Such studies suggest that migraine, especially with aura, could be a risk factor for later dementia.

One important limitation of studies that compare people with migraines with controls is that a range of factors could explain an association between lower cognitive function and migraines, including socioeconomic factors, education, severe headaches requiring specialty care, and comorbidities, among others. Acute and preventative treatments could also affect cognition.

However, longitudinal studies of cognitive function in individual patients have been sparse. Questions remain, like whether cognitive performance differs between the headache period and the interictal period, as well as similar questions about the premonitory and post-drome phases. “And then there’s a long-term question: Do people with migraine show more interictal or ictal decline in cognitive performance relative to migraine-free controls?” said Dr. Lipton, professor of neurology at Albert Einstein College of Medicine in the Bronx, New York.

He showed evidence from a retrospective study by Lundbeck conducted at four sites that asked patients with chronic migraine about bothersome symptoms both before and after treatment. More than three-fourths (77.7%) rated “difficulty concentrating or thinking clearly” as a bothersome symptom.

Following treatment, 5.0% said their cognitive issues had completely improved, 32.0% that they were “very much” improved, 26.0% moderately improved, 23.0% slightly improved, and 14.0% not at all improved.

“I am not saying this is a rigorous study, but I am saying that it illustrates two points that are important for us today: One is that brain fog is very common in a subspecialty care sample of headache patients like the ones many of us treat, and it also suggests that there’s hope that treatment can improve cognitive impairment as migraine gets better,” said Dr. Lipton.

Cognition has received less attention than other migraine symptoms, and treatment can be a two-edged sword: “There’s some evidence that some treatments can reduce cognitive impairment, and obvious evidence that some treatments, topiramate and tricyclics, can induce cognitive impairment,” said Dr. Lipton.

Studies that compare cognition within the same patient at different time periods can get around some of the limitations of comparisons between populations, but face their own challenges. “Single shot” cognitive measures may not be reliably repeatable and differences seen on “good” versus “bad” days or proximity to recent headaches.

The solution, Dr. Lipton believes, is intensive repeated measures that avoid the practice effect, in which a participant improves at a test due to repetition.

He summarized a study that was presented later in the day at a poster session, which used smartphones or other devices to test 19 participants five times per day, over 5 days, in natural environments. Devices gathered both subjective and objective assessments of cognition, along with information on mood, stress, and status and fluctuations in pain, and have the potential to go further by measuring things like physical exertion, heart rate, pollution levels, and other variables.

“It clearly improves the reliability and the validity of cognitive assessment and makes it possible to link cognition to the stage of the headache cycle,” said Dr. Lipton.

The researchers found worse cognitive performance during the headache phase as compared with the interictal phase. “Objective cognitive performance measurably declines during the headache phase, and the next step is to fully control for acute medications that people may take during the headache phase,” said Dr. Lipton.

He expressed hope that improved measurements can improve outcomes, if it’s possible to identify therapies that don’t impact cognition. “We think it’s very likely that certain classes of acute and preventive medications may not cause cognitive impairment, and there is a strong hope that they may actually reduce the cognitive burden of disease and potentially even reduce cognitive decline. Those are areas that I’m very excited to explore in the future,” said Dr. Lipton.

The results emphasize the need to treat patients early, according to Nada Hindiyeh, MD, who attended the session and was asked for comment. “Generally, patients are going to come to you with episodic migraines. When migraines start to increase in frequency and severity, that means all of these other symptoms are going to come along with it and be increased in frequency and severity, so it’s important to recognize this early so you can get patients on the right treatments and preventives to really prevent these episodes from happening and prevent that cognitive decline,” said Dr. Hindiyeh, director of headache neurology at Metrodora Institute, West Valley City, Utah.

Dr. Lipton has financial relationships with Aeon, AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Pfizer, Teva, Axon, CoolTech, and Manistee. Dr. Hindiyeh has no relevant financial disclosures.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In a population of Black/African American and Hispanic/Latino patients with multiple sclerosis (MS), ocrelizumab had high efficacy and an acceptable safety profile, according to the results of a 1-year analysis of the CHIMES trial. The study is the first-ever prospective study of an MS disease-modifying therapy (DMT) exclusively performed in under-represented populations, and offers lessons to researchers aiming to design more inclusive clinical trials to bolster participation by under-represented populations.

“The goal was to better understand efficacy of therapy in under-represented populations because we typically have very low numbers of these patients in our clinical trials, although there are multiple studies over the past decades suggesting that there may be poorer outcomes in Black and Hispanic individuals, particularly in the United States, and that there also may be more aggressive disease,” said Mitzi Williams, MD, who presented the study in a poster session at the annual meeting of the Consortium of Multiple Sclerosis Centers.

The team recruited 113 Black participants and 69 Hispanic participants, and, in fact, over-recruited the target number by 25%, and did so 2 months before the launch of the study in July 2020, which just happened to be in the midst of a global pandemic.

After 48 weeks of ocrelizumab treatment, 46.0% of Black participants and 58.0% of Hispanic participants achieved no evidence of disease activity in three components (NEDA-3), while 94.7% and 95.7% were free from relapses, respectively, and 94.7% and 94.2% were free from disease worsening. Serious adverse events occurred in 6.2% and 4.3% of each group, respectively, and there were no new safety signals in either group.

“The good news is that the efficacy and safety was very similar to what we saw in other clinical trials. I don’t think we really expected it to be much different, because when we think about race, it’s a social construct, not a biologic construct. What we do hope to find out is more about some of the interplay of social determinants of health, and how getting on high efficacy treatment can improve and increase productivity and outcomes in the long term,” said Dr. Williams, who is medical director of Joi Life Wellness Group, Smyrna, Georgia.

The researchers succeeded by involving patient advocates and advocacy organizations at the very earliest stages of the trial design. “We were very intentional about looking at things like social determinants of health, childcare, transportation, and things like that to ease some of the burden of participating in the trial, obviously in a legal and compliant way,” said Dr. Williams. The team also ensured complete and accurate translation of patient materials into Spanish.

The study was also a phase 4 trial, which may have simplified recruitment. “So it’s a therapy that’s already approved, which may make people feel more comfortable, but obviously the goal is for our phase 3 trials to make sure that we are recruiting represented populations. We’re taking these learnings and applying them to the broader clinical trial population so that hopefully we won’t have to come back and do phase 4 studies like this,” said Dr. Williams.

She noted that the results of more inclusive studies don’t just benefit underserved populations. “You have groups of people that are suffering and having more disability from a condition, and you need to understand why. When we broaden the population to understand those that are most vulnerable and underserved and [having the worst outcomes], it really helps us to better treat everybody. Because if we can get a hold of those factors that make us do the worst, then we can also better understand the factors that make us do the best,” said Dr. Williams.
 

Inclusive Recruitment in Clinical Trials

Asked for comment, Ahmed Obeidat, MD, PhD, highlighted the importance of inclusive recruitment. “The study is very important because historically and even in most recent clinical trials, these groups were markedly under-represented and most completed clinical trials derive conclusions based on the study of a nondiverse, White-non-Hispanic predominant population,” said Dr. Obeidat, who is an associate professor at the Medical College of Wisconsin, Milwaukee. He pointed to a systematic review showing that the median percentage of White participants in MS clinical trials was 93% and ranged from 86% to 98%.

“Several factors may contribute to the disparity in clinical trial participation, and solutions must be explored and developed. CHIMES is a first step in this direction where the study itself is designed to address disparity in MS clinical trial participation,” said Dr. Obeidat.

Dr. Obeidat also pointed to the need to consider other forms of diversity in clinical trials, such as older patients and those with advanced disability. “Investigators, coordinators, and other staff should all strive to be as inclusive as possible in clinical trials,” he said.

Dr. Williams has received consulting fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech Inc., Janssen, Novartis, Sanofi, and TG Therapeutics, and serves on speakers bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Janssen, Genentech, and TG Therapeutics. Dr. Ahmed Z. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, Tennessee — In pediatric multiple sclerosis (MS), the optimal dose of ocrelizumab is the same as the 600 mg adult dose for patients weighing more than 35 kg, according to pharmacokinetic/pharmacodynamic (PK/PD) data from the OPERETTA 1 phase 2 clinical trial. The safety profile was similar to adult patients.

“While we believe the disease to be the same in children and adolescents, [MS] is distinguished by its very inflammatory nature, oftentimes causing two to three times the number of relapses per year as their adult-onset colleagues,” said Teri Schreiner, MD, during a presentation of the results at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Approved therapies for pediatric MS include fingolimod in the United States and Europe, as well as dimethyl fumarate in Europe. “There’s a real need for high-efficacy treatment [in pediatric patients], again referring back to this disease being very inflammatory in children and adolescents. We oftentimes will use medications off label but this is clearly suboptimal as we lack safety data, and oftentimes run into difficulty with insurance approval of off-label use of medicine,” said Dr. Schreiner, who is an associate professor of neurology at University of Colorado School of Medicine, Aurora.

To determine the dose in pediatric patients that would produce comparable PK and PD to adults, the researchers dosed six patients aged 10-18 with 300 mg ocrelizumab, and 17 such patients with 600 mg ocrelizumab during a 24-week dose-exploration period, followed by a 264-week optional extension period. The cohorts were separated based on weight of less than or more than 40 kg. The mean ages were 11.2 years (mean weight, 34.9 kg) and 15.3 years (mean weight, 62.3 kg), respectively.

During the dose-exploration period, seven blood draws were performed to characterize PK. “When the PK data was analyzed, we saw that the proper cut-off point was 35 kilos. At less than 35 kilos, the appropriate dose was half of that adult dose, so 300 milligrams every 6 months, whereas above 35 kilos, the proper dose was actually 600, or the adult dose. Given the rarity of pediatric-onset MS patients less than 35 kilos, most patients will benefit from the adult dose of 600 milligrams twice yearly,” said Dr. Schreiner.

PD data were also encouraging. “The primary PD was the absence of CD-19 B cells, and that was tracked over time. While there were a few patients in both cohorts that had modest reconstitution, there was no patient in our study that crossed the retreatment threshold, and all blood samples were negative for anti-drug antibodies,” said Dr. Schreiner.

Adverse events occurred in five of six patients in the 300 mg group (83%; 4 grade 2, 1 grade 3) and 100% of patients in the 600 mg group (1 grade 1, 9 grade 2, 6 grade 3, 1 grade 4). There was one serious adverse event in the 300 mg group (16.7%) and four serious adverse events in the 600 mg group (23.5%). None led to treatment discontinuation. “This is largely consistent with what was seen in the adult studies of ocrelizumab,” said Dr. Schreiner.

Roche is now recruiting for the phase 3 OPERETTA 2 trial, which will use the 600 mg dose and compare outcomes to a fingolimod arm.
 

Establishing Safety in the Pediatric Population

“In [pediatric onset MS] it’s an important piece of information to design OPERETTA 2 and to dose ocrelizumab in pediatric-onset MS in general,” said Jeffrey A Cohen, MD, professor of neurology at the Cleveland Clinic, who was asked for comment.

During the Q&A period, Dr. Schreiner was asked whether it is possible to extrapolate experience from rituximab to the pediatric population. “They’re very similar molecules, and we know the mechanisms of action, but I think part of the importance of doing these studies is to get the safety data so that we actually can say with certainty, we are giving you a drug that has this list of side effects and we know about them definitively. We all use other high-efficacy medications, but I don’t think we can exactly extrapolate,” said Dr. Schreiner.

Session moderator Amy Perrin Ross, APN, noted the lack of approved pediatric therapies for MS. “This is an extremely important study, because we at least in the lower 48 are quite limited in our resources for approved pediatric cases. Information like this will make it easier for a potential pediatric indication, which would then make it easier on us to go after [treatment of the disease in this population]. The weight-based dosing, I think, is really a good thing. Patients have been asking for weight-based dosing on everything for many years,” she said.

Ahmed Obeidat, MD, PhD, associate professor at the Medical College of Wisconsin, also praised the study. “While pediatric MS is rare, it is an area of unmet need when it comes to disease-modifying therapies as only fingolimod is FDA-approved, and many use B cell–depleting therapy, such as rituximab, off label to treat children with MS with good outcomes. The need for guidance on the dosing of B cell–depleting therapy is a main priority for research in pediatric MS,” he said.

The study was funded by Roche. Dr. Schreiner has consulted for Roche and Cycle Pharmaceuticals. Dr. Cohen has consulted for Astoria, Bristol Myers Squibb, Convelo, EMD Serono Inc, FiND, INMune, and Sandoz. Dr. Obeidat has financial relationships with Alexion Pharmaceuticals, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Ms. Ross has consulted for EMD Serono, BMS, Horizon, Alexion, TG Therapeutics, Novartis, Roche, and Sanofi.

NASHVILLE, TENNESSEE — Exercise has a long history in multiple sclerosis (MS). In 1838, the Scottish physician John Abercrombie reported that a patient with “a diminution of muscular power,” who could walk but only unsteadily, decided after various failed treatments like “evacuations and spare diet” to try “violent exercise.” He walked 5-6 miles on a warm evening, as quickly as he was able, and returned home “much fatigued, and considerably heated. Next morning he had severe pains in the calves of his legs, but his other complaints were much diminished, and in a few days disappeared. He has ever since enjoyed good health,” Dr. Abercrombie was quoted in Multiple Sclerosis: The History of a Disease by T. Jock Murray.

The first randomized, controlled trial of an exercise intervention for MS didn’t appear in the literature until 1988, but more than 200 have been published in the years since, according to Robert Motl, PhD, who spoke about exercise interventions for MS at the annual meeting of the Consortium of Multiple Sclerosis Centers.

bruslifrucuthafrafraclidruswefruvebigawrechebebiclosputrapriracoswuvitamitregurowrostogithauisishipitrowustuchuhowrowrichathiuuwabusehidefrinetrespodanaclustoclohaclekamedrecliuisticrurebuwiprecacipas

NASHVILLE, TENNESSEE — Exercise has a long history in multiple sclerosis (MS). In 1838, the Scottish physician John Abercrombie reported that a patient with “a diminution of muscular power,” who could walk but only unsteadily, decided after various failed treatments like “evacuations and spare diet” to try “violent exercise.” He walked 5-6 miles on a warm evening, as quickly as he was able, and returned home “much fatigued, and considerably heated. Next morning he had severe pains in the calves of his legs, but his other complaints were much diminished, and in a few days disappeared. He has ever since enjoyed good health,” Dr. Abercrombie was quoted in Multiple Sclerosis: The History of a Disease by T. Jock Murray.

The first randomized, controlled trial of an exercise intervention for MS didn’t appear in the literature until 1988, but more than 200 have been published in the years since, according to Robert Motl, PhD, who spoke about exercise interventions for MS at the annual meeting of the Consortium of Multiple Sclerosis Centers.

bruslifrucuthafrafraclidruswefruvebigawrechebebiclosputrapriracoswuvitamitregurowrostogithauisishipitrowustuchuhowrowrichathiuuwabusehidefrinetrespodanaclustoclohaclekamedrecliuisticrurebuwiprecacipas

NASHVILLE, TENNESSEE — Exercise has a long history in multiple sclerosis (MS). In 1838, the Scottish physician John Abercrombie reported that a patient with “a diminution of muscular power,” who could walk but only unsteadily, decided after various failed treatments like “evacuations and spare diet” to try “violent exercise.” He walked 5-6 miles on a warm evening, as quickly as he was able, and returned home “much fatigued, and considerably heated. Next morning he had severe pains in the calves of his legs, but his other complaints were much diminished, and in a few days disappeared. He has ever since enjoyed good health,” Dr. Abercrombie was quoted in Multiple Sclerosis: The History of a Disease by T. Jock Murray.

The first randomized, controlled trial of an exercise intervention for MS didn’t appear in the literature until 1988, but more than 200 have been published in the years since, according to Robert Motl, PhD, who spoke about exercise interventions for MS at the annual meeting of the Consortium of Multiple Sclerosis Centers.

bruslifrucuthafrafraclidruswefruvebigawrechebebiclosputrapriracoswuvitamitregurowrostogithauisishipitrowustuchuhowrowrichathiuuwabusehidefrinetrespodanaclustoclohaclekamedrecliuisticrurebuwiprecacipas

CHICAGO — Have a great tech idea to improve gastroenterology? Start-up companies have the potential to transform the practice of medicine, and to make founders a nice pot of money, but it is a difficult road. At the 2024 AGA Tech Summit, held at the Chicago headquarters of MATTER, a global healthcare startup incubator, investors and gastroenterologists discussed some of the key challenges and opportunities for GI startups.

The road is daunting, and founders must be dedicated to their companies but also maintain life balance. “It is very easy, following your passion, for your life to get out of check. I don’t know what the divorce rate is for entrepreneurs, but I personally was a victim of that. The culture that we built was addictive and it became all encompassing, and at the same time [I neglected] my home life,” Scott Fraser, managing director of the consulting company Fraser Healthcare, said during a “Scars and Stripes” panel at the summit.

vicriswakicludrilospobishidabolupresepruchigitricoslucuthed

For those willing to navigate those waters, there is help. Investors are prepared to provide seed money for companies with good ideas and a strong market. AGA itself has stepped into the investment field with its GI Opportunity Fund, which it launched in 2022 through a partnership with Varia Ventures. The fund’s capital comes from AGA members, with a minimum investment of $25,000. To date, AGA has made investments in six companies, at around $100,000 per company. “It’s not a large amount that we’re investing. We’re a lead investor that signals to other venture capital companies that this is a viable company,” Tom Serena, CEO of AGA, said in an interview.

The fund grew out of AGA’s commitment to boosting early-stage companies in the gastroenterology space. AGA has always supported GI device and tech companies through its Center for GI Innovation and Technology, which sponsored the AGA Tech Summit. The center now provides resources and advice for GI innovators and startups. The AGA Tech Summit has created a gathering place for entrepreneurs and innovators to share their experiences and learn from one another. “But what we were missing was the last mile, which is getting funding to the companies,” said Mr. Serena. The summit itself has been modified to increase the venture capital presence. “That’s the networking we’re trying to [create] here. Venture capitalists are well acquainted with these companies, but we feel that AGA can bring clinical due diligence, and the startups want to be exposed to venture capital,” said Mr. Serena.

During the “Learn from VC Strategists” panel, investors shared advice for entrepreneurs. The emphasis throughout was on marketable ideas that can fundamentally change healthcare practice, though inventions may not have the whiz-bang appeal of some new technologies of years past.

“We’re particularly focused on clinical models that actually work. There were a lot of companies for many years that were doing things that had minimal impact, or very incremental impact. Maybe they were helping identify certain patients, but they weren’t actually engaging those patients. We’re now looking very end-to-end and trying to make sure that it’s not just a good idea, but one that you can actually roll out, engage patients, and see the [return on investment] in that patient data,” said Kelsey Maguire, managing director of the Blue Venture Fund, which is a collaborative effort across Blue Cross Blue Shield companies.

suposwauahavedrislubipichocejewuliwojaweuostochedroveswotidebrinacukepubuclicrucovuphadraphastiuevugocrislesperuluhanacrabrashiciwruchikebedrolusletestanipochusemeshikophodriwrajirohaphaslistimaracatobrufrimowadruprohutreuilocresh

Jung_Barbara_2023_web.jpg

uatredujuclecrofrotropratreslatronibaswulojasadritrenuhejohostewriwrajuproclo

lovosterasheshoslilofrotricrutejidriuobobrestiprestefrupremowivonututrolouuwuristahugucremathuduruchidawrejoslenewatritobrukigitiwritecrupeswibriwradriclegep

CHICAGO — Have a great tech idea to improve gastroenterology? Start-up companies have the potential to transform the practice of medicine, and to make founders a nice pot of money, but it is a difficult road. At the 2024 AGA Tech Summit, held at the Chicago headquarters of MATTER, a global healthcare startup incubator, investors and gastroenterologists discussed some of the key challenges and opportunities for GI startups.

The road is daunting, and founders must be dedicated to their companies but also maintain life balance. “It is very easy, following your passion, for your life to get out of check. I don’t know what the divorce rate is for entrepreneurs, but I personally was a victim of that. The culture that we built was addictive and it became all encompassing, and at the same time [I neglected] my home life,” Scott Fraser, managing director of the consulting company Fraser Healthcare, said during a “Scars and Stripes” panel at the summit.

vicriswakicludrilospobishidabolupresepruchigitricoslucuthed

For those willing to navigate those waters, there is help. Investors are prepared to provide seed money for companies with good ideas and a strong market. AGA itself has stepped into the investment field with its GI Opportunity Fund, which it launched in 2022 through a partnership with Varia Ventures. The fund’s capital comes from AGA members, with a minimum investment of $25,000. To date, AGA has made investments in six companies, at around $100,000 per company. “It’s not a large amount that we’re investing. We’re a lead investor that signals to other venture capital companies that this is a viable company,” Tom Serena, CEO of AGA, said in an interview.

The fund grew out of AGA’s commitment to boosting early-stage companies in the gastroenterology space. AGA has always supported GI device and tech companies through its Center for GI Innovation and Technology, which sponsored the AGA Tech Summit. The center now provides resources and advice for GI innovators and startups. The AGA Tech Summit has created a gathering place for entrepreneurs and innovators to share their experiences and learn from one another. “But what we were missing was the last mile, which is getting funding to the companies,” said Mr. Serena. The summit itself has been modified to increase the venture capital presence. “That’s the networking we’re trying to [create] here. Venture capitalists are well acquainted with these companies, but we feel that AGA can bring clinical due diligence, and the startups want to be exposed to venture capital,” said Mr. Serena.

During the “Learn from VC Strategists” panel, investors shared advice for entrepreneurs. The emphasis throughout was on marketable ideas that can fundamentally change healthcare practice, though inventions may not have the whiz-bang appeal of some new technologies of years past.

“We’re particularly focused on clinical models that actually work. There were a lot of companies for many years that were doing things that had minimal impact, or very incremental impact. Maybe they were helping identify certain patients, but they weren’t actually engaging those patients. We’re now looking very end-to-end and trying to make sure that it’s not just a good idea, but one that you can actually roll out, engage patients, and see the [return on investment] in that patient data,” said Kelsey Maguire, managing director of the Blue Venture Fund, which is a collaborative effort across Blue Cross Blue Shield companies.

suposwauahavedrislubipichocejewuliwojaweuostochedroveswotidebrinacukepubuclicrucovuphadraphastiuevugocrislesperuluhanacrabrashiciwruchikebedrolusletestanipochusemeshikophodriwrajirohaphaslistimaracatobrufrimowadruprohutreuilocresh

Jung_Barbara_2023_web.jpg

uatredujuclecrofrotropratreslatronibaswulojasadritrenuhejohostewriwrajuproclo

lovosterasheshoslilofrotricrutejidriuobobrestiprestefrupremowivonututrolouuwuristahugucremathuduruchidawrejoslenewatritobrukigitiwritecrupeswibriwradriclegep

CHICAGO — Have a great tech idea to improve gastroenterology? Start-up companies have the potential to transform the practice of medicine, and to make founders a nice pot of money, but it is a difficult road. At the 2024 AGA Tech Summit, held at the Chicago headquarters of MATTER, a global healthcare startup incubator, investors and gastroenterologists discussed some of the key challenges and opportunities for GI startups.

The road is daunting, and founders must be dedicated to their companies but also maintain life balance. “It is very easy, following your passion, for your life to get out of check. I don’t know what the divorce rate is for entrepreneurs, but I personally was a victim of that. The culture that we built was addictive and it became all encompassing, and at the same time [I neglected] my home life,” Scott Fraser, managing director of the consulting company Fraser Healthcare, said during a “Scars and Stripes” panel at the summit.

vicriswakicludrilospobishidabolupresepruchigitricoslucuthed

For those willing to navigate those waters, there is help. Investors are prepared to provide seed money for companies with good ideas and a strong market. AGA itself has stepped into the investment field with its GI Opportunity Fund, which it launched in 2022 through a partnership with Varia Ventures. The fund’s capital comes from AGA members, with a minimum investment of $25,000. To date, AGA has made investments in six companies, at around $100,000 per company. “It’s not a large amount that we’re investing. We’re a lead investor that signals to other venture capital companies that this is a viable company,” Tom Serena, CEO of AGA, said in an interview.

The fund grew out of AGA’s commitment to boosting early-stage companies in the gastroenterology space. AGA has always supported GI device and tech companies through its Center for GI Innovation and Technology, which sponsored the AGA Tech Summit. The center now provides resources and advice for GI innovators and startups. The AGA Tech Summit has created a gathering place for entrepreneurs and innovators to share their experiences and learn from one another. “But what we were missing was the last mile, which is getting funding to the companies,” said Mr. Serena. The summit itself has been modified to increase the venture capital presence. “That’s the networking we’re trying to [create] here. Venture capitalists are well acquainted with these companies, but we feel that AGA can bring clinical due diligence, and the startups want to be exposed to venture capital,” said Mr. Serena.

During the “Learn from VC Strategists” panel, investors shared advice for entrepreneurs. The emphasis throughout was on marketable ideas that can fundamentally change healthcare practice, though inventions may not have the whiz-bang appeal of some new technologies of years past.

“We’re particularly focused on clinical models that actually work. There were a lot of companies for many years that were doing things that had minimal impact, or very incremental impact. Maybe they were helping identify certain patients, but they weren’t actually engaging those patients. We’re now looking very end-to-end and trying to make sure that it’s not just a good idea, but one that you can actually roll out, engage patients, and see the [return on investment] in that patient data,” said Kelsey Maguire, managing director of the Blue Venture Fund, which is a collaborative effort across Blue Cross Blue Shield companies.

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