Study Background and Disease Burden
Migraine is a prevalent neurological disorder characterized by recurrent moderate to severe headache episodes, frequently accompanied by nausea, photophobia, and phonophobia. Episodic migraine, defined as having fewer than 15 headache days monthly, affects millions worldwide, significantly impairing quality of life and productivity. Despite the availability of some preventive therapies, many patients experience inadequate relief or intolerable side effects. Angiotensin receptor blockers (ARBs), particularly candesartan, have emerged as potential migraine preventives due to their vascular and neuroprotective properties. However, evidence from large well-controlled trials has been limited. This phase 2 trial aimed to comprehensively evaluate the efficacy, safety, and tolerability of candesartan in episodic migraine prevention, addressing a notable gap in migraine therapeutics.
Study Design
This multicentric, randomised, triple-blind, placebo-controlled, parallel-group phase 2 trial was conducted across nine hospitals in Norway and one hospital in Estonia, chosen for their expertise in neurology and research infrastructure. Adults aged 18 to 64 years, with a clinical diagnosis of episodic migraine experiencing 2 to 8 migraine attacks monthly (with or without aura), were enrolled. Participants were randomized in a 1:1:1 ratio to receive either candesartan 16 mg, candesartan 8 mg, or placebo once daily for a 12-week period. The use of acute migraine medications was permitted, but other preventive treatments were prohibited during the trial. Blinding extended to patients, clinical staff, and the trial statisticians to minimize bias. The primary endpoint was the change in the mean number of migraine days over four weeks, comparing the baseline period to weeks 9 through 12 in the intention-to-treat population. Safety assessments included all participants who took at least one dose of the study medication.
Key Findings
Between April 2021 and April 2024, 1340 individuals were screened for eligibility; 806 were excluded, with 534 ultimately enrolled. Following further exclusions, 457 participants were randomized: 156 received candesartan 16 mg, 150 received candesartan 8 mg, and 151 were assigned placebo. The cohort had a mean age of 38.7 years (SD 10.0), predominantly female (86%), and an average baseline of 5.7 migraine days per month (SD 2.5).
By weeks 9 to 12, the candesartan 16 mg group exhibited a mean reduction of 2.04 migraine days (95% CI 1.65–2.41; p<0.0001) compared with a 0.82-day reduction in the placebo group (95% CI 0.38–1.23; p=0.0003). The between-group difference favored candesartan by –1.22 days (95% CI –1.75 to –0.70; p<0.0001), demonstrating a clinically meaningful preventive effect. The 8 mg dose outcomes were not specified as statistically significant against placebo in the summary provided, indicating less efficacy at the lower dose.
Regarding safety, dizziness was the most common adverse event with candesartan 16 mg, reported by 30% of participants compared to 13% with placebo. Serious adverse events occurred in 3% of the 16 mg group versus 1% in placebo, but adverse events leading to drug discontinuation were similar (3% in both groups). The safety profile suggests candesartan is well tolerated; however, dizziness warrants clinical attention.
Expert Commentary
This phase 2 trial robustly confirms data from prior smaller studies, solidifying candesartan 16 mg as an effective preventive therapy for episodic migraine. Its mechanism as an angiotensin II receptor antagonist may mediate beneficial effects on cerebral vasculature and neural excitability, reducing migraine frequency. The triple-blinded design and multicenter execution enhance the generalizability and reliability of findings. Nonetheless, some considerations remain. The trial duration was 12 weeks — longer-term efficacy and safety data are necessary for chronic migraine management. Additionally, the trial population was predominantly female, reflecting migraine epidemiology but necessitating further exploration in more diverse cohorts. The higher incidence of dizziness, although manageable, should be discussed with patients in clinical settings.
Comparatively, candesartan offers an oral, once-daily preventive option distinct from other classes such as beta blockers or anticonvulsants, potentially benefiting patients intolerant or unresponsive to these agents. Current migraine treatment guidelines increasingly emphasize individualized therapy; thus, candesartan may fill an important niche. Ongoing and future phase 3 trials and real-world registry data will be vital to confirm these outcomes and evaluate long-term safety.
Conclusion
This randomized, triple-blind, placebo-controlled phase 2 trial demonstrates that daily administration of candesartan 16 mg significantly reduces migraine days in patients with episodic migraine, with an acceptable tolerability profile. These results support candesartan’s use as a clinically meaningful preventive treatment option. Future research should focus on long-term outcomes, comparative effectiveness, and patient-reported quality of life metrics to solidify its role in clinical practice.
References
Øie LR, Wergeland T, Salvesen Ø, et al. Candesartan versus placebo for migraine prevention in patients with episodic migraine: a randomised, triple-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2025 Oct;24(10):817-827. doi:10.1016/S1474-4422(25)00269-8. PMID: 40975098.
Beside this pivotal trial, recent reviews on migraine prevention strategies and ARB-related migraine research can provide additional context:
1. Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174–182.
2. Jackson JL, Cogbill E, Santana-Davila R, et al. Angiotensin receptor blockers for migraine prophylaxis: a systematic review and meta-analysis. Headache. 2019;59(8):1225–1234.
These resources support the clinical plausibility and emerging role of candesartan in migraine prevention.