- Design
- phase 3b, randomised, double-dummy, double-blind, active-controlled head-to-head trial over 24 weeks (TEMPLE)
- Population
- 540 adults with migraine and at least 4 migraine days per month across 12 countries; 89% female, 96% White
- Primary outcome
- discontinuation due to treatment-emergent adverse events during the 24-week double-blind period
- Effect
- 12% (33/273) with atogepant vs 30% (79/267) with topiramate (RR 0.4; 95% CI 0.3-0.6); 50% responder rate 64% vs 39% (RR 1.6; 1.4-2.0); monthly migraine days -6.3 vs -4.5 (difference -1.8; -2.5 to -1.0)
TEMPLE randomised 540 adults with at least four migraine days a month, across 12 countries, to atogepant 60 mg once daily or topiramate at the highest tolerated dose of 50, 75 or 100 mg daily, double-dummy and double-blind for 24 weeks. The primary endpoint was tolerability: discontinuation because of treatment-emergent adverse events.
Twelve per cent of the atogepant group stopped for adverse events against 30% of the topiramate group. Treatment-related adverse events of any kind were reported by 56% against 78%. This is the trial that quantifies what every headache clinic already suspected about topiramate.
The efficacy result was not a trade-off in the other direction. A 50% or greater reduction in monthly migraine days was achieved by 64% on atogepant against 39% on topiramate, and the reduction in monthly migraine days was 6.3 against 4.5 — a difference of 1.8 days a month. Winning on both tolerability and efficacy in a head-to-head trial is uncommon.
The constraint in Indian practice is cost, and it is a large one. Topiramate is inexpensive and widely available; atogepant is neither. A first-line recommendation that a patient cannot fill is not a recommendation. What this trial changes is the second decision — what to do when topiramate is not tolerated, which on these figures will be nearly a third of the patients started on it.
- Warn patients starting topiramate that roughly one in three stops it for side effects, and review early rather than at three months
- Where topiramate is not tolerated, an oral CGRP receptor antagonist is now the comparator with direct evidence behind it
- Discuss cost before prescribing atogepant; an unaffordable prescription becomes an untreated migraine
- Count baseline monthly migraine days in a diary — the effect size here is expressed in days, and you cannot judge response without the baseline
- Note that the trial population was 96% White and 89% female; generalisability to Indian men with migraine is untested
The statistics, in plain English
The primary endpoint was discontinuation for adverse events, a relative risk of 0.4 with a 95% confidence interval of 0.3 to 0.6 — atogepant patients were about 60% less likely to stop. Using tolerability rather than efficacy as the primary endpoint is deliberate and sensible for preventive migraine treatment, where the drug that is still being taken at six months is the one that works. The efficacy difference of 1.8 monthly migraine days, with an interval of -2.5 to -1.0, is statistically clear; whether about two fewer headache days a month is worth the cost difference is a separate judgement the trial cannot make. The trial was funded by the manufacturer of atogepant, which does not invalidate a double-blind randomised comparison but is worth knowing.
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