Jan Klatt

A Double-Blind, Randomized, Placebo/Active Controlled Crossover Evaluation of the Efficacy and Safety of Ritalin® LA in Children with Attention-Deficit/Hyperactivity Disorder in a Laboratory Classroom Setting

OBJECTIVES The primary objective of this study was to demonstrate efficacy of Ritalin(®) LA 20 mg by showing superiority to placebo and noninferiority to Medikinet(®) Retard in a laboratory classroom setting. Secondary objectives included safety/tolerability and further efficacy parameters. METHODS A total of 147 children with attention-deficit/hyperactivity disorder (ADHD) diagnosed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and aged 6-14 (81% males) and known to be methylphenidate (MPH) responders were enrolled in this multicenter, double-blind, randomized, placebo/active-controlled, three-period (7 days each) crossover study. The Swanson, Kotlin, Agler, M-Flynn, and Pelham (SKAMP) scale was used for efficacy ratings. The mean of SKAMP Combined ratings performed at 10:30 a.m., at 12:00 a.m., and at 1:30 p.m. was defined as the primary parameter. RESULTS In all, 146 patients completed all treatment periods. Intensity and frequency of adverse events were comparable between the two formulations. Ritalin(®) LA demonstrated superiority compared to placebo (p<0.0001). The observed difference in the SKAMP scores between Ritalin(®) LA and Medikinet(®) Retard between the hours 1.5 until 4.5 did not exceed the noninferiority margin (p=0.0003); therefore, the difference is regarded as not clinically relevant. Similar results were obtained for the secondary efficacy variables. CONCLUSION Ritalin(®) LA is an efficacious, well-tolerated treatment option for children aged 6-14 with ADHD.

Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study

BACKGROUND A substantial proportion of patients with migraine does not respond to, or cannot tolerate, oral preventive treatments. Erenumab is a novel CGRP-receptor antibody with preventive efficacy in migraine. We assessed its efficacy and tolerability in patients with episodic migraine in whom previous treatment with two-to-four migraine preventives had been unsuccessful. METHODS LIBERTY was a 12-week, double-blind, placebo-controlled randomised study at 59 sites in 16 countries. Eligible patients were aged 18-65 years and had a history of episodic migraine with or without aura for at least 12 months, had migraine for an average of 4-14 days per month during the 3 months before screening, and had been treated unsuccessfully (in terms of either efficacy or tolerability, or both) with between two and four preventive treatments. Eligible participants were randomly assigned (1:1) to receive either erenumab 140 mg (via two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks. Randomisation was by interactive response technology and was stratified by monthly frequency of migraine headache (4-7 vs 8-14 migraine days per month) during the baseline phase. Cenduit generated the randomisation list and assigned participants to groups. Participants, investigators, people doing various assessments, and the study sponsor were masked to treatment assignment. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in the mean number of monthly migraine days during weeks 9-12. Efficacy was measured in the full analysis set, which included all randomly assigned patients who started their assigned treatment and completed at least one post-baseline monthly migraine day measurement. Safety and tolerability were assessed by recording adverse events and by physical examination, assessment of vital signs, clinical laboratory assessments, and electrocardiography. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT03096834. The trial is closed to new participants, but the open-label extension phase is ongoing. FINDINGS Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of 246 (39%) participants had previously unsuccessfully tried two preventive drugs, 93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%) patients in the erenumab had a 50% or greater reduction from baseline in the mean number of monthly migraine days, compared with 17 (14%) in the placebo group (odds ratio 2·7 [95% CI 1·4-5·2]; p=0·002). The tolerability and safety profiles of erenumab and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven (6%) participants in both groups. INTERPRETATION Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options. FUNDING Novartis Pharma.

Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study:

Background Erenumab was effective and well tolerated in a pivotal clinical trial of chronic migraine. Here, we evaluated efficacy and safety of monthly erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s) (≥ 1, ≥ 2 prior failed medication categories) and in patients who had never failed. Methods Subgroup analyses evaluated change from baseline in monthly migraine days; achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days; and change in monthly acute migraine-specific medication days. Adverse events were evaluated for each subgroup. Results Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days (primary endpoint) at Month 3 (treatment difference [95% CI], never failed subgroup: −2.2 [−4.1, −0.3] for 70 mg and −0.5 [−2.4, 1.5] for 140 mg; ≥ 1 prior failed medication categories subgroup: −2.5 [−3.8, −1.2], for 70 mg and −3.3 [−4.6, −2.1] for 140 mg; ≥ 2 prior failed medication categories subgroup: −2.7 [−4.2, −1.2], for 70 mg and −4.3 [−5.8, −2.8] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days. There were no new or unexpected safety issues. Conclusion Erenumab showed consistent efficacy in chronic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups.

Benefit-risk assessment of erenumab and current migraine prophylactic treatments using the likelihood of being helped or harmed

Objective This study evaluated the benefit-risk profile of erenumab relative to other therapies approved for migraine prophylaxis and available in the majority of European countries. Methods Trials were identified via a published systematic literature review updated to December 2017 using MEDLINE. Erenumab’s pivotal trials study reports were also included (NCT02066415, NCT02456740). From these sources, ≥ 50% responder rates and discontinuations due to adverse events were extracted to generate numbers needed to treat and harm and likelihood of being helped or harmed, a quantitative benefit-risk measure. Results Eleven articles (nine randomized clinical trials) met the inclusion/exclusion criteria. Low numbers needed to treat (range: 4–13) were observed for most treatments, while numbers needed to harm showed substantial differences (erenumab’s higher numbers needed to harm indicating better tolerability). In chronic and episodic migraine, likelihoods of being helped or harmed for erenumab 70 mg were 143 and 167, and 42 and 167 for erenumab 140 mg. Likelihoods of being helped or harmed in chronic migraine were 2 and 3 for topiramate (two studies) and 4 for onabotulinumtoxinA. In episodic migraine, likelihoods of being helped or harmed were 2 for topiramate and 2 for propranolol. Conclusions While all prophylactic treatments were more likely to help than harm (likelihood of being helped or harmed > 1), erenumab showed a likelihood of being helped or harmed of high magnitude, supporting its favorable benefit-risk profile across the entire migraine frequency spectrum, in contrast with other prophylactic treatments.