New Methods for Evaluating Preventive Migraine Treatment

Not Applicable

Recruiting

• Conditions: Migraine; Migraine With or Without Aura; Headache Disorders; Chronic Migraine, Headache
• Interventions: Drug: Active drug for chronic migraine treatment.; Drug: Placebo Subcutaneous injection

• Registration Number: NCT07071506
• Lead Sponsor: University of Aarhus

Brief Summary

The study aims to estimate treatment effects in a balanced placebo design (BPD) to specify to which extent contextual factors interact in preventive migraine treatment and influence adverse event occurrence in patients with chronic migraine. Using a clinical within-subjects design, patients with chronic migraine will receive four treatment conditions in a randomized order.

Detailed Description

The existing paradigm for testing the effect of treatment is the double-blind 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 studies 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 targets some of the shortcomings of the RCT by balancing the information given to the patients with the actual treatment administered. In this project, patients suffering from chronic migraine will receive a total of 4 injections over 8 months. Half of them are femanezumab, while the other half are placebo (an inactive injection). The injections (fremanezumab and placebo) look the same, and neither the patient nor the investigator know which injection will be administered. The order will be randomized. The injections are given with different information about what the patients are receiving. To avoid a carry-over effect, the patients will receive one injection every second month. The first month will be without treatment whereupon the patient will receive the first injection. During the first 28 days before and after each administration, patients rate outcome measures in an electronic pain/headache diary at home. In addition, they will also fill out questionnaires assessing their quality of life, psychological parameters and the headache burden.

Study Timeline

• Study Start: 2025-03-04
• Status Verified: 2025-05
• Study First Submitted: 2025-05-28
• Study First Submitted QC: 2025-07-08
• Last Update Submitted: 2025-07-08
• Study First Posted: 2025-07-17
• Last Update Posted: 2025-07-17
• Primary Completion: 2028-09
• Study Completion: 2028-09-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

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 chronic migraine (headache occurring ≥ 15 days per month for > 3 months, which on at least 8 days per month has the features of migraine headache) diagnosed before age 50
4. Qualifying for preventive migraine treatment (screened by neurologist)
5. Ability to speak and read Danish

Exclusion Criteria

1. Use of onabotulinumtoxinA as preventive migraine treatment during the 4 months before screening
2. Use of other preventive migraine treatment other than CGRP antagonists (However, participants are allowed to be on one stable preventive medication (antidepressant, calcium channel blockers, beta blockers or antiepileptic)- 2 months prior to screening until end of study , if necessary), devices for migraine prevention such as transcranial magnetic stimulation and use of nerve blocks 3 months prior to screening
3. Use of opioid or barbiturate medications in the last four weeks before participation in the study
4. Secondary headache disorders including medication overuse headache
5. Severe psychiatric, vascular disease, or known liver disease
6. Alcohol abuse, drug abuse, or substance abuse
7. Current or planned pregnancy and lactation

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Active group	Active drug for chronic migraine treatment.	Active drug
Placebo group	Placebo Subcutaneous injection	Inactive placebo

Primary Outcome Measures

Name	Time	Method
Moderate/severe headache days	Through study completion, an average of 8 months	Total number of moderate/severe headache days will be measured 28 days before and after each treatment administration. Headache days will be recorded by the presence of headache (yes/no), peak pain intensity (mild/moderate/severe), and duration (\< 4h or ≥ 4h), acute medication intake type (triptan/ergotamine/other) and migraine associated symptoms.
Headache/pain intensity	8 months	Headache/pain intensity rated on a 11-point Numerical Rating Scale (0=no pain; 10=worst pain intensity) will also be measured 28 days before and after each treatment administration.
Adverse events	24 hours, 14 and 28 days after each treatment administration	Occurrence of adverse events in each treatment condition recorded by the presence of adverse events ascribed to the treatment, measured by free recall and by prompting.

Secondary Outcome Measures

Name	Time	Method
Intensity of migraine	Through study completion, an average of 8 months	A categorical, four-point rating scale will be used to rate each migraine day as absent, mild, moderate, or severe. It is is graded mild when it does not inhibit work or other activities, moderate when it inhibits but does not prohibit work or other activities, and severe when it prohibits work and other activities.
Acute treatment utilization	Through study completion, an average of 8 months	The use of acute migraine medication will be recorded, including the number of days and the specific drug used.
Hospital Anxiety and Depression Scale (HADS)	Pre-treatment and 28 days after each treatment administration	It is a 14-item measure designed to assess anxiety and depression symptoms. It is rated on a 4-point Likert scale. It will be measured pre- and post-treatment of each treatment condition.
HIT-6	Pre-treatment and 28 days after each treatment administration	Headache impact test (HIT-6) measures the impact that headache has on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It consists of 6 questions. Each question can be answered with 5 responses (never, rarely, sometimes, very often, or always), which has the following numerical values (6, 8, 10, 11, and 13, respectively).
Migraine days	Through study completion, an average of 8 months	Total number of migraine days will be measured 28 days before and after each treatment condition.
Positive and negative affect (PANAS)	Pre-treatment and 28 days after each treatment administration	PANAS will be used to measure positive and negative emotions or feelings pre- and post-treatment of each treatment condition. 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).
Intensity of experienced adverse events	24 hours, 14 days and 28 days after each treatment administration	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)
Quality of life (SF-12)	Pre-treatment and 28 days after each treatment administration	Short-form-12 (SF-12) is a self-reported outcome measure assessing the impact of health on an individual's everyday life. It consists of two components- physical (PCS-12) and mental (MCS-12). The summary scores are scored using norm-based scoring, where means of 50 and standard deviations of 10 are achieved.

Trial Locations

Locations (2)

Department of Psychology and Behavioral sciences, Aarhus BSS, Aarhus University; 🇩🇰 Aarhus C, Denmark

Department of Clinical Medicine, Aarhus University Hospital; 🇩🇰 Aarhus N, Denmark