The Nordic Chronic Migraine Trial of CGRP Monoclonal Antibody and Onabotulinumtoxin A Dual Therapy Compared to CGRP mAbs Monotherapy

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

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.

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.

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.