Cabergoline for Episodic Migraine

Official title

Prevention and Treatment of Episodic Migraine by Cabergoline Therapy (PROTECT). A Randomized, Placebo-controlled, Double-blind, Investigator-initiated Trial

Overview

The goal of this randomized, placebo-controlled, double-blind clinical trial is to evaluate the efficacy, safety, and tolerability of cabergoline for the prevention of episodic migraine in adults with 4-14 monthly migraine days (MMD). The main questions it aims to answer are: 1. Does once-weekly cabergoline (0.5 mg or 1.0 mg) reduce MMD compared to placebo? 2. What are the effects of cabergoline on headache severity, acute medication use, and patient-reported outcomes? 3. Is cabergoline safe to use in individuals with migraine? Participants will: Complete a 4-week baseline period to document migraine frequency and classify headache days. Be randomly assigned to one of three treatment arms: 1. Cabergoline 0.5 mg/week 2. Cabergoline 1.0 mg/week 3. Placebo Participate in a 12-week double-blind treatment phase, followed by a 12-week open-label treatment phase where all participants receive cabergoline (0.5 mg or 1.0 mg once weekly). Record daily headache activity, acute medication use, and severity using an electronic diary. Complete validated headache questionnaires and provide blood samples for biomarker analysis at baseline, week 12, and week 24. The study also includes exploratory analyses of genetic predictors of treatment response and metabolic markers to assess the broader effects of cabergoline.

Detailed description

Migraine is a common and often disabling neurological disorder. While there are several treatments available, many individuals continue to experience frequent attacks, side effects from medications, or limited access to newer therapies due to high costs.

Cabergoline is a medication that activates dopamine receptors and has shown promising effects in migraine. A small, pilot study found that a low dose of cabergoline (0.5 mg per week) reduced the number of migraine days per month in patients with episodic migraine. It was well tolerated, with few side effects and good treatment adherence.

The PROTECT trial is a larger clinical study that aims to confirm these results. The trial will evaluate whether cabergoline, taken once weekly, is effective in reducing the number of monthly migraine days compared to placebo. It will also test a higher dose (1.0 mg/week) to investigate whether a stronger effect can be achieved without increasing side effects.

The trial consists of two treatment phases. In the first phase, participants will be randomly assigned to receive either cabergoline 0.5 mg, cabergoline 1.0 mg, or placebo once weekly for 12 weeks. In the second phase, all participants will receive cabergoline for another 12 weeks, in an open-label setting. This will allow researchers to study longer-term treatment effects, adherence, and tolerability. A final safety follow-up phase will last four weeks.

Throughout the study, participants will report their migraine symptoms, medication use, and headache severity in a secure electronic diary. They will also complete questionnaires about headache-related disability, work productivity, and overall improvement. Blood samples will be collected to study the underlying biological mechanisms of migraine, and explore whether certain genetic or hormonal markers can help predict who benefits most from cabergoline.

The main outcome of the study is the change in the number of monthly migraine days during the last four weeks of the double-blind phase. Other outcomes include changes in headache severity, use of acute medication, and quality-of-life scores. The study will also monitor changes in health markers such as cholesterol, inflammation, and prolactin levels.

The PROTECT trial will include adults with episodic migraine (defined as having 4 to 14 migraine days per month). Participants must be at least 18 years old and have had a stable pattern of migraine attacks and acute treatment for the past three months. People with chronic migraine, certain headache types, or other medical conditions will not be eligible.

Participants will be recruited from headache clinics, general practitioners, and online platforms. All participants will provide written informed consent before entering the study.

This trial is conducted by an independent academic research group and is designed to evaluate a low-cost, well-known medication for a new use. If successful, cabergoline could provide a new, accessible preventive option for people with migraine.

Interventions

• Drug Cabergoline 0.5 MG
  Participants will receive cabergoline 0.5 mg as oral tablets, taken once weekly as an add-on treatment for 12 weeks during the double-blind treatment phase. Participants who received cabergoline 0.5 mg during the double-blind phase will continue with the same 0.5 mg dose in the open-label phase.
• Drug Placebo
  Participants will receive placebo as oral tablets, taken once weekly as an add-on treatment for 12 weeks during the double-blind treatment phase. In the open-label phase, these participants will transition to active cabergoline treatment, receiving either 0.5 mg or 1.0 mg once weekly, depending on their randomized allocation at the start of the open-label phase. The placebo tablets will be formulated to match the cabergoline tablets in size, shape, and color, and should be taken under the same c
• Drug Cabergoline 1 MG
  Participants will receive cabergoline 1.0 mg as oral tablets, taken once weekly as an add-on treatment for 12 weeks during the double-blind treatment phase. Participants who received cabergoline 1.0 mg during the double-blind phase will continue with the same 1.0 mg dose in the open-label phase.

Primary outcome measures

• Change in Monthly Migraine Days (MMD) [Time frame: Baseline to the last four weeks of the double-blind treatment phase]

Secondary outcome measures (12)

• Responder rate (proportion of participants achieving ≥50% reduction in MMD) [Time frame: Baseline to the last four weeks of the double-blind treatment phase.]
• Change in number of moderate/severe headache days [Time frame: Baseline to the last four weeks of the double-blind treatment phase.]
• Headache severity [Time frame: The last four weeks of the double-blind treatment phase.]
• Changes in acute medication use. [Time frame: Baseline to the last four weeks of the double-blind treatment phase.]
• Migraine Disability Assessment Scale (MIDAS) [Time frame: Baseline to the end of the double-blind treatment phase (week 12).]
• Headache Impact Test - 6 items (HIT-6) [Time frame: Baseline to the end of the double-blind treatment phase (week 12).]
• Work Productivity and Activity Impairment (WPAI) [Time frame: Baseline to the end of the double-blind treatment phase (week 12).]
• Patient's Global Impression of Change (PGIC) [Time frame: The end of the double-blind treatment phase (Week 12)]
• Safety and tolerability of cabergoline (incidence of adverse events) [Time frame: From the beginning of the treatment phase (week 0) until the end of the safety follow-up (week 28).]
• Sustained effect of cabergoline treatment in change in MMD. [Time frame: Baseline to the last four weeks of the open-label phase, and from the last four weeks of the double-blind phase to the last four weeks of the open-label phase.]
• Sustained effect of cabergoline on responder rate (defined as the proportion of participants achieving a ≥50% reduction in monthly migraine days). [Time frame: Baseline to the last four weeks of the open-label phase, and from the last four weeks of the double-blind phase to the last four weeks of the open-label phase.]
• Sustained effects of cabergoline on the frequency of moderate/severe headache days. [Time frame: Baseline to the last four weeks of the open-label phase, and from the last four weeks of the double-blind phase to the last four weeks of the open-label phase.]

Eligibility criteria

Inclusion criteria

• Age ≥18 years
• Episodic migraine according to ICHD-3 criteria
• 4-14 monthly migraine days (MMD) in the last 3 months prior to inclusion
• Stable acute migraine medication use for at least 3 months prior to inclusion
• Written informed consent

Exclusion criteria

• < 4 MMD or ≥ 15 MMD during the baseline period
• Chronic migraine (≥15 headache days per month)
• Trigeminal autonomic cephalalgias and neuralgias
• Secondary headache conditions
• Other common primary headache types (e.g. tension-type headache) if attacks are frequent (present on an average of >1 day/month and >12 days/year)
• Presumed medication-overuse headache
• Recent changes in preventive migraine treatment (≥3 months prior to study inclusion)
• History of pulmonary, retroperitoneal, or pericardial disorders, including heart valve disease
• Severe untreated hypertension
• Use of drugs with dopamine antagonistic or agonistic properties
• Psychiatric disorders requiring pharmacological treatment
• Women of child-bearing potential (i.e. not chemically or surgically sterilized, or not postmeno-pausal) and male participants with partners of child-bearing potential, who are unwilling to use a medically accepted method of contraception, considered reliable by the investigator, from signing of informed consent and throughout the study
• Women who have a positive pregnancy test at randomization
• Women who are breast-feeding
• Allergy or hypersensitivity to cabergoline or similar compounds
• Concurrent participation in another clinical trial that, in the judgement of the investigator, may interfere with the conduct or outcomes of the present study
• Inability of the subject, in the opinion of the investigator, to understand and/or comply with study medications or procedures, or any conditions that, in the opinion of the investigator, may render the subject unable to complete the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Denmark · 1 center

• Aarhus University Hospital — Aarhus N

Publications

• Hjelholt AJ, Bach FW, Kasch H, Stovring H, Jensen TS, Jorgensen JOL. Cabergoline as a preventive migraine treatment: A randomized clinical pilot trial. PLoS One. 2025 Apr 1;20(4):e0320937. doi: 10.1371/journal.pone.0320937. eCollection 2025. PMID 40168298

Identifiers

NCT: NCT07072910 · AU-PROTECT-2025 · 2025-522323-10-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗