A migraine is a headache with severe throbbing pain or a pulsating sensation, usually on one side of the head. It is often accompanied by feeling or being sick and a sensitivity to bright lights and sound. Migraines are caused by a series of events when the brain gets stimulated or activated, which causes the release of chemicals that cause pain. IPN10200 is a medication that stops the release of these chemical messengers.

Participants with episodic migraine (EM) or chronic migraine (CM) will be included in both Step 1 and Step 2. "Headache days" are when participants experience headaches that meet the criteria for a migraine or a headache without the additional migraine-specific symptoms. "Migraine days" occur when the headache displays clear migraine characteristics.

This study aims to determine:

• The safety and efficacy of injecting IPN10200 directly into the muscles of the head and neck to prevent EM and CM,
• The right amount (dose) of IPN10200 to inject at each point,
• The total amount (dose) of IPN10200 that provides the best balance between safety and efficacy preventing migraines.

Participants will need to complete a daily electronic migraine Diary (eDiary) and questionnaires throughout the study. The total study duration for a participant will be up to 44 weeks.

The study will consist of 3 periods:

1. A 'screening period' to assess whether the participant can take part in the study.
2. Step 1 is divided in two cohorts. The study will assess sequentially the safety of two doses of IPN10200, a lower dose in the cohort 1 and a higher dose in cohort 2. Participants will be administered with the study drug or placebo. The treatment is injected in muscles of the head, face and neck. The safety of participants is monitored throughout the 36 weeks at each cohort.
3. Step 2: In this step, new eligible participants will be divided into two groups based on their diagnosis (EM or CM). These groups will then be randomly assigned to one of three intervention groups: Dose A, Dose B, or a placebo. The intervention will be given in a series of injections in muscles of the head, face and neck. Participants will be monitored for both efficacy and safety until they complete the Week 36 visit (the end of study).

Inclusion Criteria:

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF. Participant has provided written informed consent and signed privacy/data protection documentation;
2. Male or female ≥18 to 80 years of age at the time of signing the informed consent;
3. Diagnosis of either EM or CM, per ICHD-3 criteria, for at least 12 months prior to the screening visit;
4. Diagnosis of migraine at ≤50 years of age;
5. Participants in the EM group: History of EM diagnosis and headache frequency (i.e. migraine and non-migraine headache): ≤14 headache days in the 4 weeks prior to randomisation on study Day 1 based on information recorded in the eDiary; migraine frequency: ≥6 migraine days in the 4 weeks prior to randomisation on study Day 1 based on information recorded in the eDiary;
6. Participants in the CM group: History of CM diagnosis and headache frequency (i.e. migraine and non-migraine headache): ≥15 headache days in the 4 weeks prior to randomisation on study Day 1 based on information recorded in the eDiary; migraine frequency: ≥8 migraine days in the 4 weeks prior to randomisation on study Day 1 based on information recorded in the eDiary;
7. Participant with a history of use of at least one preventive treatment for migraine.

Exclusion Criteria:

1. 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;

2. Headache attributed to another disorder (e.g. secondary headaches), except medication overuse headache (MOH);

3. Current uncontrolled psychiatric or psychological condition, or one that could confound assessment of headaches/migraines or interfere with study participation;

4. Risk of self-harm or harm to others as evidenced by past suicidal behaviour or endorsing items 3, 4, or 5 on the C-SSRS at screening or Day 1.

5. Participants presenting with a swallowing disorder of any origin which might be exacerbated by botulinum toxin treatment, such as:

   - Grade 3 or 4 on the Dysphagia Severity Scale (severe dysphagia) with swallowing difficulties and requiring a change in diet.

6. Clinically relevant skin condition or infection that could interfere with injection of study intervention;

7. Participant has any medical condition or situation that would make them unsuitable for participation in the study;

8. Participant receiving more than one allowable concomitant migraine preventive treatment;

9. Known history of an inadequate response to >4 medications prescribed for the prevention of migraine (2 of which have different mechanisms of action to botulinum toxin);

10. Use of any of the following medications in the specified timeframe prior to the screening visit:

    • Botulinum toxin for migraine within 24 weeks (or for any other medical/aesthetic reason within 16 weeks);
    • Prior use of mAbs blocking CGRP pathway within 12 weeks for preventative treatment of migraine
    • Prior use of oral CGRP receptor antagonist (gepants) for preventative treatment of migraine within 2 weeks;
    • Anaesthetic or steroid injection in any region targeted for treatment with study medication within 4 weeks;
    • Use of cannabidiol or other types of cannabinoids within 30 days;
    • Use of medical device to treat migraine within 4 weeks (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);
    • Use of other intervention to treat migraine that is assessed to interfere with study evaluations within 4 weeks (e.g. acupuncture in the head and neck region, cranial traction, nociceptive trigeminal inhibition, occipital nerve block treatments and dental splints for headache);
    • Use of opioids or barbiturates for more than 2 days/month within the last 4 weeks.

11. Concurrent participation in another interventional clinical study (or within specified timeframe according to national or local legislation or requirements);

12. Diagnosis of other significant pain disorders that could confound the assessment of headaches/migraines or interfere with study participation, including but not limited to chronic pain disorders such as fibromyalgia, chronic low back pain and complex regional pain syndrome;

13. Pregnant women, nursing women, premenopausal women, or WOCBP (i.e. not surgically sterile or 1 year postmenopausal) not willing to practice an acceptable contraceptive method, at the beginning of the study and for a minimum of 12 weeks following the administration of study treatment;

14. Male subjects who are not vasectomised and who have female partners of childbearing potential and are not willing to use condoms with spermicide for a minimum of 12 weeks following the initial double-blind administration of the treatment;

15. History of alcohol or drug abuse within 5 years of the screening visit (excluding medication overuse for headache);

16. Body mass index (BMI) ≥35 kg/m² at the screening visit;

17. Known clinically significant hypersensitivity to any of the study drugs, excipients or materials used to administer the study drug;

18. Patients who, in the clinician's judgment, are actively suicidal, and therefore, deemed to be at significant risk for suicide.

19. A diagnosis of a neuromuscular disorder or respiratory disorder, such as myasthenia gravis, Lambert-Eaton syndrome or amyotrophic lateral sclerosis that in the opinion of the investigator would compromise the safety of the study participant.

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications.

Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants.

Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and/or EU.

Further details on Ipsen's sharing criteria and process for sharing are available here (https://www.ipsen.com/science/clinical-trials/clinical-data-transparency/).

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