MIGRAINE · White paper
Migraine Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About migraine — and why its trials are hard
Migraine is a common, disabling primary neurological disorder characterized by recurrent attacks of moderate-to-severe, often unilateral pulsating headache lasting 4-72 hours, frequently with nausea, photophobia, phonophobia, and sometimes aura. It most affects adults aged 25-55 and is two-to-three times more common in women, reflecting hormonal influences. The dominant neurovascular model implicates activation of the trigeminovascular system and release of calcitonin gene-related peptide (CGRP), which has transformed therapy. Acute treatment historically relied on triptans (5-HT1B/1D agonists) such as sumatriptan; newer options include ditans (lasmiditan) and gepants (ubrogepant, rimegepant). Prevention now includes anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab), oral gepants (atogepant, rimegepant), onabotulinumtoxinA for chronic migraine, and older agents such as topiramate. Trials measure reduction in monthly migraine days, 2-hour pain freedom, and responder rates, and are challenged by high placebo response and historical CGRP-antagonist hepatotoxicity (telcagepant).
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Sumatriptan (Imitrex) | 1991 | Acute treatment of migraine (first triptan, 5-HT1B/1D agonist) | Pivotal triptan trials | Headache relief at 2 hours | Roughly 50-70% headache relief at 2 hours vs ~25-35% placebo (varies by formulation) |
| OnabotulinumtoxinA (Botox) | 2010 | Preventive treatment of chronic migraine (>=15 headache days/month) | PREEMPT 1 and 2 | Change in frequency of headache days | ~ -8.4 headache days vs -6.6 with placebo (pooled PREEMPT) |
| Erenumab (Aimovig) | 2018 | Preventive treatment of migraine (first FDA-approved anti-CGRP receptor monoclonal antibody) | STRIVE | Change in monthly migraine days | 140 mg reduced monthly migraine days by ~3.7 vs ~1.8 with placebo |
| Ubrogepant (Ubrelvy) | 2020 | Acute treatment of migraine with or without aura (oral CGRP receptor antagonist/gepant) | ACHIEVE I and II | Pain freedom at 2 hours | ~19-21% pain-free at 2 hours vs ~12% placebo |
| Rimegepant (Nurtec ODT) | 2020 | Acute treatment (2020) and preventive treatment (2021) of migraine (gepant) | Acute Study 303; preventive Study 305 | 2-hour pain freedom (acute); reduction in monthly migraine days (preventive) | ~21% pain-free at 2h vs ~11% placebo; preventive ~ -4.3 vs -3.5 monthly migraine days |
| Atogepant (Qulipta) | 2021 | Preventive treatment of episodic migraine (2021); expanded to chronic migraine (2023) (oral gepant) | ADVANCE | Change in mean monthly migraine days | 60 mg reduced monthly migraine days by ~ -4.2 vs -2.5 with placebo |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in migraine development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Telcagepant — Phase III (Merck) | Development halted | Hepatotoxicity (elevated liver enzymes) with regular dosing outweighed efficacy |
| MK-3207 — Phase II (Merck) | Discontinued | Liver-toxicity signals (delayed hepatic laboratory abnormalities) |
| BI 44370 TA — Phase II (Boehringer Ingelheim) | Discontinued | Lack of efficacy relative to development threshold |
Choosing the right endpoint
Primary endpoints that matter in migraine trials
- Reduction in monthly migraine days — Primary efficacy measure for preventive therapies
- Pain freedom / pain relief at 2 hours — Standard co-primary endpoints for acute-treatment trials
- Responder rate (>=50% reduction) — Proportion achieving >=50% decrease in monthly migraine days
- Most bothersome symptom freedom at 2 hours — Acute-trial co-primary alongside pain freedom (nausea, photophobia, or phonophobia)
- Patient-reported outcomes (MIDAS, HIT-6) — Assess disability and headache impact on daily life
How iNGENū runs migraine trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
The full white paper: approved-product analyses, pivotal endpoints and trial-design strategy. Open-access · no sign-in.
Frequently asked questions
Migraine clinical trials — FAQs
How do CGRP monoclonal antibodies differ from gepants?
Why did early CGRP receptor antagonists like telcagepant fail?
What is the main efficacy endpoint in migraine prevention trials?
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