Oral CGRP receptor antagonists have been approved for migraine prevention on placebo-controlled evidence, which tells you they work but not whether they are better than what you already prescribe. TEMPLE is the head-to-head. It was a phase 3b, double-dummy, double-blind trial across 12 countries, randomising 540 adults with at least four migraine days a month to atogepant 60 mg once daily or topiramate at the highest tolerated dose of 50, 75 or 100 mg daily, over a 24-week double-blind period.
The primary endpoint was tolerability, measured as discontinuation for treatment-emergent adverse events. That occurred in 33 of 273 (12%) on atogepant against 79 of 267 (30%) on topiramate, a relative risk of 0.4 (95% CI 0.3 to 0.6, p<0.0001). Treatment-related adverse events of any kind were 56% against 78%. Efficacy went the same way: at least a 50% reduction in monthly migraine days in 64% against 39% (RR 1.6, 95% CI 1.4 to 2.0), and a mean reduction of 6.3 against 4.5 migraine days per month, a difference of 1.8 days (95% CI 1.0 to 2.5).
A drug beating the comparator on both tolerability and efficacy is not a common result, and it is a genuinely useful one for a decision clinicians make constantly. The caveats need stating plainly. The trial was funded by the manufacturer of atogepant. Topiramate was titrated to the highest tolerated dose, which maximises both its efficacy and its side effects, and it is possible a gentler topiramate strategy would have looked different on discontinuation. And 96% of participants were White, in European and North American centres.
In Indian practice the constraint is price rather than evidence. Topiramate costs very little; atogepant does not. What TEMPLE changes is the conversation with a patient who has already failed topiramate on side effects — a common story, given that nearly a third stopped it here — where you can now say that a specific alternative was more tolerable and more effective in a direct comparison, rather than offering it as a hopeful next step. Note also the pregnancy angle: given the fetal growth data below, topiramate is a poor choice in women who may conceive, and this gives another reason to look elsewhere.
- In a patient who has stopped topiramate because of side effects, atogepant is a directly evidenced alternative.
- Expect roughly one in three patients started on titrated topiramate to discontinue for adverse effects within six months.
- The efficacy gap was 1.8 migraine days per month — real, but smaller than the tolerability gap.
- Factor in the funding source and the near-entirely White trial population when generalising.
- Avoid topiramate altogether in women who may become pregnant; there are better first choices.
The statistics, in plain English
The tolerability result is the one to trust most, because it was the prespecified primary endpoint: a relative risk of 0.4 with an interval of 0.3 to 0.6 means atogepant produced roughly 60% fewer discontinuations, measured precisely. The efficacy results were secondary endpoints, so they support the conclusion rather than establishing it independently. One structural point: because far more patients stopped topiramate, the two arms differed in who remained on treatment, and an efficacy comparison in that situation partly reflects tolerability rather than pure pharmacological effect. The double-dummy design — everyone taking both a tablet and a matching placebo — is what kept blinding intact across two very different dosing schedules.
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