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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active group | Active Comparator | Active drug |
|
| Placebo group | Placebo Comparator | Inactive placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active drug for chronic migraine treatment. | Drug | Standard dose of Fremanezumab, 225 mg (Ajovy) injected subcutaneously |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 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. | 24 hours, 14 and 28 days after each treatment administration |
| Measure | Description | Time Frame |
|---|---|---|
| Migraine days | Total number of migraine days will be measured 28 days before and after each treatment condition. | Measured every day during the 8 month trial period |
| Acute treatment utilization |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Sigrid Juhl Lunde, MSc, PhD | Contact | 4587165956 | lunde@psy.au.dk |
| Name | Affiliation | Role |
|---|---|---|
| Lene Vase, MSc, PhD, DMSc | Dept. of Psychology and Behavioural Sciences, Aarhus University, Aarhus, Denmark | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Psychology and Behavioral sciences, Aarhus BSS, Aarhus University | Recruiting | Aarhus C | Denmark | 8000 | Denmark |
De-identified individual participant data underlying the results reported in the study, including demographic data, baseline characteristics, and outcome measures.
Data will be available following publication of the primary results, with no predefined end date.
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.
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| ID | Term |
|---|---|
| D008881 | Migraine Disorders |
| D020773 | Headache Disorders |
| D006261 | Headache |
| ID | Term |
|---|---|
| D051270 | Headache Disorders, Primary |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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Double-blinded randomized controlled cross-over design where patients receive
1) Fremanezumab or 2) placebo, twice.
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| Placebo Subcutaneous injection | Drug | Inactive placebo (saline) injected subcutaneously in the same volume as the active drug |
|
The use of acute migraine medication will be recorded, including the specific drug used, number of days and dose.
| 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). | 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. | 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. | 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). | 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) | 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. | 28 days after each treatment administration and after completion of the trial |
| 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). | 28 days before treatment administration and immediately after treatment administration |
| Department of Neurology, Aarhus University Hospital | Recruiting | Aarhus N | Denmark | 8200 | Denmark |
|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |