TEMPLE
Tolerability, safety, and efficacy of atogepant versus topiramate in adults with migraine (TEMPLE): a randomised, head-to-head, phase 3b trial
Year of Publication: 2026
Authors: Reuter U, Van Dycke A, Versijpt J, et al
Journal: The Lancet Neurology
Citation: Lancet Neurol 2026;25(9):806-817. DOI: 10.1016/S1474-4422(26)00214-0
Link: https://doi.org/10.1016/S1474-4422(26)00214-0
PDF: https://www.thelancet.com/action/showPdf...%2826%2900214-0
PDF: Clinical Question
In adults with migraine eligible for oral prophylaxis, does atogepant 60 mg once daily provide superior tolerability and efficacy compared with topiramate at the highest tolerated dose?
Bottom Line
In a mixed episodic/chronic migraine population, atogepant 60 mg once daily produced far fewer TEAE-related discontinuations than topiramate over 24 weeks (12% vs 30%; RR 0·4) and was superior on all six ranked secondary efficacy/functional endpoints, including ≥50% MMD response (64% vs 39%), MMD reduction (−6·3 vs −4·5), HIT-6, MSQ-RFR, PGIC, and PROMIS cognitive-function scores.
Major Points
- Phase 3b, randomised, double-dummy, active-controlled trial at 73 sites in 12 countries (Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Portugal, UK).
- 545 adults (18–80y) with migraine ≥4 MMD randomised 1:1 to atogepant 60 mg QD or topiramate up-titrated to highest tolerated dose (50, 75, or 100 mg/day); 24-week double-blind period + ongoing 52-week open-label extension.
- Baseline: 89% female, 96% White, mean age 39·6, mean 11·0 MMD; 28% met chronic migraine criteria; 40% had prior migraine preventives.
- Primary endpoint (safety pop): TEAE-related discontinuation 33/273 (12%) atogepant vs 79/267 (30%) topiramate; RR 0·4 (95% CI 0·3–0·6), p<0·0001 — separated during 6-week up-titration and persisted.
- Secondary efficacy (mITT): ≥50% MMD responders at months 4–6 = 173/270 (64%) atogepant vs 101/257 (39%) topiramate; RR 1·6 (1·4–2·0), p<0·0001.
- MMD change months 4–6: LSM −6·3 (SE 0·3) atogepant vs −4·5 (0·3) topiramate; Δ −1·8 (−2·5 to −1·0), p<0·0001; separation apparent by month 1 (−4·7 vs −2·4).
- Functional outcomes at wk 24: HIT-6 Δ −4·3 (−5·8 to −2·7); MSQ v2.1 RFR Δ +10·4 (6·6–14·2); PGIC much/very-much-better 69% vs 37%; PROMIS-CF at wk 6 Δ +5·0 (3·3–6·7); all p<0·0001.
- Safety: TEAEs 77% (atogepant) vs 89% (topiramate); treatment-related 56% vs 78%; SAEs 6 vs 3 (only 1 atogepant anaphylaxis judged related); no deaths.
- Signature AE differences: paraesthesia 5% vs 41%; disturbance in attention 7% vs 10%; hypoaesthesia 1% vs 6%; nausea 20% vs 16%; constipation 10% vs 5%; ≥5% weight loss 29% vs 31%; serum bicarbonate <0·9×ULN in 26% of topiramate group.
- Post-hoc completer analysis retained atogepant superiority (≥50% MMD 74% vs 49%; MMD Δ −6·6 vs −5·0; both nominal p<0·001), arguing efficacy edge is not solely explained by differential dropout.
Design
Study Type: Phase 3b, randomised, double-dummy, active-controlled, multicentre trial
Randomization: 1
Blinding: Double-blind: participants, investigators, and site personnel masked to treatment assignment (aware of blinded topiramate dose); double-dummy tablets + capsules
Enrollment Period: Oct 7, 2023 – April 28, 2025
Follow-up Duration: 24-week double-blind (6-week up-titration + 18-week maintenance) + ongoing 52-week open-label extension + 4-week safety follow-up
Centers: 73
Countries: Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Portugal, United Kingdom
Sample Size: 545
Power Calculation: N=520 (260/arm) provided ≥95% power to detect a 15% between-group difference in TEAE-related discontinuation (assumed 20% atogepant vs 35% topiramate) at one-sided α=0·025.
Analysis: Primary endpoint in safety population using stratified Miettinen-Nurminen method (adjusted for chronic migraine status); secondary endpoints in mITT using mixed model for repeated measures / generalised linear mixed model; serial gate-keeping to control overall type-1 error at α=0·05; SAS v9.4.
Inclusion Criteria
- Aged 18–80 years at screening
- Documented history of migraine (with or without aura) ≥12 months per ICHD-3
- Migraine onset before age 50 years
- ≥4 migraine days/month on average across the 3 months before visit 1
- ≥4 migraine days during the last 28 days of the combined screening and baseline period per eDiary
- eDiary compliance ≥20/28 days before randomisation
- Eligible for conventional migraine prophylaxis (propranolol, metoprolol, amitriptyline, flunarizine, topiramate, or onabotulinumtoxinA)
- Suitable for topiramate per Summary of Product Characteristics/Product Monograph (no contraindications such as nephrolithiasis, renal impairment, eye disease, metabolic acidosis)
- Female participants of childbearing potential: negative pregnancy tests and highly effective contraception
Exclusion Criteria
- Migraine that cannot be reliably distinguished from other headache types
- Pain conditions likely to interfere with headaches (e.g., fibromyalgia)
- Psychiatric or significant neurological disorders other than migraine
- Major systemic disease not stable for >1 year
- Significant cardiovascular or cerebrovascular disease (recent MI, stroke, severe heart failure)
- History of cancer within past 5 years (excluding certain skin/cervical cancers)
- Gastrointestinal issues affecting drug absorption
- Recent acute hepatitis or chronic liver disease
- Prior exposure to topiramate or atogepant
- Use of any migraine preventive medication within 30 days before screening or during the trial
- Clinically significant laboratory abnormalities: ALT/AST >1×ULN, total bilirubin >1×ULN (except Gilbert's), serum albumin <2·8 g/dL
Baseline Characteristics
| Characteristic | Atogepant (n=273) | Topiramate (n=267) |
|---|---|---|
| Age, years (mean, SD) | 39·2 (11·9) | 40·1 (12·3) |
| Female n (%) | 240 (88%) | 239 (90%) |
| Male n (%) | 33 (12%) | 28 (10%) |
| White n (%) | 261 (96%) | 256 (96%) |
| Asian n (%) | 4 (1%) | 8 (3%) |
| Black or African American n (%) | 3 (1%) | 2 (1%) |
| Hispanic n (%) | 12 (4%) | 11 (4%) |
| Weight, kg (mean, SD) | 71·6 (17) | 72·3 (17) |
| Height, cm (mean, SD) | 167·3 (8) | 167·4 (8) |
| BMI, kg/m² (mean, SD) | 25·5 (5) | 25·7 (5) |
| Baseline monthly migraine days (mean, SD) | 11·1 (5) | 10·9 (5) |
| MMD 4–<8 n (%) | 79 (29%) | 75 (28%) |
| MMD 8–<15 n (%) | 137 (50%) | 138 (52%) |
| MMD ≥15 n (%) | 57 (21%) | 51 (19%) |
| Prior migraine preventive n (%) | 117 (43%) | 97 (36%) |
| Chronic migraine at baseline n (%) | 80 (29%) | 72 (27%) |
| MMD <4 n (%) | 3 (1%) |
Arms
| Field | Atogepant | Control |
|---|---|---|
| Intervention | Atogepant 60 mg orally once daily (with matching placebo capsules for topiramate) | Topiramate up-titrated 25 mg/day weekly to highest tolerated dose of 50, 75, or 100 mg/day (with matching placebo tablets for atogepant); maintenance modal doses 23% 50 mg, 16% 75 mg, 61% 100 mg |
| N | 273 | 267 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Proportion of participants discontinuing study treatment due to TEAEs across the 24-week double-blind period (safety population) | Primary | 79/267 (30%) | 33/273 (12%) | 0.4 | <0·0001 |
| ≥50% reduction in mean monthly migraine days during months 4–6 (mITT) | Secondary | 101/257 (39%) | 173/270 (64%) | 1.6 | <0·0001 |
| Change from baseline in mean monthly migraine days during months 4–6 (LSM) | Secondary | −4·5 (SE 0·3) [baseline 11·1 (5·1)] | −6·3 (SE 0·3) [baseline 10·9 (5·3)] | <0·0001 | |
| Change from baseline in HIT-6 total score at week 24 (LSM) | Secondary | −7·4 (SE 0·6) | −11·7 (SE 0·6) | <0·0001 | |
| Change from baseline in MSQ v2.1 Role Function–Restrictive domain at week 24 (LSM) | Secondary | +23·1 (SE 1·4) | +33·5 (SE 1·4) | <0·0001 | |
| PGIC rating of much better or very much better at week 24 | Secondary | 96/257 (37%) | 186/270 (69%) | 1.8 | <0·0001 |
| Change from baseline in PROMIS-CF Abilities score at week 6 (LSM) | Secondary | +0·2 (SE 0·6) [n=142] | +5·2 (SE 0·6) [n=184] | <0·0001 | |
| Any treatment-emergent adverse event | Safety | 237/267 (89%) | 210/273 (77%) | ||
| Treatment-related TEAE | Safety | 208/267 (78%) | 153/273 (56%) | ||
| Severe TEAE | Safety | 4/267 (1%) | 5/273 (2%) | ||
| Serious TEAE | Safety | 3/267 (1%) | 6/273 (2%) — 1 anaphylactic reaction related to atogepant | ||
| TEAE leading to treatment discontinuation (primary endpoint) | Safety | 79/267 (30%) | 33/273 (12%) | 0.4 | |
| Death | Safety | 0 | 0 | ||
| Paraesthesia | Safety | 110/267 (41%) | 14/273 (5%) | ||
| Nausea | Safety | 44/267 (16%) | 54/273 (20%) | ||
| Fatigue | Safety | 38/267 (14%) | 42/273 (15%) | ||
| Nasopharyngitis | Safety | 34/267 (13%) | 30/273 (11%) | ||
| Dizziness | Safety | 28/267 (10%) | 21/273 (8%) | ||
| Decreased appetite | Safety | 27/267 (10%) | 34/273 (12%) | ||
| Disturbance in attention | Safety | 26/267 (10%) | 19/273 (7%) | ||
| Hypoaesthesia | Safety | 15/267 (6%) | 2/273 (1%) | ||
| Constipation | Safety | 13/267 (5%) | 27/273 (10%) | ||
| Mean weight change over 24 weeks | Safety | −1·9 kg (SD 3·2) | −1·5 kg (SD 3·5) | ||
| ≥5% weight loss during double-blind period | Safety | ~31% | ~29% | ||
| Serum bicarbonate <0·9×ULN (potentially clinically significant decrease) | Safety | 26% | not observed | ||
| ALT ≥3×ULN (adjudicated) | Safety | included in the 3 adjudicated cases | included in the 3 adjudicated cases — 1 case probably related to study drug (moderate, resolved on withdrawal) |
Subgroup Analysis
Prespecified stratification by country and chronic migraine status; sensitivity analyses supported the primary MMD-response finding. Post-hoc completer analysis (participants who completed the full 24-week DB period on study drug) preserved atogepant superiority: ≥50% MMD reduction 154/209 (74%) vs 79/163 (49%), RR 1·5 (1·3–1·8), nominal p<0·0001; MMD change −6·6 (SE 0·3) vs −5·0 (0·3), Δ −1·6 (−2·5 to −0·8), nominal p=0·0002.
Criticisms
- No placebo group — active-controlled design limits ability to characterise placebo/nocebo effects and true effect sizes vs no treatment.
- Blinding integrity was not formally assessed; differing AE profiles (paraesthesia, cognitive AEs on topiramate) risk functional unblinding despite the double-dummy design.
- Population overwhelmingly female (89%) and White (96%) from Europe/Canada/Israel — limited generalisability to men and to Black, Hispanic, Asian, or US-based populations.
- Fixed titration/dosing per protocol did not allow dose reduction of either study drug in response to AEs, which may inflate topiramate discontinuations relative to real-world flexible dosing.
- PROMIS-CF measured at week 6 (end of up-titration) — up-titration AEs on topiramate may inflate the cognitive difference; PROMIS-CF is not yet fully validated for migraine.
- Funded, designed, analysed, and manuscript-reviewed by AbbVie (atogepant sponsor); most non-academic authors are AbbVie employees.
- Only 24-week double-blind data reported; 52-week open-label extension results still pending — durability and long-term safety comparisons not yet available.
- Topiramate titration cap at 100 mg/day is lower than some prescribing scenarios; whether slower or lower-dose regimens narrow the tolerability gap is unclear.
Funding
AbbVie (sponsor of atogepant). The funder participated in study design, data collection, analysis, interpretation, medical writing, and manuscript review/approval.
Based on: TEMPLE (The Lancet Neurology, 2026)
Authors: Reuter U, Van Dycke A, Versijpt J, et al
Citation: Lancet Neurol 2026;25(9):806-817. DOI: 10.1016/S1474-4422(26)00214-0
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