An interventional study of Active drug for chronic migraine treatment. and Placebo Subcutaneous injection in Migraine, Migraine With or Without Aura and Headache Disorders, sponsored by University of Aarhus. Recruiting at 2 sites in Denmark. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-05-19.
Sponsored by University of Aarhus · Not applicable, Interventional, and Basic science
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, balanced placebo design, patients with chronic migraine will receive four treatment conditions in a randomized order.
The existing paradigm for testing the effect of treatment 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 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 (BPD) 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.
1,657 studies on the registry are indexed under Migraine Disorders; 339 are open to participants now.
This study's planned enrollment of 60 is below the median of 80 across 1,269 interventional studies indexed under Migraine Disorders.
Browse Migraine Disorders studies →University of Aarhus is the lead sponsor of 1,300 studies on the registry; 189 are open to participants now.
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Exclusion Criteria:
Active drug
Drug: Active drug for chronic migraine treatment.
Inactive placebo
Drug: Placebo Subcutaneous injection
Standard dose of Fremanezumab, 225 mg (Ajovy) injected subcutaneously
Inactive placebo (saline) injected subcutaneously in the same volume as the active drug
Mean change in headache intensity
Headache intensity rated on a 11-point Numerical Rating Scale (0=no pain; 10=worst pain intensity) measured 28 days before and after each treatment administration.
Time frame: Measured every day during the 8 month trial period
Mean change in moderate/severe headache days
Total number of moderate/severe headache days will be measured 28 days before and after each treatment administration. Moderate/severe headache days will be recorded by the presence of headache (yes/no), peak pain intensity (mild/moderate/severe), and duration (\< 4h or ≥ 4h), as well as acute medication intake and treatment response.
Time frame: Measured every day during the 8 month trial period
Adverse events
Occurrence of adverse events in each treatment condition recorded by the presence of adverse events ascribed to the treatment, measured using free recall and prompting. 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.
Time frame: 24 hours, 14 and 28 days after each treatment administration
Migraine days
Total number of migraine days will be measured 28 days before and after each treatment condition.
Time frame: Measured every day during the 8 month trial period
Acute treatment utilization
The use of acute migraine medication will be recorded, including the specific drug used, number of days and dose.
Time frame: Measured every day during the 8 month trial period
Positive and negative affect (PANAS)
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).
Time frame: Pre-treatment and 28 days after each treatment administration
Hospital Anxiety and Depression Scale (HADS)
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.
Time frame: Pre-treatment and 28 days after each treatment administration
Quality of life (SF-12)
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.
Time frame: Pre-treatment and 28 days after each treatment administration
HIT-6
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).
Time frame: Pre-treatment and 28 days 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)
Time frame: 24 hours, 14 days and 28 days after each treatment administration
Blinding
At the end of each treatment condition, participants indicate which treatment they believe to have received (fremanezumab 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 injection, or other reasons). After completion of all four treatment conditions, participants complete a single, retrospective assessment indicating which treatment they preferred overall. Participants are also asked to briefly describe the reasons for their preference.
Time frame: 28 days after each treatment administration and after completion of the trial
Expectations
This parameter is measured as a predictor using four 11-point NRS scales: expected headache intensity ("How intense do you expect your headache to be during the coming week?"; 0 = no pain, 10 = worst imaginable), expected improvement (0 = none, 10 = greatest possible), expected worsening (0 = none, 10 = greatest possible), and expected adverse events ("To what extent do you expect symptoms/adverse effects?"; 0 = not at all, 10 = greatest possible). Pre-treatment ratings reflect general expectations for the next 7 days. Post-treatment ratings use the same items but refer to expectations as a result of the received treatment. Immediately after each treatment, expectations are also assessed with the same four scales, focusing on the coming 28 days in relation to that treatment.
Time frame: Weekly throughout the study period and immediately after each treatment administration
Desire for headache relief
This parameter is measured as a predictor. Desire for headache relief is assessed using an 11-point ("How strong is your desire for headache relief from the treatment"; 0 = no desire, 10 = strongest possible desire).
Time frame: 28 days before treatment administration and immediately after treatment administration
Plan to share: Yes — De-identified individual participant data underlying the results reported in the study, including demographic data, baseline characteristics, and outcome measures.
Supporting information: Study protocol
Time frame: Data will be available following publication of the primary results, with no predefined end date.
Access criteria: Researchers upon reasonable request, subject to approval by the study investigators. Data will be shared with researchers upon reasonable request, subject to approval by the study investigators and in accordance with applicable data protection regulations. A data sharing agreement may be required.
No publications or documents are linked to this record.
Started Jun 2025 (actual). Primary completion is estimated for Sep 2028, 39 months after the start.
Of 309 non-industry interventional studies with no phase under Migraine Disorders, half reached primary completion within 17 months of starting (the median), counting those still running; a quarter within 8 and three quarters within 36. This study's planned 39 months is above that.
Counting every sponsor, half of 358 studies reached it within 15 months; a quarter within 7 and three quarters within 34.
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