Trial Designs for Evaluating Migraine Treatment

The study aims to test interactions between drug and placebo-responses in acute migraine treatment and to assess variation in adverse events according to treatment information provided. Using a clinical within-subjects, advanced balanced placebo design, patients with episodic migraine will receive six treatment conditions in a randomized order.

Study Overview

• Status: Recruiting
• Conditions: Migraine Without Aura; Migraine With Aura; Headache, Migraine
• Intervention / Treatment: Drug: Active drug for acute migraine treatment; Drug: Placebo Oral Tablet

Detailed Description

The existing paradigm for testing the effect of treatments is the double-blind randomized controlled trial (RCT) comparing an active drug to an inactive placebo. This comparison is done in order to control for contextual and psychological factors such as the patients' treatment expectations - a key factor in placebo responses. However, recent study results have indicated that some assumptions underlying the RCT may be incorrect and may lower the assay sensitivity and miscalculate the actual drug response. The so-called balanced placebo design (BPD) targets the shortcomings of the RCT by balancing the information given to the patients (correct or false) with the actual treatment administered (active treatment or placebo). In this project, the aim is to examine whether the active drug response and the placebo response interact in acute migraine treatment.

Patients suffering from episodic migraine will go through six treatment conditions in randomized order. They will receive acute migraine treatment (a sumatriptan pill) or inactive treatment (a placebo pill) in the event of a developing migraine attack. Using a clinical within-subjects design, the patients receive 1) sumatriptan or 2) placebo and are told that they receive a) sumatriptan or placebo, b) sumatriptan, or c) placebo. All treatments and accompanying treatment descriptions will be administered at home.

• Study Type: Interventional
• Enrollment (Estimated): 128
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sigrid Juhl Lunde, MSc, PhD; Phone Number: 4587165956; Email: lunde@psy.au.dk

Study Locations

• Denmark
  • Aarhus C, Denmark, 8000
    • Not yet recruiting
    • Dept. of Psychology and Behavioural Sciences
    • Contact: Lene Vase; Phone Number: 004530614476; Email: lenevase@psy.au.dk
  • Aarhus N, Denmark, 8200
    • Recruiting
    • Department of Neurology, Aarhus University Hospital
    • Contact: Sonja Antic; Phone Number: +457845 0000; Email: Sonant@rm.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Adults (18-65 years)
2. ≥ 1-year history of migraine with or without aura according to the International Classification of Headache Disorders (ICHD-3) diagnostic criteria
3. Known episodic migraine (≥ 1 and < 15 headache days with features of migraine on at least 2-8 days per month for > 3 months) with and without aura and diagnosed before age 50
4. Previous or active use of triptans as acute treatment for migraine
5. Ability to speak and read Danish

Exclusion Criteria:

1. Chronic migraine or history of chronic migraine in the last 12 months
2. Other concomitant primary headache types except for infrequent tension-type headache
3. Secondary headache disorders including medication overuse headache
4. Severe psychiatric, vascular or liver diseases
5. Opioid or barbiturate use in the month preceding screening
6. Current use of preventive migraine treatment (i.e., onabotulinum toxin A, and/or Calcitonin gene-related peptide (CGRP) monoclonal antibodies) (however, stable medical treatment with other migraine prophylactic agents is permitted, e.g. antidepressant, calcium channel blockers, beta blockers and antiepileptic drugs, 4 weeks prior to inclusion until the completion of participation in the study)
7. Contraindications or inability to tolerate triptans
8. Current substance use disorder
9. Implanted metallic or electronic device in the head
10. Cardiac pacemaker or implanted or wearable defibrillator
11. Use of illegal psychotropic drugs less than a week before participation in the study; regarding cannabis: less than four weeks before participation in the study
12. Current pregnancy or planned pregnancy (confirmed by pregnancy test and by use of safe contraception as defined by the Danish Medicines Agency) and lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active group; Active drug	Drug: Active drug for acute migraine treatment; Standard dose of Sumatriptan 100 mg, which is used as an acute treatment for episodic migraine
Placebo Comparator: Placebo group; Inactive placebo	Drug: Placebo Oral Tablet; Inactive placebo pill (100 mg) looking like the active drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Headache intensity	Headache intensity rated on a 11-point Numerical Rating Scale (("How intense is your headache right now?"; 0=no pain; 10=worst imaginable pain).	Immediately before and 2 hours after each treatment administration
Adverse events	Occurrence of adverse events in each treatment condition recorded by the presence of adverse events ascribed to the treatment, measured using structured prompting (fatigue/drowsiness, nausea/vomiting, altered taste, feeling of warmth, flushing, feeling of cold, heaviness, muscle pain, chest pain/pressure, tingling sensations, dizziness, shortness of breath, or any other adverse event/symptom). For each prompted symptom, participants respond "yes" or "no" and indicate whether they believe the symptom is related to the medication, the migraine attack, or another cause.	2 hours after each treatment administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and negative affect (PANAS)	PANAS will be used to measure positive and negative emotions or feelings in the present moment. Positive affectivity refers to positive emotions and expressions. Negative affectivity, on the other hand, refers to negative emotions and expressions. This scale consists of words that describe different emotions and is scored on a Likert Scale ranging from 1 to 5 (1= very slightly or not at all, 2 = little, 3 = moderately, 4 = quite a bit and 5 = extremely).	Before and 2 hours after each treatment administration
Functional disability scale	Functional disability due to migraine will be measured on a 4-point scale (0= no disability (i.e., able to function normally); 1=mild disability (i.e., able to perform all activities of daily living but with some difficulty); 2=moderate disability (i.e., unable to perform certain activities of daily living); 3=severe disability (i.e., unable to perform most to all activities of daily living or requiring bed rest)	2 hours after each treatment administration
Rescue medication	Use of rescue medication for episodic migraine (type of rescue medications, dose and time of administration) will be noted	2 hours after each treatment administration
Pain Freedom	Freedom from pain will be measured as yes/no.	2 hours after each treatment administration
Absence of the most bothersome migraine-associated symptom	Absence of the most bothersome migraine-associated symptoms such as nausea, vomiting, photophobia, and phonophobia. The participants are asked to answer the question by answering yes or no.	2 hours after each treatment administration
Intensity of experienced adverse events	Intensity of the experienced adverse events will be measured on a 11-point Numerical Rating Scale (e.g., "To what extent have you been feeling fatigue/dizziness?"; 0=not at all; 10=worst imaginable).	2 hours after each treatment administration
Most bothersome migraine-related symptom other than headache	Participants are asked to identify their most bothersome migraine-related symptom other than headache.	Immediately before each treatment administration
Presence of other migraine-related symptoms	Presence of other migraine-related symptoms, including nausea, vomiting, photophobia, phonophobia, or other symptoms is assessed dichotomously (yes/no).	2 hours after each treatment administration
Desire for pain relief	Desire for pain relief is rated on a 11-point NRS ("How strong is your desire for pain relief from the treatment you just received?"; 0 = no desire, 10 = strongest possible desire).	2 hours after each treatment administration
Blinding	Participants indicate which treatment they believe to have received (sumatriptan or placebo), how certain they are on an 11-point NRS (0 = not at all certain, 10 = completely certain), and the reasons for this response (e.g., adverse events, symptom relief, characteristics of the pill or envelope, or other reasons). After completion of all six treatment conditions, participants complete a single, retrospective assessment indicating which treatment they preferred overall or whether they perceived no meaningful difference between treatments. Participants are also asked to briefly describe the reasons for their preference.	2 hours after each treatment administration and after completion of the trial

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expectations	This parameter is measured as a predictor. Expectations are assessed using two 11-point numerical rating scales (NRSs) measuring expected headache intensity ("How intense do you expect your headache to be in two hours, once the pill has taken effect?"; 0 = no pain, 10 = worst pain imaginable) and expected treatment effect ("How effective do you expect the treatment to be?"; 0 = no treatment effect, 10 = best possible treatment effect)	Immediately after each treatment administration
Desire for pain relief	This parameter is measured as a predictor. Desire for pain relief is rated on a 11-point NRS ("How strong is your desire for pain relief from the treatment you just received?"; 0 = no desire, 10 = strongest possible desire)	Immediately after each treatment administration

Collaborators and Investigators

• Sponsor: University of Aarhus

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2024
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: September 20, 2024
• First Submitted That Met QC Criteria: September 20, 2024
• First Posted (Actual): October 1, 2024

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Headache; Episodic migraine; Adverse events; Treatment effects; Balanced placebo design
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Migraine Disorders; Headache; Migraine with Aura; Migraine without Aura
• Other Study ID Numbers: UAarhus_Acute migraine

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data underlying the results reported in the study, including demographic data, baseline characteristics, and outcome measures.
• IPD Sharing Time Frame: Data will be available following publication of the primary results, with no predefined end date.
• IPD Sharing Access Criteria: Data will be shared with researchers upon reasonable request, subject to approval by the study investigators. Data will be made available upon reasonable request to the corresponding author, subject to approval by the study investigators and in accordance with applicable data protection regulations. A data sharing agreement may be required.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

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