A Randomized Placebo-controlled Double-blind Phase III Trial to Investigate the Reduction of Monthly Migraine Days (MMDs) Over 12 Weeks of Treatment With CGRP mAbs and Onabotulinumtoxin A Intramuscularly Compared With CGRP mAbs and Placebo in Chronic Migraine

Official 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.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 70 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 450 participants

Study Arms

• CGRP and placebo (PLACEBO_COMPARATOR)
  Combination of CGRP mAbs and placebo (NaCl 0.9% Braun, 0.1 ml at the same sites) in male and female participants with chronic migraine aged 18 to 70 years.
• CGRP and onabotulinumtoxin A (ACTIVE_COMPARATOR)
  Onabotulinumtoxin A given totally 155 units at 31 sites according to modified PREEMPT or placebo (NaCl 0.9% Braun, 0.1 ml at the same sites). The treatment period is 12 weeks long.

Interventions

• DRUG: CGRP 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.
• DRUG: CGRP 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

Primary Outcomes

• Changer of Monthly Migraine Days over 12 weeks of treatment with the study medication. (12 weeks)

Secondary Outcomes

• Change of Monthly Headache Days** over 12 weeks of treatment with the study medication (12 weeks)
• Monthly number of days with rescue medication over 12 weeks of treatment with the study medication. (12 weeks)
• 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)
• Number of weekly migraine days from baseline to 12 months post-randomization. (12 weeks)
• Total number of hours at moderate or severe pain over 12 weeks of treatment. (12 weeks)

Eligibility Criteria

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.

Trial Locations

• Østfold Hospital Trust, Grålum, Norway
• Sørlandet Hospital Kristiansand, Kristiansand, Norway
• Innlandet Hospital Trust Lillehammer, Lillehammer, Norway
• Oslo University Hospital, Oslo, Norway
• Telemark Hospital Trust Skien, Skien, Norway
• St. Olav University Hospital, Trondheim, Norway

Contact Information

• Anne Hege Aamodt, Prof, MD, PhD — CONTACT
  Phone: +47 95867270
  Email: a.h.aamodt@medisin.uio.no
• Burcu Bezgal, Neurologist PhD student — CONTACT
  Phone: +47 471 51 876‬
  Email: burbez@ous-hf.no

More Migraine Trials

View all Migraine clinical trials