Chronic Migraine Headache, Migraine
Conditions
Keywords
Migraine, CGRP, Onabotulinumtoxin A, CGRP monoclonal antibody, Combination of CGRP mAbs and onabotulinumtoxin A
Brief summary
Migraine is characterized by attacks of throbbing, moderate or severe headache, often associated with nausea, vomiting, and/or sensitivity to light and/or sound. Chronic migraine, which occurs in 1-2 % of the population is characterized by 15 or more headache days/month for more than 3 months and at least 8 days/month with features of migraine headache. The study will evaluate the efficacy of onabotulinumtoxin A when added to CGRP monoclonal antibody therapy in chronic migraine prevention. Adverse events and change in disease activity will be monitored. Onabotulinumtoxin A and CGRP monoclonal antibody therapy are investigational drugs developed to prevent chronic migraine. Approximately 450 patients will be included from sites in Norway. All participants will receive CGRP monoclonal antibody therapy. Additionally, the participants will be randomized to receive onabotulinumtoxin A or placebo injections. Total study duration is 20 weeks including 3 on site visits and 3 telephone visits. After an inclusion visit the participants are registering data in an electronic headache diary using the application Brain Twin for a minimum of 4 weeks before the come to the randomization visit and the study medications are started. The duration of treatment is 12 weeks.
Detailed description
Despite an improved understanding of migraine pathophysiology and treatment in recent years, many responders for both BTA and CGRP mAbs still experience high burden of disease. Thus, there is still a great need for further improving migraine prevention therapy. At present, there are few effective treatment alternatives for chronic migraine patients and a combination therapy of CGRP mAbs and BTA is an excellent candidate that has not previously been tested in any trial to date. The combined inhibition of CGRP release in C fibres by BTA and the receptor function blockade by CGRP mAbs directed towards the ligand or the receptor in Aδ fibres is proposed to have a synergistic effect. Several observational studies, including pooled analysis of real-world evidence, supports a combination of CGRP mAbs and BTA, but the efficacy remains to be demonstrated in randomized controlled trials. Additionally, while the cost-effectiveness of pharmacological treatments of chronic migraine in the adult population-using CGRP mAbs and BTA-have been demonstrated, the cost-effectiveness of the combination therapy needs to be clarified. As both fatigue and cognitive symptoms are important for the migraine related disability and migraine related quality of life, we will also include these aspects in the endpoint evaluations . Hypothesis : Combination of CGRP mAbs and BTA reduces Monthly Headache Days (MHDs) in chronic migraine compared to single therapy. In this trial of chronic migraine the efficacy of dual therapy with CGRP monoclonal antibody and onabotulinumtoxin A compared with CGRP monoclonal antibody single therapy in participants aged 18 to 70 years with chronic migraine will be studied. The primary endpoint is the reduction of Monthly Migraine Days (MMDs) over 12 weeks. Total study duration is 20 weeks including 3 on site visits and 3 telephone visits. After an inclusion visit the participants are registering data in an electronic headache diary using the application Brain Twin for a minimum of 4 weeks before the come to the randomization visit and the study medications are started. The duration of treatment is 12 weeks. Participants will be divided into two equal groups using electronic randomization. One group will receive one treatment with botulinum toxin A, while the other group will receive injections of placebo (saline). Unblinded study personnel will prepare botulinum toxin A/placebo which will then be administered to the participants by blinded study personnel. Onabotulinum toxin A/placebo will be administered at 31 pre-defined injection sites (0.1 ml with 5 units per injection; total 3.1 ml and 155 units), in accordance with a modified version of the Phase III REsearch Evaluating (PREEMPT) protocol. At the same time, both groups will start monthly injections of CGRP inhibitors as background medication. The choice of type of CGRP inhibitor is made by the study physician or based on national guidelines. Participants will keep daily headache diaries throughout the study period to record headache frequency, intensity, use of reliever medication and type of headache. The participants have a telephone visit with a study nurse after 4 and 8 week with study medication to follow-up the administration of CGRP inhibitors, headache diary and safety. After 12 week of treatment the 3rd clinical visit is performed where the primary and secondary endpoints are registered. The participants continue to register headache diary for 4 weeks until the 3rd telephone visit which is the the end of study. Sample size estimation: A difference of 1.6 MMDs over 12 weeks of treatment between the two groups is expected with a common standard deviation of 6.0 days for the average number of MMDs over 12 weeks in the two groups. With 90% power and a two-sided significance level of 5% 450 participants (225 in each arm) are needed in the analysis to detect the above-mentioned difference.
Interventions
DRUGCGRP mAbs and onabotulinumtoxin A
CGRP mAbs given subcutanously every 4th week and onabotulinumtoxin A 155 given once intramuscularly according to adjusted PREEMPT protocol in the 12 week period of study intervention.
DRUGCGRP mAbs and placebo
CGRP mAbs given subcutanously every 4th week and placebo once intramuscularly according to adjusted PREEMPT protocol in the 12 week period of study
Sponsors
St. Olavs Hospital
Sykehuset Telemark
Sykehuset Innlandet HF
Sorlandet Hospital HF
Ostfold Hospital Trust
Oslo University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Unblinded study personnel will prepare the BTA/placebo with NaCl that will be administered to the participants by blinded study personnel. BTA/placebo with NaCl will be administered at 31 predefined injection sites (5 units per injection; 155 units in total), in accordance with a modified version of the protocol from the Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1, PREEMPT. To secure the blinding in the study, the four injections in the forehead will be placed in the upper frontal region whereas the injections in corrugator and procerus are kept.
Intervention model description
A randomized placebo-controlled double-blind phase III two-arm study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Informed and signed written consent. 2. Individuals of any sex, 18-70 years at the time of signing the informed consent. 3. Fulfilling the diagnosis chronic migraine criteria 1.3. according to the International Classification of Headache Disorders version 3 at time of inclusion. 4. Indications for treatment with CGRP mAbs according to SmPCs. 5. Indications for treatment with BTA according to SmPC. 6. No previous use of CGRP inhibitors or BTA. 7. Women of childbearing potential (WOCBP) can only be included if they use a highly effective contraception method
Exclusion criteria
1. Contraindications, allergy or hypersensitivity reactions to BTA including infection at the injection site. 2. Contraindications, allergy or hypersensitivity reactions to CGRP mAbs including serious cardiovascular illness such as myocardial infarction, stroke, unstable angina pectoris, revascularization procedures last 12 months. 3. Concomitant medication overuse headache where drug withdrawal has not been done. 4. Subject is unable to differentiate migraine from other concomitant headaches. 5. Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months before study inclusion (Visit 2). 6. Long-standing continuous headache with no headache free days or periods for a period of time \>1 years. 7. Pregnancy, planning to get pregnant, inability to use contraceptives and lactating. 8. High degree of comorbidity and/or frailty associated with reduced life expectancy or high likelihood of hospitalization, at the discretion of the investigator. 9. Alcohol or illicit drug dependence. 10. Investigators may exclude patients who, for various reasons (for example, severe psychiatric disorders), are considered unlikely to be able to complete the tasks required for participation in the study. 11. Inability to understand study procedures and to comply with them for the entire length of the study, assessed at the discretion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changer of Monthly Migraine Days over 12 weeks of treatment with the study medication. | 12 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by reduction of Monthly Migraine Days (MMDs) over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3 - primary endpoint visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of Monthly Headache Days** over 12 weeks of treatment with the study medication | 12 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by reduction of Monthly Headache Days (MHDs) over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3. |
| Monthly number of days with rescue medication over 12 weeks of treatment with the study medication. | 12 weeks | Headache diary (by using the mobile application Brain Twin) where all rescue medication is registered until Visit 3. |
| Number of treatment responders (≥ 50%, ≥75% and 100 % reduction in Monthly Migraine Headache days in each group over 12 weeks of treatment) at 12 weeks post-randomization. | 12 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by number of treatment responders ≥ 50%, ≥75% and 100 % reduction in MHD and MMDs over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3. |
| Number of weekly migraine days from baseline to 12 months post-randomization. | 12 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by weekly migraine days over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3. |
| Total number of hours at moderate or severe pain over 12 weeks of treatment. | 12 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by total headache score per month over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Bergen Insomnia Scale over 12 weeks of treatment with the study medication | 12 weeks | To assess the consequences of dual therapy with CGRP mAbs and BTA versus CGRP mAbs over 12 weeks of treatment on insomnia assessed by Bergen Insomnia Scale. The questionnaire is filled in by the participant at Visit 2 and 3. Minimum Bergen Insomnia Scale Scores is 0, maximum is 42. Higher scores mean a worse outcome. |
| Change in Fatigue Score over 12 weeks of treatment with the study medication | 12 weeks | To assess the consequences of dual therapy with CGRP mAbs and BTA versus CGRP mAbs over 12 weeks of treatment on insomnia assessed by Bergen Insomnia Scale. The questionnaire is filled in by the participant at Visit 2 and 3. Higher scores mean a worse outcome. |
| Change in cognitive impairment scale for migraine attacks - Mig-SCOG score over 12 weeks of treatment with the study medication | 12 weeks | To assess the consequences of dual therapy with CGRP mAbs and BTA versus CGRP mAbs over 12 weeks of treatment on cognitive symptoms during migraine attacks assessed by subjective cognitive impairment scale for migraine attacks - Mig-SCOG score. The questionnaire is filled in by the participant at Visit 2 and 3. Minimum score 0, maximum 18. Higher scores mean a worse outcome. |
| Patients' Global Impression of Change scale | 12 weeks | To assess the consequences of dual therapy with CGRP mAbs and BTA versus CGRP mAbs over 12 weeks of treatment on the patients´ global impression of change assessed by PGIC score. The questionnaire is filled in by the participant at Visit 3. Minimum Patients' Global Impression of Change scale 0, maximum 7. Higher scores mean a better outcome. |
| Number of treatment responders (≥ 30% reduction in mean Mean Headache Days over 12 weeks of treatment) at 12 weeks post-randomization. | 12 weeks | To assess the difference in number of treatment responders of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by difference in number of treatment responders over 12 weeks of treatment by using headache diary with the mobile application Brain Twin until assessment at Visit 3. |
| Costs and Quality of life measured by EuroQol 5D-5L before treatment initiation, and 12 weeks after treatment initiation | 12 weeks. | To assess the health economic consequences of dual therapy with CGRP mAbs and BTA versus CGRP mAbs over 12 weeks of treatment. The EQ-5D-5L Questionnaire will be filled in by the participants at Visit 2 and 3. |
| Absenteeism from work (salary, sick leave, social security). Presenteeism (lost workplace productivity), Productivity Cost | 12 weeks | To assess change of productivity loss over 12 weeks of treatment in the two groups by using the Institute for Medical Technology Assessment Productivity Cost Questionnaire to be filled in by the participant at Visit 3. The loading ranges from 0 to 1; the higher the value, the more an item is associated with a factor. |
| Assesment of resource use over 12 weeks of treatment in the two groups | 12 weeks | Health economic assessment of resource use assessed by Norwegian Kroner. |
| Number of days on sick leave from baseline to 12 weeks post-randomization. | 16 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by numbers of days of sick leave over 12 weeks of treatment. Sick leave is registered by the participant in the headache diary using the application Brain Twin and assessed at Visit 1, 2 and 3. |
| Number of crystal-clear headache-free days after 12 weeks of treatment with the study medication | 12 weeks. | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by number of crystal-clear headache-free days over 12 weeks of treatment using headache diary with the mobile application Brain Twin until assessment at Visit 3. |
| Percentage of patients fulfilling the International Classification of Headache Disorders version 3 diagnostic criteria for medication overuse headache over 12 weeks of treatment. | 12 weeks | To assess the efficacy of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients measured by change in percentage of patients fulfilling the ICHD-3 diagnostic criteria for MOH over 12 weeks of treatment. This assessment is based on information registered in the headache diary during 12 weeks and assessment at Visit 3. |
| Number of patients completing the trial and number of dropouts | 12 weeks. | To assess the feasibility of dual therapy with CGRP mAbs and BTA compared to single therapy with CGRP mAbs in chronic migraine patients over 12 weeks of treatment. This is assessed at Visit 3. |
| Change in Migraine Disability Assessment Score over 12 weeks of treatment with the study medication | 12 weeks | To assess the consequences of dual therapy with CGRP mAbs and BTA versus CGRP , mAbs over 12 weeks of treatment on headache disability assessed by Migraine Disability Assessment. This questionnaire is filled in by the participant at Visit 2 and 3. Minimum Migraine Disability Assessment score 0, maximum score 270. Higher scores mean a worse outcome. |
| Change in Hospital Anxiety and Depression Scale score over 12 weeks of treatment with the study medication | 12 weeks | To assess the consequences of dual therapy with CGRP mAbs and BTA versus CGRP mAbs over 12 weeks of treatment on anxiety and depression. HADS-A and -D questionnaire is filled in by the participant at Visit 2 and 3. Minimum Hospital Anxiety and Depression Scale score 0, maximum value 21. Higher scores mean a worse outcome. |
Countries
Norway
Contacts
Primary ContactAnne Hege Aamodt, Prof, MD, PhD
Backup ContactBurcu Bezgal, Neurologist PhD student
Outcome results
None listed