Evaluation of Carisbamate for the Treatment of Migraine
Evaluation of Carisbamate for the Treatment of Migraine
Objective: This study explored the dose-response relationship of carisbamate administered at doses of 100 mg per day, 300 mg per day, or 600 mg per day, in the prevention of migraine.
Background: Carisbamate ([S]-2-O-carbamoyl-1-o-chlorophenyl-ethanol; RWJ 333369) is a new chemical entity being studied for efficacy as adjunctive therapy in partial onset epilepsy. Because some antiepileptic drugs are also efficacious in migraine, for example, topiramate and valproate sodium, we tested carisbamate in migraine prophylaxis.
Design/Methods: This was a double-blind, placebo-controlled trial, approximately 22-week duration. The primary efficacy variable was the percent reduction from baseline through the double-blind phase in average monthly migraine frequency using a 48-hour rule. Patients were randomized 1 : 1 : 1 : 1 to treatment with carisbamate 100, 300, or 600 mg per day, or placebo. Migraine attacks were counted during a prospective 4-week baseline period, which was followed by a 2-week titration period, a 12-week maintenance period, a 1-week medication reduction period, and a 3-week observation period. Patients had an established history of migraine, with or without aura, for at least 1 year and a 3-month history of 3-12 migraine attacks per month.
Results: Patients (n = 323) were predominantly women (85%) and white (89%); mean age was 41 years. There were no statistically significant differences between any of the carisbamate groups and placebo (P ≥ .6) for the median (range) percentage reduction from baseline to end point in average monthly migraine frequency (P value vs placebo): 37% (-250%, 100%) for placebo; 33% (-210%, 100%; P = .7) CRS 100 mg/day; 27% (-100%, 100%; P = .8) CRS 300 mg/day; and 35% (-87%, 100%; P = .6) CRS 600 mg/day. Results for secondary efficacy measures (responder rate, percent reduction in average monthly migraine frequency using the 24-hour rule, and percent reduction in average monthly migraine days) were consistent (P ≥ .075). The proportion of patients discontinuing because of adverse events was similar for placebo and carisbamate-treated patients (13% each). The most common (occurring in ≥ 5% of patients) treatment-emergent adverse events in patients treated with carisbamate were fatigue (17%) and nasopharyngitis (13%). Fatigue appeared to be dose related.
Conclusions: Carisbamate was not more efficacious in migraine prophylaxis than placebo in this well-controlled study that included a suitable population. However, carisbamate monotherapy was well tolerated at doses up to 600 mg per day.
Migraine is best characterized as a chronic condition with episodic manifestations. It affects approximately 12% of adults in occidental countries. Migraine attacks are associated with a wide variety of symptoms, most notably headache, sensitivity to sensory stimuli, nausea, and vomiting. While individual attacks have the potential to produce significant impairment, the true impact of migraine is measured in the accumulated disability incurred through decades of repeated migraine attacks.
The pattern and frequency of migraine can change significantly over time. For many, migraine remains a relatively infrequent episodic condition that typically diminishes in frequency and severity by the 5th and 6th decades of life. For many others, however, migraine at some point increases in frequency, becomes chronic, and takes on characteristics of a disease state. Frequent and chronic migraine can spontaneously improve but, more often, evolves into a disabling condition with significant disability and a high risk for medication overuse. Preventive pharmacology plays a pivotal role in decreasing the frequency of migraine attacks and possibly limiting the progression of episodic to chronic migraine.
Unfortunately, pharmacologic agents used to prevent migraine are underutilized in clinical practice. A recent large epidemiologic study of migraine sufferers in the United States suggested that while at least 26% of people suffering with migraine met criteria for preventive pharmacology only 13% of migraine sufferers were utilizing preventive medications. Further, most migraine sufferers utilize acute treatment medications to the exclusion of preventive pharmacology. Reasons for this underutilization of preventive migraine medications are varied, but include marginal clinical benefit and potential adverse events. Consequently, there is a clinical need to find medications with high efficacy and good tolerability for prevention of migraine.
Divalproate sodium and topiramate, both antiepileptic medications, have received regulatory approval for migraine prevention in the US and topiramate is approved for migraine prevention in Europe. Other antiepileptic drugs (AEDs) have been studied in smaller trials and several, though not all, studies have suggested positive benefits of AEDs as migraine prophylactic medications. Interestingly, lamotrigine has demonstrated benefit in preventing aura. The mechanisms by which AEDs confer benefit in migraine are not completely understood and it appears that simply having benefit in epilepsy does not guarantee therapeutic efficacy in migraine.
Carisbamate ([S]-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a new chemical entity that is being studied for efficacy as adjunctive therapy in partial onset epilepsy and for prophylaxis of migraine. The mechanism of action is unknown, despite comprehensive receptor binding and functional assays, but appears to be unique from that known to other anticonvulsant agents. Pharmacokinetic studies in humans indicate rapid and complete absorption, moderate protein binding, linear dose proportionality between 100 and 1500 mg for single doses, and an elimination half-life of approximately 12 hours allowing for twice daily dosing. The major biotransformation pathways for carisbamate are direct glucuronidation and hydrolysis of the carbamate ester followed by oxidation of the aliphatic side chain. It is not metabolized by the cytochrome P450 system. Carisbamate showed a broad spectrum of activity in rodent seizure and epilepsy models. Proof of concept of carisbamate as an AED was seen in a photosensitivity model and a phase II clinical trial demonstrated carisbamate's efficacy as adjunctive therapy for partial onset seizures. The present study explored the dose to response relationship of carisbamate in prevention of migraine at doses of 100, 300, and 600 mg per day vs placebo.
Abstract and Introduction
Abstract
Objective: This study explored the dose-response relationship of carisbamate administered at doses of 100 mg per day, 300 mg per day, or 600 mg per day, in the prevention of migraine.
Background: Carisbamate ([S]-2-O-carbamoyl-1-o-chlorophenyl-ethanol; RWJ 333369) is a new chemical entity being studied for efficacy as adjunctive therapy in partial onset epilepsy. Because some antiepileptic drugs are also efficacious in migraine, for example, topiramate and valproate sodium, we tested carisbamate in migraine prophylaxis.
Design/Methods: This was a double-blind, placebo-controlled trial, approximately 22-week duration. The primary efficacy variable was the percent reduction from baseline through the double-blind phase in average monthly migraine frequency using a 48-hour rule. Patients were randomized 1 : 1 : 1 : 1 to treatment with carisbamate 100, 300, or 600 mg per day, or placebo. Migraine attacks were counted during a prospective 4-week baseline period, which was followed by a 2-week titration period, a 12-week maintenance period, a 1-week medication reduction period, and a 3-week observation period. Patients had an established history of migraine, with or without aura, for at least 1 year and a 3-month history of 3-12 migraine attacks per month.
Results: Patients (n = 323) were predominantly women (85%) and white (89%); mean age was 41 years. There were no statistically significant differences between any of the carisbamate groups and placebo (P ≥ .6) for the median (range) percentage reduction from baseline to end point in average monthly migraine frequency (P value vs placebo): 37% (-250%, 100%) for placebo; 33% (-210%, 100%; P = .7) CRS 100 mg/day; 27% (-100%, 100%; P = .8) CRS 300 mg/day; and 35% (-87%, 100%; P = .6) CRS 600 mg/day. Results for secondary efficacy measures (responder rate, percent reduction in average monthly migraine frequency using the 24-hour rule, and percent reduction in average monthly migraine days) were consistent (P ≥ .075). The proportion of patients discontinuing because of adverse events was similar for placebo and carisbamate-treated patients (13% each). The most common (occurring in ≥ 5% of patients) treatment-emergent adverse events in patients treated with carisbamate were fatigue (17%) and nasopharyngitis (13%). Fatigue appeared to be dose related.
Conclusions: Carisbamate was not more efficacious in migraine prophylaxis than placebo in this well-controlled study that included a suitable population. However, carisbamate monotherapy was well tolerated at doses up to 600 mg per day.
Introduction
Migraine is best characterized as a chronic condition with episodic manifestations. It affects approximately 12% of adults in occidental countries. Migraine attacks are associated with a wide variety of symptoms, most notably headache, sensitivity to sensory stimuli, nausea, and vomiting. While individual attacks have the potential to produce significant impairment, the true impact of migraine is measured in the accumulated disability incurred through decades of repeated migraine attacks.
The pattern and frequency of migraine can change significantly over time. For many, migraine remains a relatively infrequent episodic condition that typically diminishes in frequency and severity by the 5th and 6th decades of life. For many others, however, migraine at some point increases in frequency, becomes chronic, and takes on characteristics of a disease state. Frequent and chronic migraine can spontaneously improve but, more often, evolves into a disabling condition with significant disability and a high risk for medication overuse. Preventive pharmacology plays a pivotal role in decreasing the frequency of migraine attacks and possibly limiting the progression of episodic to chronic migraine.
Unfortunately, pharmacologic agents used to prevent migraine are underutilized in clinical practice. A recent large epidemiologic study of migraine sufferers in the United States suggested that while at least 26% of people suffering with migraine met criteria for preventive pharmacology only 13% of migraine sufferers were utilizing preventive medications. Further, most migraine sufferers utilize acute treatment medications to the exclusion of preventive pharmacology. Reasons for this underutilization of preventive migraine medications are varied, but include marginal clinical benefit and potential adverse events. Consequently, there is a clinical need to find medications with high efficacy and good tolerability for prevention of migraine.
Divalproate sodium and topiramate, both antiepileptic medications, have received regulatory approval for migraine prevention in the US and topiramate is approved for migraine prevention in Europe. Other antiepileptic drugs (AEDs) have been studied in smaller trials and several, though not all, studies have suggested positive benefits of AEDs as migraine prophylactic medications. Interestingly, lamotrigine has demonstrated benefit in preventing aura. The mechanisms by which AEDs confer benefit in migraine are not completely understood and it appears that simply having benefit in epilepsy does not guarantee therapeutic efficacy in migraine.
Carisbamate ([S]-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a new chemical entity that is being studied for efficacy as adjunctive therapy in partial onset epilepsy and for prophylaxis of migraine. The mechanism of action is unknown, despite comprehensive receptor binding and functional assays, but appears to be unique from that known to other anticonvulsant agents. Pharmacokinetic studies in humans indicate rapid and complete absorption, moderate protein binding, linear dose proportionality between 100 and 1500 mg for single doses, and an elimination half-life of approximately 12 hours allowing for twice daily dosing. The major biotransformation pathways for carisbamate are direct glucuronidation and hydrolysis of the carbamate ester followed by oxidation of the aliphatic side chain. It is not metabolized by the cytochrome P450 system. Carisbamate showed a broad spectrum of activity in rodent seizure and epilepsy models. Proof of concept of carisbamate as an AED was seen in a photosensitivity model and a phase II clinical trial demonstrated carisbamate's efficacy as adjunctive therapy for partial onset seizures. The present study explored the dose to response relationship of carisbamate in prevention of migraine at doses of 100, 300, and 600 mg per day vs placebo.