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The Impact of OnabotulinumtoxinA vs. Placebo on Efficacy Outcomes in Headache Day Responder and Nonresponder Patients with Chronic Migraine.

ABSTRACT: INTRODUCTION:The phase 3 PREEMPT trials demonstrated efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. OnabotulinumtoxinA significantly reduced headache frequency from baseline vs. placebo at 24 weeks; however, this measure may not fully capture the benefits of treatment. We evaluated the impact of onabotulinumtoxinA on patient-reported outcomes according to headache responder status. METHODS:A post hoc analysis pooled 24-week data from the placebo-controlled, randomized, double-blind treatment phases of the PREEMPT trials. Patients were stratified by randomized treatment (onabotulinumtoxinA vs. placebo) and headache day responder status (responder vs. nonresponder). Headache day responders had a???50% headache day reduction from baseline measured at weeks 21-24. Outcomes evaluated were patient-reported reductions in moderate-to-severe headache days, Headache Impact Test, and Migraine-Specific Quality of Life Questionnaire. Missing values were estimated using a modified last-observation-carried-forward approach. RESULTS:In the pooled analysis population (N?=?1384; onabotulinumtoxinA, n?=?688; placebo, n?=?696), headache day responder rates were 308/688 (45%) for onabotulinumtoxinA- and 238/696 (34%) for placebo-treated patients. At 24 weeks compared with baseline, onabotulinumtoxinA nonresponders showed significantly (all P?

SUBMITTER: Silberstein SD

PROVIDER: S-EPMC7648816 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The Impact of OnabotulinumtoxinA vs. Placebo on Efficacy Outcomes in Headache Day Responder and Nonresponder Patients with Chronic Migraine.

Silberstein Stephen D SD Diener Hans-Christoph HC Dodick David W DW Manack Adams Aubrey A DeGryse Ronald E RE Lipton Richard B RB

Pain and therapy 20201007 2

<h4>Introduction</h4>The phase 3 PREEMPT trials demonstrated efficacy and tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. OnabotulinumtoxinA significantly reduced headache frequency from baseline vs. placebo at 24 weeks; however, this measure may not fully capture the benefits of treatment. We evaluated the impact of onabotulinumtoxinA on patient-reported outcomes according to headache responder status.<h4>Methods</h4>A post hoc analysis pooled 24-week ...[more]

PMID: 33026630

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Project description:ObjectiveTo compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention.BackgroundThe efficacy* of onabotulinumtoxinA and topiramate has been established in placebo-controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real-world conditions, representing a blend of efficacy and tolerability).MethodsIn this multicenter, randomized, parallel-group, post-authorization, open-label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate "immediate release" 50-100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29-32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs).ResultsWe enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 [86%]; topiramate, n = 28 [20%]). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 [5%]; topiramate, n = 27 [19%]) and AEs (onabotulinumtoxinA, n = 5 [4%]; topiramate, n = 72 [51%]). Eighty topiramate patients crossed over to onabotulinumtoxinA. In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% [56/140] vs 12% [17/142], respectively; adjusted OR, 4.9 [95% CI, 2.7-9.1]; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA.ConclusionsWhile using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment.

Project description:INTRODUCTION/OBJECTIVE:Chronic migraine (CM) is associated with impaired health-related quality of life and substantial socioeconomic burden, but many people with CM are underdiagnosed and do not receive appropriate preventive treatment. OnabotulinumtoxinA and topiramate have demonstrated efficacy (treatment benefit under ideal conditions) for the prevention of headaches in people with CM in clinical trials, but real-world studies suggest markedly different clinical effectiveness (treatment benefit based on a blend of efficacy and tolerability). This study sought to evaluate patient-reported outcomes (PROs) of onabotulinumtoxinA versus topiramate immediate release for people with CM. METHODS:FORWARD was a prospective, multicenter, randomized, parallel-group, open-label, phase 4 study comparing onabotulinumtoxinA 155 U every 12?weeks with topiramate 50 to 100?mg/day for ?36?weeks in people with CM. PROs measured included the Headache Impact Test (HIT-6), 9-item Patient Health Questionnaire Quick Depression Assessment (PHQ-9), Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP), and Functional Impact of Migraine Questionnaire (FIMQ). RESULTS:A total of 282 patients were randomized and treated with onabotulinumtoxinA (n?=?140) or topiramate (n?=?142). From baseline to week 30, mean HIT-6 test scores improved significantly in patients taking onabotulinumtoxinA compared with topiramate (P?<?.001). Improvements in depression over time were observed via larger changes in PHQ-9 scores with onabotulinumtoxinA than topiramate (P?<?.001). Work productivity assessed via WPAI:SHP scores revealed significant improvements with onabotulinumtoxinA versus topiramate in Work Productivity Loss (P?=?.024) and Activity Impairment (P?<?.001) domains. Results from the FIMQ also revealed a larger reduction from baseline with onabotulinumtoxinA vs topiramate (P?<?.0001). CONCLUSION:OnabotulinumtoxinA treatment had more favorable real-world effectiveness than topiramate on depression, headache impact, functioning and daily living, activity, and work productivity. The overall study results suggest that the beneficial effects on a range of PROs are the result of improved effectiveness when onabotulinumtoxinA is used as preventive treatment for CM. TRIAL REGISTRATION: CLINICALTRIALS.GOV:NCT02191579; https://clinicaltrials.gov/ct2/show/NCT02191579.

Project description:BackgroundOnabotulinumtoxinA is effective in preventing chronic migraine (CM); however, the benefit of onabotulinumtoxinA in patients with CM with daily headache is unknown because these patients are typically excluded from clinical trials. This subanalysis of the COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without daily headache.MethodsIn total, 715 patients received onabotulinumtoxinA 155 U with or without concomitant oral preventive treatment. Patients who had complete daily diary records for the 28 days of the baseline period were stratified based on daily headache status. The primary outcome variable was reduction in headache-day frequency per 28-day period at 108 weeks (after 9 treatment cycles) relative to baseline. Exploratory outcomes included moderate to severe headache days, migraine disability (using the Migraine Disability Assessment [MIDAS] questionnaire), and health-related quality of life (Migraine-Specific Quality-of-Life Questionnaire v2 [MSQ]). Adverse events and their relatedness were recorded.ResultsOverall, 641 patients had complete daily diary records at baseline. In patients with daily headache (n = 138) versus without (n = 503), treatment with onabotulinumtoxinA was associated with a significant mean (SD) reduction in 28-day headache-day frequency relative to baseline at week 108 (- 10.5 [9.2] vs - 12.2 [6.7], respectively; both P < 0.001) with no significant between-group difference (P = 0.132). The mean (SD) reduction in moderate to severe headache days at week 108 was significant in patients with and without daily headache (- 11.5 [9.4] and - 9.9 [6.4]; P < 0.001) with no significant between-group difference (P = 0.153). Mean (SD) MIDAS scores significantly improved from baseline at week 108 (- 43.3 [73.4] and - 43.6 [46.7]; both P < 0.001), with no significant between-group difference (P = 0.962). Similarly, mean (SD) MSQ subscale scores significantly improved from baseline at week 108 for patients with and without daily headache. OnabotulinumtoxinA was well tolerated in patients with and without daily headache.ConclusionResults indicate that onabotulinumtoxinA is associated with reductions from baseline in headache-day frequency and improvements in disability and quality of life for up to 108 weeks in people with CM with daily headache; however, a longer duration of treatment was required to fully realize the treatment effect on headache. No new safety concerns were identified.

Project description:BACKGROUND:Chronic migraine is a neurological condition with a large individual and socioeconomic burden of disease. The recently completed Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical development program established the efficacy and safety of onabotulinumtoxinA as a prophylactic treatment for chronic migraine patients. However, clinical questions remain. A long-term evaluation study of onabotulinumtoxinA aims to address some of the remaining questions in the treatment of chronic migraine. The clinical rationale, study design, and treatment plan of this ongoing study are reviewed in this paper. METHODS/DESIGN:The Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) study will enroll approximately 500 adult patients with chronic migraine at international sites. Patients will be evaluated over 108 weeks, following a 4-week baseline period. Qualified subjects will receive 155 U of onabotulinumtoxinA every 12 weeks for 9 open-label cycles. The primary endpoint will be mean change from baseline in frequency of headache days at 108 weeks. Other endpoints will include additional assessments of the efficacy and safety of onabotulinumtoxinA and the effect of onabotulinumtoxinA on quality-of-life measures, disability, and health economic outcomes. The impact of onabotulinumtoxinA on common comorbidities (eg, sleep, anxiety, and fatigue) will also be assessed. DISCUSSION:Recruitment and enrollment are ongoing. Post-approval, open-label studies are often designed to more closely resemble clinical practice and provide an opportunity to continue the evaluation of the efficacy and safety of approved treatments. By creating a large database and analyzing a variety of outcome measures over an extended time frame, the COMPEL study will seek to contribute substantially to the existing knowledge of the chronic migraine population and the long-term management of this debilitating disorder. CLINICAL TRIAL REGISTRATION NUMBER:NCT01516892.

Project description:BackgroundOnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is desirable.MethodsThe Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) Study ( ClinicalTrials.gov , NCT01516892) is an international, multicenter, open-label long-term prospective study. Adults with CM received 155 U of onabotulinumtoxinA (31 sites in a fixed-site, fixed-dose paradigm across 7 head/neck muscles) every 12 weeks (±7 days) for 9 treatment cycles (108 weeks). The primary outcome was headache day reductions at 108 weeks; secondary outcomes were headache day reductions at 60 weeks and change in the 6-item Headache Impact Test (HIT-6) score. Safety and tolerability were assessed by reviewing the frequency and nature of adverse events (AEs). AEs were determined at each visit through patient self-report, general non-directed and, for specific AEs, directed questioning, and physical examination. Subgroup analyses for safety and efficacy included, but were not limited to, patients with/without concomitant oral preventive treatment and acute medication overuse at baseline.ResultsEnrolled patients (N = 716) were 18-73 years old and most were female (n = 607, 84.8%). At baseline, patients reported an average 22.0 (SD = 4.8) headache days per month. 52.1% of patients (n = 373) completed the study. By 60 and 108 weeks, a significant reduction in headache days (- 9.2 days and - 10.7 days, respectively, P < 0.0001) was observed. Significant improvements (P < 0.0001) in HIT-6 scores (- 7.1 point change at week 108) were also demonstrated. 131 patients (18.3%) reported ≥1 treatment-emergent adverse events; most frequently reported was neck pain (n = 29, 4.1%). One patient reported a serious treatment-related adverse event (rash). No deaths were reported.ConclusionsThe COMPEL Study provides additional clinical evidence for the consistency of the efficacy and for the long-term safety and tolerability of onabotulinumtoxinA for the prevention of headache in those with CM who have been treated with onabotulinumtoxinA every 12 weeks over 2 years (9 treatments) with the fixed-site, fixed-dose injection paradigm.Trial registrationTrial registration number: NCT01516892 . Name of registry: clinicaltrials.gov . Date of registration: January 20 2012. Date of enrollment of first patient: December 2011.

Project description:Aims:Migraine is a global phenomenon, affecting more than 10% of the world's population. It is characterized by unilateral headache that may be accompanied by vomiting, nausea, photophobia and phonophobia. Some patients with chronic migraine respond to extra-cranial botulinum toxin type A injection, although the benefits observed are temporary. The rationale for surgical trigger site deactivation is to achieve lasting symptomatic improvement or permanent relief from migraine. Methods:We performed a PRISMA-compliant systematic review of clinical studies evaluating surgical intervention for migraine by searching Ovid MEDLINE and EMBASE databases from inception to June 2017. Studies were independently screened by two authors. Data were extracted on study characteristics, migraine outcomes, adverse events and recurrence. The quality of evidence was assessed using the GRADE approach. The review protocol was prospectively registered on the PROSPERO database (CRD42017068577). Results:The search strategy identified 789 articles; of them, 18 studies (4 RCTs and 14 case series) were eligible for analysis. Surgical interventions were heterogeneous and variably involved peripheral nerve decompression by myectomy or foraminotomy, nerve excision, artery resection and/or nasal surgery. All studies reported significant reductions in migraine intensity, frequency, duration and composite headache scores following surgery. Study heterogeneity precluded formal meta-analysis. Where reported, adverse event rates varied markedly between studies. The quality of included studies was consistently low or very low. Conclusion:There is insufficient evidence to support the effectiveness of any specific surgical intervention for chronic migraine, especially with regard to permanent relief; however, all included studies report improvements in key outcomes following migraine surgery. A definitive, well-powered RCT with objective surgical and patient-reported outcome measures and robust adverse event reporting is required.

Project description:ObjectiveTo examine the influences of depression and anxiety on headache-related disability in people with episodic migraine or chronic migraine.BackgroundDepression and anxiety are common comorbidities in people with migraine, especially among those with chronic migraine.MethodsThis cross-sectional analysis of data from the longitudinal, internet-based Chronic Migraine Epidemiology and Outcomes Study assessed sociodemographic and headache features, and headache-related disability (Migraine Disability Assessment Scale). Four groups were defined based on scores from validated screeners for depression (9-item Patient Health Questionnaire) and anxiety (7-item Generalized Anxiety Disorder Scale): depression alone, anxiety alone, both, or neither.ResultsRespondents (N = 16,788) were predominantly women (74.4% [12,494/16,788]) and white (84.0% [14,044/16,788]); mean age was 41 years. Depression was more likely in persons with chronic migraine vs episodic migraine (56.6% [836/1476] vs 30.0% [4589/15,312]; P < .001), as were anxiety (48.4% [715/1476] vs 28.1% 4307/15,312]; P < .001) and coexisting depression and anxiety (42.0% [620/1476] vs 20.8% [3192/15,312]; P < .001). After controlling for headache frequency and other covariates, depression alone, and anxiety alone were associated with 56.0% (rate ratio [RR], 1.56; 95% confidence interval [CI], 1.46-1.66) and 39.0% (RR, 1.39; 95% CI, 1.30-1.50) increased risks of moderate/severe migraine-related disability (both P < .001), respectively; the combination had an even greater effect on risk of moderate/severe disability (79.0% increase; RR, 1.79; 95% CI, 1.71-1.87; P < .001).ConclusionsDepression alone and anxiety alone are associated with greater headache-related disability after controlling for sociodemographic and headache features. Coexisting depression and anxiety are more strongly associated with disability than either comorbidity in isolation. Interventions targeting depression and anxiety as well as migraine itself may improve headache-related disability in people with migraine.

Dataset Information

The Impact of OnabotulinumtoxinA vs. Placebo on Efficacy Outcomes in Headache Day Responder and Nonresponder Patients with Chronic Migraine.

Publications

The Impact of OnabotulinumtoxinA vs. Placebo on Efficacy Outcomes in Headache Day Responder and Nonresponder Patients with Chronic Migraine.

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