Candesartan versus placebo for migraine prevention in patients with episodic migraine: a randomised, triple-blind, placebo-controlled, phase 2 trial

Abstract

Background

Effective and well-tolerated preventive treatments for migraine remain few, and the angiotensin receptor blocker candesartan has shown promise in small studies. This study aimed to evaluate the safety, tolerability, and efficacy of candesartan for the preventive treatment of episodic migraine.

Methods

This randomised, triple-blind, placebo-controlled, parallel-group, phase 2 trial was done at nine hospitals across Norway and one large hospital in Estonia, selected for their neurological services and research capacity. Adults aged 18–64 years, experiencing between two and eight migraine attacks (with or without aura) per month were randomly assigned (1:1:1) to receive oral candesartan 16 mg, candesartan 8 mg, or placebo daily for 12 weeks. Acute migraine medication was permitted during the trial but the use of other preventive treatments were prohibited. Participants, site personnel, and the trial statistician were all masked to treatment allocation. The primary endpoint was the change in the mean number of migraine days per 4 weeks from baseline to weeks 9–12, analysed in the intention-to-treat population (participants with at least one post-baseline measurement during the masked treatment period). Safety analyses included all participants who received at least one dose of the trial drug. This trial is registered with ClinicalTrials.gov (NCT04574713; Oct 5, 2020) and is completed.

Findings

Between April 9, 2021, and April 12, 2024, 1340 individuals were assessed for eligibility, 806 were deemed ineligible, and 534 were enrolled in the trial. Of these, 77 were excluded, and 457 participants were randomly assigned to candesartan 16 mg (n=156), candesartan 8 mg (n=150), or placebo (n=151). The mean age of the trial population was 38·7 years (SD 10·0); 391 (86%) participants were female and 66 (14%) were male. The mean number of migraine days was 5·7 (SD 2·5) at baseline. By weeks 9–12, the reduction in migraine days was 2·04 days (95% CI 1·65–2·41 p<0·0001) in the candesartan 16 mg group compared with 0·82 days (0·38–1·23; p=0·0003) in the placebo group ((difference between groups –1·22 [95% CI –1·75 to –0·70]; p<0·0001). The most common adverse event with candesartan 16 mg was dizziness, reported in 46 (30%) of 156 participants, compared with 19 (13%) of 151 in the placebo group. Serious adverse events were reported in four (3%) participants in the candesartan 16 mg group and one (1%) participant in the placebo group. Adverse events leading to discontinuation occurred in four (3%) participants in both the candesartan 16 mg and placebo groups.

Interpretation

Daily administration of candesartan 16 mg is effective and well tolerated as a preventive treatment for episodic migraine. These findings support its role as a clinically meaningful and evidence-based option for migraine prevention. However, further clinical trials and real-world data from registry studies are necessary to assess its long-term efficacy.

Funding

Norwegian Research Council.