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

Lise Rystad Øie¹, Tore Wergeland², Øyvind Salvesen³, G Ril Bruvik Gravdahl², Irina Aschehoug⁴, Sasha Gulati⁵, Marte-Helene Bj Rk⁶, Christofer Lundqvist⁷, Karl Bj Rnar Alstadhaug⁸, Bendik Slagsvold Winsvold⁹, Anne Hege Aamodt¹⁰, Iben Cornelia Larsen¹¹, Magne Geir B E¹², Mark Braschinsky¹³, Bernd Müller¹⁴, Kjersti Gr Tta Vetvik¹⁵, Kai Ivar Müller¹², Kjersti Aaseth¹⁶, Andrej Netland Khanevski¹⁷, Ane Bakke Øvrevik¹⁸, Håkon Magne Vegrim¹⁹, Jenny Lindroos¹⁹, Karine Eid⁶, Helene Engstrand²⁰, Burcu Bezgal²¹, Martha Brakestad Larsen¹⁴, Joakim H Gsteggen Østhus², Lars Jacob Stovner²², Erling Tronvik²

Affiliations

¹ Department of Neurology, St Olavs University Hospital, Trondheim, Norway; Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: lise.r.oie@ntnu.no.
² Department of Neurology, St Olavs University Hospital, Trondheim, Norway; Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
³ Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Neurology, St Olavs University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ Department of Neurosurgery, St Olavs University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁶ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Neurology, Haukeland University hospital, Bergen, Norway.
⁷ Health Services Research Unit, University of Oslo Campus, Akershus University Hospital, L⊘renskog, Norway; Department of Neurology, Akershus University Hospital, L⊘renskog, Norway.
⁸ Department of Neurology, Nordland Hospital, Bod⊘, Norway.
⁹ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁰ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹¹ Department of Neurology, University Hospital of North-Norway, Troms⊘, Norway.
¹² Department of Neurology, Hospital of Southern Norway, Kristiansand, Norway.
¹³ Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Neurology Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁴ Department of Neurology, Molde Hospital, Molde, Norway.
¹⁵ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Akershus University Hospital, L⊘renskog, Norway.
¹⁶ Department of Neurology, Akershus University Hospital, L⊘renskog, Norway.
¹⁷ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Haukeland University hospital, Bergen, Norway.
¹⁸ Department of Neurology, Haukeland University hospital, Bergen, Norway.
¹⁹ Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Neurology, Haukeland University hospital, Bergen, Norway.
²⁰ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²¹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
²² Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.

PMID: 40975098
DOI: 10.1016/S1474-4422(25)00269-8

Clinical Trial

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

Lise Rystad Øie et al. Lancet Neurol. 2025 Oct.

. 2025 Oct;24(10):817-827.

doi: 10.1016/S1474-4422(25)00269-8.

Authors

Affiliations

¹ Department of Neurology, St Olavs University Hospital, Trondheim, Norway; Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: lise.r.oie@ntnu.no.
² Department of Neurology, St Olavs University Hospital, Trondheim, Norway; Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
³ Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Neurology, St Olavs University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ Department of Neurosurgery, St Olavs University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁶ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Neurology, Haukeland University hospital, Bergen, Norway.
⁷ Health Services Research Unit, University of Oslo Campus, Akershus University Hospital, L⊘renskog, Norway; Department of Neurology, Akershus University Hospital, L⊘renskog, Norway.
⁸ Department of Neurology, Nordland Hospital, Bod⊘, Norway.
⁹ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁰ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹¹ Department of Neurology, University Hospital of North-Norway, Troms⊘, Norway.
¹² Department of Neurology, Hospital of Southern Norway, Kristiansand, Norway.
¹³ Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Neurology Clinic, Tartu University Hospital, Tartu, Estonia.
¹⁴ Department of Neurology, Molde Hospital, Molde, Norway.
¹⁵ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Akershus University Hospital, L⊘renskog, Norway.
¹⁶ Department of Neurology, Akershus University Hospital, L⊘renskog, Norway.
¹⁷ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Haukeland University hospital, Bergen, Norway.
¹⁸ Department of Neurology, Haukeland University hospital, Bergen, Norway.
¹⁹ Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Neurology, Haukeland University hospital, Bergen, Norway.
²⁰ Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²¹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
²² Norwegian Centre for Headache Research, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.

PMID: 40975098
DOI: 10.1016/S1474-4422(25)00269-8

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.

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Conflict of interest statement

Declaration of interests LRØ has received advisory board honoraria from Roche. TW has received honoraria from TEVA, Roche, Lilly, Lundbeck and has stocks in two MedTech companies (Vilje Bionics and Keimon Medical). GBG has received honoraria for lectures and presentation from Novartis, TEVA, and Lundbeck. M-HB has received advisory board honoraria from Jazz Pharmaceuticals, Angelini Pharma, Lundbeck, Pfizer, and Eisai, and honoraria for lectures from Eisai, AbbVie, Angelini Pharma, Novartis, Pfizer, BestPractice (funded by the pharmaceutical industry), and Organon. Her institution (University of Bergen) has received fees from contract research conducted for Novartis and is listed as a marketing authorisation holder for valproate. CL has received honoraria for study board membership from Lundbeck Pharma and for lectures and presentations from Abbvie Pharma, Lundbeck, Novartis, and Roche. KBA has received speaker-fees from Biogen, Lundbeck, TEVA, Novartis, and Roche, and has also received honoraria for participation in advisory boards sponsored by TEVA, Biogen, Lilly, and Novartis. AHA reports unrestricted research grants from Boehringer Ingelheim; honoraria for lectures from BMS and Pfizer, Teva, Abbvie, Lundbeck, and Novartis; and participation in advisory boards for Lundbeck and Abbvie. KGV has received personal honoraria for participation in advisory boards for Lundbeck, TEVA, Pfizer, Novartis, and personal honoraria for lectures for Lundbeck, TEVA, Pfizer, and Novartis. HMV has received speaker honoraria from Angelini Pharma Nordics. KE has received speaker honoraria from Novartis. LJS is the director of Lifting The Burden, an international charitable organisation running the Global Campaign Against Headache and a research committee member of the Norwegian Brain Council, a charitable organisation. ET has received personal fees for lectures and advisory boards from Novartis, Eli Lilly, Abbvie, TEVA, Roche, Lundbeck, Pfizer, Biogen, and Organon. ET is a consultant for and holds stocks and intellectual property in Man & Science and Nordic Brain Tech, and holds shares in Keimon Medical. ET has received non-personal research grants from European Commission, Norwegian Research Council, KlinBeForsk, and Nordic Innovation, and has conducted commissioned (non-personal) research for Lundbeck. All other authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous