A Study to Evaluate the Effectiveness and Safety of Dysport® for the Prevention of Episodic Migraine in Adults

Study Overview
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Brief Summary
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The purpose of this study is to understand the safety and effectiveness of the study drug, Dysport® when compared with placebo in preventing episodic migraine. A migraine is a headache with severe throbbing pain or a pulsating sensation, usually on one side of the head, and is often accompanied by feeling or being sick and a sensitivity to bright lights and sound. Episodic Migraine is defined as having less than 15 days of headache a month with at least 6 days with migraine headaches. Migraines are caused by a series of events which cause the brain to get stimulated / activated, which results in the release of chemicals that cause pain. Dysport® is a formulation of Botulinum toxin type A (BoNT-A), a medication that stops the release of these chemical messengers. The study will consist of 3 periods: A 'screening period' of 6 to 12 weeks to assess whether the participant can take part to the study and requires 1 visit. A first Treatment Phase of 24 weeks. On Day 1 and at Week 12 of the first Treatment Phase, participants will receive injections into various muscles across the head, neck, face and shoulders. The injections will contain either a dose A or a dose ''B'' of Dysport® or a placebo (an inactive substance or treatment that looks the same as, and is given in the same way as, an active drug or intervention/treatment being studied). Participants will make 4 visits to the clinic in person and have 4 remote (online) visits. A second Treatment Phase of 24 weeks (extension phase). At Week 24 and at Week 36, all participants will get Dysport® (dose A or dose B). There will be 3 in person visits and 4 remote visits. Participants will need to complete an e-diary and questionnaires throughout the study. Participants will undergo blood samplings, urine collections, physical examinations, and clinical evaluations. They may continue some other medications, but the details need to be recorded. The total study duration for a participant will be up to 60 weeks (approx. 14 months).

Official Title
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A Phase III, Randomised, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study With Extension Phase to Evaluate the Efficacy and Safety of Dysport® for the Prevention of Episodic Migraine in Adult Participants

Conditions
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Episodic Migraine

Intervention / Treatment
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* Biological: Botulinum toxin type A
* Biological: Botulinum toxin type A
* Other: Placebo
* Biological: Botulinum toxin type A
* Biological: Botulinum toxin type A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Participant must be ≥18 years of age inclusive, at the time of signing the informed consent and privacy/data protection documentation. Participant has a diagnosis for more than 12 months, prior to screening visit, of migraine with aura or migraine without aura according to the International Classification of Headache Disorders definition and diagnostic criteria Migraine onset occurred when participant was <50 years of age. Has baseline number of monthly headache days (MHD) of <15 and baseline number of monthly migraine days (MMD) of ≥6, using eDiary data collected during the 4 weeks nearest to randomisation on Day 1 (but prior to randomisation). Has baseline number of valid diary days ≥22 days collected during the 4 weeks nearest to randomisation on Day 1. Exclusion Criteria : History or current diagnosis of migraine with brainstem aura, retinal migraine, complications of migraine, tension-type headache, trigeminal autonomic cephalalgias, hypnic headache, hemicrania continua, or new daily persistent headache. Headache attributed to another disorder (e.g. secondary headaches), except medication overuse headache, which is permitted. Use of any of the following medications in the specified timeframe prior to start of completion of the screening daily headache eDiary: a. Within 24 weeks i. Botulinum toxin for migraine (or for any other medical/aesthetic reason within 16 weeks) b. Within 12 weeks i. CGRP antagonists (monoclonal antibody or gepant) for preventive treatment of migraine (acute treatment of headache/migraine with a gepant is permitted) ii. Cannabinol or other types of cannabinoids c. Within 4 weeks i. Anaesthetic or steroid injection in any region targeted for injection with study intervention ii. Use of medical device to treat migraine (e.g. non-invasive neuromodulation therapies such as nerve stimulation (gammaCore), transcranial magnetic stimulation (cephaly), external trigeminal nerve stimulation, transcutaneous electrical nerve stimulation, and peripheral neuroelectrical stimulation) iii. Other interventions for migraine assessed to interfere with study evaluations (e.g. acupuncture in head and neck region, cranial traction, nociceptive trigeminal inhibition, occipital nerve block treatments, and dental splints for headache) iv. Use of opioids or barbiturates for more than 2 days/month. Note: participants are permitted to take one concomitant migraine preventative treatment (not listed above); however, the dose of this medication should be stable for ≥3 months before start of the screening eDiary.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dysport® dose A<br>Participant will receive four treatment cycles, each separated by an interval of 12 weeks. Double-blind placebo-controlled (DBPC) Phase: Dysport® dose A administered intramuscularly on Day 1 and Week 12. Extension Phase: Dysport® dose A administered intramuscularly at Week 24 and Week 36 (final follow-up at Week 48) | Biological: Botulinum toxin type A<br>* Dose A U /Injection (U/I) , Intramuscular (IM) on every 12 weeks during a period of 36 weeks with a total of 4 injections.<br>* Other names: Dysport®;|
| Experimental: Dysport® dose B<br>Participant will receive four treatment cycles, each separated by an interval of 12 weeks. DBPC Phase: Dysport® dose B administered intramuscularly on Day 1 and Week 12. Extension Phase: Dysport® dose B administered intramuscularly at Week 24 and Week 36 (final follow-up at Week 48) | Biological: Botulinum toxin type A<br>* Dose B U/I, IM on every 12 weeks during a period of 36 weeks with a total of 4 injections.<br>* Other names: Dysport®;|
| Placebo Comparator: Placebo - Dysport dose A<br>Participant will receive four treatment cycles, each separated by an interval of 12 weeks. DBPC Phase: Placebo dose A administered intramuscularly on Day 1 and Week 12. Extension Phase: Dysport® dose A administered intramuscularly at Week 24 and Week 36 (final follow-up at Week 48). | Other: Placebo<br>* 0 U/I, IM on Day 1 and Week 12 with a total of 2 injections.<br>Biological: Botulinum toxin type A<br>* Dose A U/I, IM on Week 24 and Week 36 with a total of 2 injections.<br>* Other names: Dysport®;|
| Placebo Comparator: Placebo - Dysport dose B<br>Participant will receive four treatment cycles, each separated by an interval of 12 weeks. DBPC Phase: Placebo dose B administered intramuscularly on Day 1 and Week 12. Extension Phase: Dysport® dose B administered intramuscularly at Week 24 and Week 36 (final follow-up at Week 48). | Other: Placebo<br>* 0 U/I, IM on Day 1 and Week 12 with a total of 2 injections.<br>Biological: Botulinum toxin type A<br>* Dose B U/I, IM on Week 24 and Week 36 with a total of 2 injections.<br>* Other names: Dysport®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in monthly migraine days (MMD) | The monthly migraine days (MMD) is assessed by a daily eDiary, completed by the participant, to evaluate the efficacy of Dysport® compared to placebo. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in MMD of ≥50% | The monthly migraine days (MMD) is assessed by a daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Change from baseline in MMD of ≥75% | The monthly migraine days (MMD) is assessed by a daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Cumulative number of MMD | The cumulative number of monthly migraine days (MMD) is assessed by a daily eDiary. | From Day 1 to Week 24 | 
| Change from baseline in MMD of moderate or severe intensity | The intensity of MMD is assessed by a daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Change from baseline in monthly headache days (MHD) of moderate or severe intensity | The intensity of monthly headache days (MHD) is assessed by a daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Change from baseline in MHD of moderate or severe intensity of ≥50% | The intensity of monthly headache days (MHD) is assessed by a daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Change from baseline in MHD of moderate or severe intensity of ≥75% | The intensity of monthly headache days (MHD) is assessed by a daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Cumulative number of MHD of moderate to severe intensity | The cumulative number of monthly headache days (MHD) is assessed by a daily eDiary. | From Day 1 to Week 24 | 
| Change from baseline in the number of days per month of acute migraine medication intake | The acute migraine medication intake will be recorded in the daily eDiary Acute migraine medication is defined as triptan, ergotamine, gepant, or ditan | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Headache medication overuser (yes, no) | The headache medication overuse will be assessed by a concomitant medication log completed at each visit and acute medication taken to treat acute attack will be recorded in the daily eDiary. The headache medication overuse is defined as a participant with ≥10 days/month if ergotamine, triptan, gepant, ditan, opioid or combination analgesic, or ≥15 days/month if non-opioid analgesic (such as paracetamol, aspirin, NSAID) | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Use of acute migraine medication (yes or no) | The use of acute migraine medication will be recorded in the daily eDiary. | Every 4 weeks from Week 4 (Weeks 1-4) to Week 24 (Weeks 21-24) | 
| Patient's Global Impression of Change (PGIC) score | The PGIC will be assessed by a questionnaire (7-point scale, score of 1 indicates very much improved and score of 7 indicates very much worse) | At Week 12 and Week 24 | 
| Change from baseline of ≥1 and ≥2 grades in PGIC score | The PGIC will be assessed by a questionnaire (7-point scale, score of 1 indicates very much improved and score of 7 indicates very much worse) | At Week 12 and Week 24 | 
| Change from baseline in role function restrictive domain of Migraine Specific Quality of Life Questionnaire (MSQ) | The MSQ will be assessed by a questionnaire (Scores range from 0-100, higher scores indicate a better quality of life) | At Week 12 and Week 24 | 
| Change from baseline in total MSQ score | The MSQ will be assessed by a questionnaire (Scores range from 0-100, higher scores indicate a better quality of life) | At Week 12 and Week 24 | 
| Change in MSQ score to the minimally important difference/change (MID/MIC) | The MSQ will be assessed by a questionnaire (Scores range from 0-100, higher scores indicate a better quality of life) | At Week 12 and Week 24 | 
| Change from baseline in total 6-item Headache Impact Test (HIT-6) score | The HIT-6 will be assessed by a questionnaire (scores range from 36-78 and higher scores indicate a greater impact of headache on subject's life) | At Week 12 and Week 24 | 
| Change in total 6-item Headache Impact Text (HIT-6) score to the minimally important difference/change (MID/MIC) | The HIT-6 will be assessed by a questionnaire (scores range from 36-78 and higher scores indicate a greater impact of headache on subject's life) | At Week 12 and Week 24 | 
| Change from baseline in Short Form 12 (SF-12) Questionnaire score | The SF-12 will be assessed by a questionnaire (scores range from 0-100, with higher scores indicating better functioning) | At Week 12 and Week 24 | 
| Change from baseline to Chronic migraine status | Transition to Chronic migraine status will be assessed by the daily eDiary and defined as number of participants with ≥15 MHD and ≥8 MMD | At Week 24 (Week 21-24) | 
| Time to onset of effect | Time to onset of effect is defined as the first time point post randomisation where MMD is reduced from baseline ≥50% | From first time point post randomisation to Week 24 | 
| Incidence of Treatment emergent adverse event (TEAEs) | An Adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to Week 24 | 
| Percentage of Participants with clinically significant changes in vital signs | Percentage of participants with clinically significant changes in vital signs will be reported. The clinical significance will be graded by the investigator. | From baseline up to Week 24 | 
| Percentage of participants with clinically significant laboratory parameters (blood chemistry, haematology) | Percentage of participants with clinically significant change in laboratory parameters (blood chemistry, hematology and coagulation) will be reported. The clinical significance will graded by the investigator. | From baseline up to Week 24 | 
| Treatment-emergence of suicidal ideation/suicidal behaviour | It will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire that consists of 4 subscales: Ideation severity subscale: questions answered yes/no, severity of ideation scored 1-5 with 5 being most severe Intensity of ideation subscale : scores range from 2-25 with higher scores indicating more severe intensity of ideation. Suicide behaviour subscale:4 types of suicidal behaviours are scored yes/no Behaviour Lethality subscale: actual lethality/medical damage scores 0-5, with 5 being most severe (death) and potential lethality scores 0-2 with 2 being more potentially lethal. | From baseline up to Week 24 | 
| Percentage of participants with Binding antibodies to Dysport® | It will be assessed by collecting blood samples at baseline and Week 24. The determination of putative antibodies against BoNT-A will be evaluated using a validated method of electrochemiluminescence assays (ECLA) for the presence of binding antibodies to BoNT-A. | At Week 24 | 
| Percentage of participants with neutralising antibodies to Dysport® | It will be performed only with confirmed positive samples in ECLA (confirmation of presence of binding antibodies) . The characterization of antibodies against BoNT-A will be evaluated using a validated method of cell-based assays (CBA) for the presence of neutralising antibodies to BoNT-A | At Week 24 |