Reporting withdrawals due to adverse events in single-attack acute migraine clinical trials

In a recent paper on a large double-blind, randomized, placebo-controlled, single-dose trial with the novel calcitonin gene-related peptide (CGRP) antagonist BMS-927711, the drug was superior to placebo (1). The overall incidence of adverse events (AEs) was comparable across the placebo and six active treatment groups with BMS-927711 10 mg–600 mg (1). It was in addition stated: “No deaths were reported, and no patients discontinued because of AEs” (1). Withdrawal of patients because of AEs can be an important parameter in long-term acute trials with repeated dosing of drugs and in some cross-over acute trials, and is especially clinically relevant in prophylactic migraine trials. Thus in the three pivotal trials of topiramate for migraine prophylaxis approximately one-quarter of patients discontinued the trials when treated with topiramate 100 mg daily (2–4), a clinically relevant observation. Reporting on withdrawal of patients because of AEs has been recommended by the Drug Trial Committee of the International Headache Society (IHS) both in 2008 (5) and in 2012 (6) with use both in acute and prophylactic trials.

However, to state that “no patients discontinued because of AEs” in a single-dose, controlled acute treatment trial in migraine is generally meaningless. After the patients has taken the single dose of drug or placebo and reported the results for 24 to 48 hours the trial, is finished for that patient and there is no continuation of the trial from which the patient can withdraw.

To estimate the extent of the use of reporting withdrawals in single-dose migraine trials, we searched PubMed for five years, 2009 to 2013, with the search words: acute and treatment and migraine and trial; and found 26 acute, double-blind trials with single-dose administration of drugs or placebo. Reading the results section on adverse events in these paper resulted in four trials with “no patients discontinued because of AEs” (Tfelt-Hansen, personal observation, 2014). In addition, in one trial on iontophoretic transdermal sumatriptan the patch should be kept on for four hours and five of 234 (2.1%) of patients discontinued the administration because of local AEs (7). In this special case reporting on withdrawal due to local AEs was relevant and demonstrated good tolerability of the iontophoretic patch in the large majority of patients.

Why bother about the reporting of “no patients discontinued because of AEs” in single-dose trials when this is used in only a minority of the papers in the last five years? First, official guidelines of IHS should not include meaningless recommendations. Second, the statement may wrongly inform the reader that the drug has an excellent tolerability. Thus in one trial of a 5-HT_1F receptor agonist, lasmiditan, no patient discontinued the trial (not reported as a parameter) but lasmiditan resulted in 76% (232/305) AEs vs 26% (19/86) for placebo (8).

In conclusion, the IHS’s guidelines should in future editions not recommend reporting of withdrawal due to AEs as a tolerability parameter in single-dose acute migraine trials, and paragraph 1.3.17 (6) should be changed accordingly.