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

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.