OnabotulinumtoxinA and Topiramate for Chronic Migraine
Objective.— This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM).
Methods.— A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4-week baseline period and a 12-week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache-free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12-week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26.
Results.— This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within-group finding.
Conclusion.— OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.
Historically migraine has been considered an episodic pain syndrome. As such, treatment has largely focused on terminating or ameliorating symptoms associated with the acute event of migraine. To this point during the 1980s and 1990s the Food and Drug Administration (FDA) approved 9 drugs for acute treatment of migraine but only divalproate sodium was approved for migraine prevention. As an understanding of the chronic nature of migraine has evolved, the importance of preventive therapy has become increasingly evident. Consequently, there have been several clinical trials of preventive therapy for migraine within the last decade, which has led to FDA approval of a second anti-epileptic medication (AED) for the prevention of migraine, topiramate in 2003. Curiously other AED medications failed to demonstrate efficacy in preventing migraine despite presumed advances in understanding migraine pathophysiology. Whether this reflects limitations in our scientific understanding of the biology of migraine prevention, or the methodological limitations in designing successful and meaningful clinical trials of pharmacological agents for migraine prevention or both, is a matter of debate.
OnabotulinumtoxinA (botulinum toxin type A) was first reported to prevent migraine by Binder in 1991. Since that time, numerous clinical trials have been conducted with onabotulinumtoxinA yielding mixed results. The American Association of Neurology published a consensus paper in 2008 suggesting that onabotulinumtoxinA was ineffective as a migraine preventive for episodic migraine and inconclusive for chronic migraine (CM). Since then, Dodick, Aurora, and Diener reported that in 2 large separate parallel studies on subjects with CM, statistically significant efficacy for onabotulinumtoxinA over placebo. Ensuing debate has challenged whether the findings of this study are truly clinically relevant although a statistical measure of meaningful clinical relevance has yet been defined. More recently, onabotulinumtoxinA has been licensed by the Medicine and Healthcare Products Regulatory Agency in the UK for the prophylaxis of headaches in adults who have CM. This may suggest that the debate over the migraine preventive potential of onabotulinumtoxinA in CM is becoming less ambiguous.
The study presented here is designed to approximate clinical decision making and assimilation of risks and benefits that clinicians use to assess migraine preventive medication in the "real world" clinical care of migraine patients. The primary endpoint in this study is a Global Physician Assessment based on interviews and diary analyses between investigator and subject. The authors believe that this methodology permits a more integrated and relevant evaluation of efficacy than simply a P value of prespecified endpoints. Historically endpoints, such as the number of migraine episodes or headache days in a specified time period, have stood as the gold standard for success of migraine preventive therapy yet interestingly evidence for these endpoints being clinically meaningful are largely based on consensus. To this end, the study presented is an effort to help augment and clarify what has been a murky and often inconclusive exploration of onabotulinumtoxinA in the prevention of migraine.
Abstract and Introduction
Abstract
Objective.— This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM).
Methods.— A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4-week baseline period and a 12-week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache-free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12-week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26.
Results.— This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within-group finding.
Conclusion.— OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.
Introduction
Historically migraine has been considered an episodic pain syndrome. As such, treatment has largely focused on terminating or ameliorating symptoms associated with the acute event of migraine. To this point during the 1980s and 1990s the Food and Drug Administration (FDA) approved 9 drugs for acute treatment of migraine but only divalproate sodium was approved for migraine prevention. As an understanding of the chronic nature of migraine has evolved, the importance of preventive therapy has become increasingly evident. Consequently, there have been several clinical trials of preventive therapy for migraine within the last decade, which has led to FDA approval of a second anti-epileptic medication (AED) for the prevention of migraine, topiramate in 2003. Curiously other AED medications failed to demonstrate efficacy in preventing migraine despite presumed advances in understanding migraine pathophysiology. Whether this reflects limitations in our scientific understanding of the biology of migraine prevention, or the methodological limitations in designing successful and meaningful clinical trials of pharmacological agents for migraine prevention or both, is a matter of debate.
OnabotulinumtoxinA (botulinum toxin type A) was first reported to prevent migraine by Binder in 1991. Since that time, numerous clinical trials have been conducted with onabotulinumtoxinA yielding mixed results. The American Association of Neurology published a consensus paper in 2008 suggesting that onabotulinumtoxinA was ineffective as a migraine preventive for episodic migraine and inconclusive for chronic migraine (CM). Since then, Dodick, Aurora, and Diener reported that in 2 large separate parallel studies on subjects with CM, statistically significant efficacy for onabotulinumtoxinA over placebo. Ensuing debate has challenged whether the findings of this study are truly clinically relevant although a statistical measure of meaningful clinical relevance has yet been defined. More recently, onabotulinumtoxinA has been licensed by the Medicine and Healthcare Products Regulatory Agency in the UK for the prophylaxis of headaches in adults who have CM. This may suggest that the debate over the migraine preventive potential of onabotulinumtoxinA in CM is becoming less ambiguous.
The study presented here is designed to approximate clinical decision making and assimilation of risks and benefits that clinicians use to assess migraine preventive medication in the "real world" clinical care of migraine patients. The primary endpoint in this study is a Global Physician Assessment based on interviews and diary analyses between investigator and subject. The authors believe that this methodology permits a more integrated and relevant evaluation of efficacy than simply a P value of prespecified endpoints. Historically endpoints, such as the number of migraine episodes or headache days in a specified time period, have stood as the gold standard for success of migraine preventive therapy yet interestingly evidence for these endpoints being clinically meaningful are largely based on consensus. To this end, the study presented is an effort to help augment and clarify what has been a murky and often inconclusive exploration of onabotulinumtoxinA in the prevention of migraine.
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