Paul Winner

Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial

BACKGROUND Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. METHODS In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936. FINDINGS 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0.0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0.0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0.0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0.0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0.0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. INTERPRETATION Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. FUNDING Merck Research Laboratories.

A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents.

Objective. To compare the efficacy and tolerability of sumatriptan nasal spray (NS; 5 mg, 10 mg, and 20 mg) with placebo for the treatment of acute migraine in adolescents. Methods. A randomized, double-blind, placebo-controlled, single-attack study was conducted in 653 US adolescents (12–17 years of age). Patients with at least a 6-month history of migraine, who met International Headache Society criteria for migraine (with or without aura) were eligible for participation. Headache relief 2 hours postdose, complete relief, presence or absence of associated symptoms, headache recurrence, and use of rescue medications were recorded. The primary efficacy endpoint was headache relief 2 hours postdose sumatriptan NS (20 mg) versus placebo. Safety and tolerability were assessed by examining adverse events, changes in electrocardiograms, vital signs, physical examinations, and clinical laboratory tests. Results. Headache relief 1 hour postdose was significantly greater for patients using 10 mg (56%) and 20 mg (56%) of sumatriptan NS compared with placebo (41%). Headache relief 2 hours postdose was significantly greater for patients using 5 mg of sumatriptan NS (66%) compared with placebo (53%), and approached statistical significance for 20 mg (63%) compared with placebo (53%). Complete relief 2 hours postdose was significantly greater for patients using 20 mg of sumatriptan NS compared with placebo (36% vs 25%, respectively). Each dose of sumatriptan (5 mg, 10 mg, and 20 mg) was superior to placebo with respect to the cumulative percentages of patients first reporting headache relief within 2 hours of dosing (Kaplan-Meier). The sumatriptan 20-mg dose was superior to placebo with respect to the cumulative percentages of patients first reporting complete relief within 2 hours of dosing (Kaplan-Meier). Photophobia and phonophobia were significantly reduced 2 hours postdose for sumatriptan NS (20 mg), compared with placebo (36% vs 48% and 25% vs 44%, respectively). Taste disturbance was the most commonly reported adverse event (2%, 19%, 30%, and 26% for placebo, 5 mg, 10 mg, and 20 mg, respectively). No drug-related serious adverse events or clinically relevant changes in laboratory parameters, electrocardiograms, or vital signs were reported. Conclusions. Sumatriptan NS is effective and well-tolerated for the treatment of acute migraine in adolescents, with the 20-mg dose providing the best overall efficacy and tolerability profiles.

A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis

Objective To evaluate the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment of migraine headache. Methods This was a double-blind, randomized, placebo-controlled, parallel-group study. Subjects with more than two migraine headache attacks during a 4-week baseline were randomly assigned in a 1:1 ratio at each center to receive either extended-release divalproex sodium or matching placebo once daily for 12 weeks. Subjects initiated treatment on 500 mg once daily for 1 week, and the dose was then increased to 1,000 mg once daily with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. Reduction from baseline in 4-week migraine headache rate was the primary efficacy variable. Migraine headaches separated by a <24-hour headache-free interval were counted as single migraines in calculating migraine headache rates. Tolerance and safety were also evaluated. Results The mean reductions in 4-week migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extended-release divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p = 0.006); reductions with extended-release divalproex sodium were significantly greater than with placebo in all three 4-week segments of the treatment period. No significant differences were detected between treatment groups in either the overall incidence or in the incidence of any specific treatment-emergent adverse event; 8% of subjects treated with extended-release divalproex sodium and 9% of those treated with placebo discontinued for adverse events. Conclusion Extended-release divalproex sodium is an efficacious, well-tolerated, safe, and easy-to-use once-a-day prophylactic antimigraine medication.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders

Objective: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. Methods: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders–IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. Results: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (–5.5 ± 6.9 vs –3.0 ± 8.7, p = 0.063) and Tic Symptom Self-Report total score (–4.7 ± 6.5 vs –2.9 ± 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (–0.7 ± 1.2 vs –0.1 ± 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (–10.9 ± 10.9 vs –4.9 ± 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (–0.8 ± 1.1 vs –0.3 ± 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. Conclusions: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Analyses of the 56-Week PREEMPT Clinical Program

Objective.— To evaluate safety and efficacy of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine.

Topiramate for Migraine Prevention in Children: A Randomized, Double-Blind, Placebo-Controlled Trial

Objective.—To assess the efficacy and safety of topiramate for the prevention of pediatric migraine with or without aura in a double‐blind, randomized, placebo‐controlled trial.

Chronic Daily Headache Prophylaxis With Tizanidine: A Double‐Blind, Placebo‐Controlled, Multicenter Outcome Study

Objective.—To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension‐type headache).

Rizatriptan 5 mg for the acute treatment of migraine in adolescents: A randomized, double-blind, placebo-controlled study

Objective.—To investigate the tolerability and efficacy of rizatriptan 5 mg in adolescent migraineurs.

Use of the ICHD-II criteria in the diagnosis of pediatric migraine

Objective.—To evaluate the sensitivity of the new International Classification of Headache Disorders‐2nd edition (ICHD‐II) criteria in the diagnosis of childhood migraine and to propose specific criteria for the diagnosis of childhood migraine.

Migraine in adolescents Association with socioeconomic status and family history

Objective: The influence of socioeconomic status on the prevalence of migraine is unknown in adolescents. Accordingly, we investigated the prevalence of migraine in a large sample of adolescents by sociodemographic features. Methods: A validated headache questionnaire was mailed to 120,000 households representative of the US population. All individuals in the household were interviewed (probands and their parents). We calculated sex-specific prevalence estimates of migraine in adolescents derived by age, race, urban vs rural residence, household income, region of the country, and parental status of migraine, using log-linear models. Results: A total of 32,015 adolescents were identified. Surveys were returned by 18,714 of them (58.4% response rate).The 1-year prevalence of migraine was 6.3% (5.0% in boys and 7.7% in girls). The prevalence was higher in girls than in boys older than 12 and in whites than African Americans. In families with an annual income lower than