Elsevier

The Lancet

Volume 372, Issue 9656, 20 December 2008–2 January 2009, Pages 2115-2123
The Lancet

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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

https://doi.org/10.1016/S0140-6736(08)61626-8Get rights and content

Summary

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.

Introduction

Migraine is a common disease and a leading cause of disability.1 Triptans, agonists of the serotonin receptor 5-HT1B/1D, are currently viewed as the best acute migraine-specific treatments, although some patients respond poorly or are unresponsive.2, 3 Generally well tolerated, triptans can be associated with side-effects such as dizziness, paraesthesia, throat tightness, and chest discomfort (not thought to be of cardiac origin in most patients),4 which can cause some patients to discontinue or change treatment.5, 6 Furthermore, because of potential vasoconstrictor effects, triptans are contraindicated in patients with substantial underlying cardiovascular disease, uncontrolled hypertension, and certain migraine subtypes, including hemiplegic and basilar-type migraine.4, 7 Hence, new treatments for migraine are needed for people who do not respond well to current therapies or who are at substantial risk of cardiovascular disease.

Calcitonin gene-related peptide (CGRP) is a neuropeptide thought to have a key role in the pathophysiology of migraine.8, 9, 10 CGRP concentrations in the cranial circulation may be increased during a migraine attack11 and CGRP given intravenously triggers a migraine-like headache in people who have migraines.12 CGRP receptors are found throughout the trigeminal pathways involved in migraine headache pain and have been localised to primary sensory neurons in the trigeminal ganglion, central second-order pain-relay neurons in the trigeminal nucleus caudalis, and smooth muscle cells of the meningeal vasculature.13, 14 Antagonism of these receptors has thus become an important target for new migraine treatments. Since antagonists of CGRP receptor do not seem to have direct vasoconstrictor properties, they might be free of the cardiovascular concerns associated with triptans.15

An initial proof-of-concept study reported that an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant), was effective and well-tolerated in the acute treatment of migraine.16 Because most migraine attacks are treated on an outpatient basis, intravenous formulations are not practically or commercially viable as acute treatments, and oral CGRP antagonists are needed. MK-0974 (telcagepant) is an oral CGRP receptor antagonist being investigated in clinical trials.17, 18, 19 The initial phase II proof-of-concept study used an adaptive dose-ranging design to assess the efficacy and safety of doses from 25 mg to 600 mg.19 All doses were well-tolerated. Doses of 300 mg to 600 mg were more effective than placebo and had efficacy comparable to the established triptan rizatriptan.

The primary aim of this study was to confirm the efficacy and safety profile of telcagepant compared with those of placebo and a triptan in the acute treatment of migraine in a large phase III trial. The phase II study suggested that the efficacy of telcagepant doses between 300 mg and 600 mg were comparable. The 300 mg dose was chosen as the primary dose for further investigation. A 150 mg dose was selected as a second dose in this study to further define the dose–response curve. Zolmitriptan 5 mg (the maximum recommended dose in the USA) was chosen as an active comparator because it is among the most widely used and effective of the oral triptan treatments.2

Assessment of effects on migraine symptoms focused on the 2 h time point, which is the standard time point recommended for migraine trials.20 Sustained efficacy measures, which assess duration of response over longer periods while accounting for headache recurrence and the use of rescue drugs, were also assessed.20 Results of previous studies with olcegepant and telcagepant, showed that CGRP receptor antagonists might be more effective than triptans on sustained measures.

Section snippets

Study population and design

Patients were recruited from primary care and headache centres. Patients were eligible for the study if they were ≥18 years of age, had a history of migraine for at least 1 year, and in the 2 months prior to the screening visit had had one to eight moderate or severe migraine attacks per month with or without aura (International Headache Society criteria)21 that typically lasted 4–72 h untreated. Patients were required to have good general health. Patients with a history or clinical evidence of

Results

Figure 1 is the trial profile. A total of 1380 patients were treated. Of these, 850 were from European sites and 530 were from US sites. Table 1 summarises characteristics of the patients taking treatment and the baseline characteristics of treated migraine attacks. The mean age of treated patients was 42·3 years and 85% were women. Most patients usually used a triptan, a non-steroidal anti-inflammatory drug, or both, to treat their migraine attacks. Most treated headaches were not preceded by

Discussion

Our study in 1380 people with migraine confirmed that an oral 300 mg dose of the CGRP-receptor antagonist telcagepant is effective in the treatment of a moderate or severe migraine attack. This was true across a range of outcome measures. On the basis of closed-testing procedure, formal statistical significance versus placebo can only be claimed for telcagepant 300 mg on the co-primary endpoints and key secondary endpoint. However, on the basis of nominal p values and inspection of the data,

References (26)

  • PL Durham

    Calcitonin gene-related peptide (CGRP) and migraine

    Headache

    (2006)
  • PJ Goadsby

    Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches

    Drugs

    (2005)
  • L Edvinsson

    Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache

    Cephalalgia

    (2004)
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