Cocoa Extract for Migraine Trial (CORAL)

Cocoa Flavanols for Migraine: A Pilot Study

The goal of this clinical trial is to assess the feasibility of recruitment and adherence to a high-dose cocoa extract supplement in individuals diagnosed with episodic migraine. The main questions it aims to answer are:

• Will we be able to enroll 114 participants during the recruitment period?
• Will participants take study pills daily during the pill-taking period?

Researchers will compare two doses of cocoa extract to placebo to determine the acceptability of higher doses of cocoa extract supplementation in this patient population.

Participants will be asked to:

• Provide two urine samples
• Complete daily questionnaires
• Take four study pills a day for 12 weeks

Study Overview

• Status: Recruiting
• Conditions: Migraine
• Intervention / Treatment: Dietary supplement: Cocoa extract placebo; Dietary supplement: Cocoa extract

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pamela M Rist, ScD; Phone Number: 877-517-2555; Email: bwhcoral@mgb.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Pamela M Rist, ScD; Email: bwhcoral@mgb.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women and men aged ≥18 years

• Self-reported clinician diagnosis of migraine with or without aura which does not meet criteria for chronic migraine (according to the International Classification of Headache Disorders 3rd edition)

  • Individuals with self-reported migraine will need to report a clinician diagnosis of migraine and be classified as having migraine or probable migraine by the American Migraine Study (AMS) migraine screener. The AMS migraine screener, which has a sensitivity of 100% and a specificity of 82% for the diagnosis of migraine will be used to confirm self-reported migraine status.
  • History of migraine dating for at least one year
• Self-report of 4 to 14 migraine attacks during the 30 days prior to enrollment in the study

• Completion of at least 22 headache diary days during the 28 day run-in period

  o Report migraine frequency between 4 to 14 days during the 28 day run-in period

• If currently using medications to prevent or treat migraine, no new medication use within the past 3 months
• No new use of behavioral interventions within the past 3 months and/or agree to not begin new behavioral interventions during this trial
• Be willing to complete all study procedures and be randomized to all interventional groups
• Be fluent in English
• Own an iPhone or Android device and be willing to download MyCap to the device

Exclusion Criteria:

• Self-reported history of stroke or transient ischemic attack; history of brain surgery or spine surgery; currently receiving treatment for a concussion; and self-reported diagnosis of cluster headache, brain tumor, brain aneurysm, traumatic brain injury, multiple sclerosis, epilepsy, schizophrenia, or bipolar disorder
• Kidney failure or current dialysis treatment or any medical condition which the participant believes could lead to difficulty complying with the protocol
• Current alcohol or substance abuse (self-reported)
• Self-reported clinician diagnosis of medication overuse headache
• Currently or recently (past 6 months) received Botox treatment for migraine
• Failure to return the baseline urine sample
• Currently pregnant, nursing, or intending to become pregnant during the study period.
• Unwilling to forgo use of out-of-study supplements of cocoa extract during the trial
• Extreme sensitivity to caffeine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants assigned to this arm will take four placebo pills per day.	Dietary supplement: Cocoa extract placebo; Cocoa extract placebo
Experimental: 500 mg cocoa extract; Participants assigned to this arm will take two 250 mg cocoa extract pills per day and two placebo pills per day	Dietary supplement: Cocoa extract; Cocoa extract manufactured as 250 mg capsules
Experimental: 1000 mg cocoa extract; Participants assigned to this arm will take four 250 mg cocoa extract pills per day	Dietary supplement: Cocoa extract; Cocoa extract manufactured as 250 mg capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment	We will be able to recruit and randomize 114 eligible individuals	15 months
Retention	Retention will be quantified by the proportion of subjects who record their migraines for at least 22 out of 28 days during run-in and the last four weeks of the intervention and complete all questionnaires at baseline and follow-up	From run-in to end of treatment at 12 weeks
Adherence	Adherence will be calculated as the proportion of participants who miss no more than 12 days of study pills (i.e. participants will consume study pills on 85% of the intervention days)	12 week intervention period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Migraine days	Number of migraine attacks as recorded in migraine diaries	Four week run-in period and final four weeks of the 12 week intervention period
Responder rate	Proportion of individuals who experience a ≥50% reduction in migraine days	Four week run-in period and final four weeks of the 12 week intervention period
Migraine severity	Four-point scale with categories of "absent, mild, moderate, or severe".	Four week run-in period and final four weeks of the 12 week intervention period
Adverse events	Potential side effects and adverse events	12 week intervention period
Reports of worsening of migraine symptoms	Worsening of photophobia, phonophobia, or osmophobia, and worsening of aura symptoms in the past week compared to the week prior	12 week intervention period
Allodynia Symptom Checklist	Survey assessing how often individuals with migraine experience allodynia	Baseline and end of the 12 week intervention period
Headache Related Disability (HIT-6)	Evaluates the impact headaches have on a patient's life and	Baseline and end of the 12 week intervention period
PROMIS-29	Measures of patient-reported health status for physical, mental, and social well-being	Baseline and end of the 12 week intervention period
Urine levels of gamma-valerolactone metabolites (gVLM)	Biomarker of dietary flavanol intake	Four week run-in period and final four weeks of the 12 week intervention period

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Center for Complementary and Integrative Health (NCCIH)
• Investigators: Principal Investigator: Pamela M Rist, ScD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 29, 2025
• First Submitted That Met QC Criteria: January 29, 2025
• First Posted (Actual): February 5, 2025

Study Record Updates

• Last Update Posted (Actual): July 14, 2025
• Last Update Submitted That Met QC Criteria: July 9, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: migraine; cocoa extract; cocoa flavanol
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: 2024P003655; U01AT012611 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Cleaned, item-level spreadsheet data for all variables will be shared openly, along with example quantifications and transformations from initial raw data
• IPD Sharing Time Frame: Data will be shared no later than time of the final publication of study results or the end of the performance period, whichever comes first. The duration of preservation and sharing of the data will be a minimum of 10 years after the end of the funding period.
• IPD Sharing Access Criteria: Data and supporting materials will be shared on the Harvard Dataverse. The data that is shared will be shared by unrestricted download.
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No