A Study to Evaluate the Long-Term Safety of M207 in the Acute Treatment of Migraine

This is an open-label, twelve-month safety study. There is a screening period followed by a run-in period (14 to 21 days) to determine eligibility for treatment with study medication based on daily eDiary data collection. Qualified subjects will receive study medication on Day 1 for up to twelve months for the treatment of migraine headaches. Migraines will be treated with a single dose, consisting of two patches, but subjects can treat multiple migraine attacks throughout the 12 months. Using the eDiary to confirm they are experiencing a qualified migraine, subjects will self-administer the patches and continue to respond to questions in the eDiary for 48 hours post treatment administration.

• M207 Microneedle System (Drug), also known as ZP-Zolmitriptan Intracutaneous Microneedle System, ADAM-Zolmitriptan: M207 Microneedle System 3.8 mg

Primary outcomes

• Number of Subjects With Any Treatment-emergent Adverse Events (TEAE) Over 12 Months [0 to 12 months]: Number and % of subjects in safety population with any treatment-emergent adverse event(s) during the study. TEAE is defined as any new adverse event (AE) that started after first patch application. This was an open-label study with no control group. No statistical analyses were performed. Application site skin reactions including erythema, swelling, haemorrhage, bruise, pain, and pruritus were collected systematically via subject e-diary and/or investigator skin assessment at study visits. All other AEs were spontaneously reported by subject or observed upon examination.

Secondary outcomes

• Percentage of Migraine Attacks for Which Pain Freedom Was Achieved at 2 Hours Post-dose [2 hours for each Migraine, up to 12 months for each subject]: Percentage of migraine attacks for which pain freedom defined as a pain level of 'None' (Grade 0 on pain severity scale where 0: None, 1: Mild, 2: Moderate, 3: Severe, and lower values represent a better outcome) was achieved at 2 hours post-dose without the use of rescue medication. This was an open-label study with no control group. No statistical analyses were performed.
• Percentage of Migraine Attacks for Which Most Bothersome Symptom Freedom Was Achieved at 2 Hours Post-dose [2 hours for each Migraine, up to 12 months for each subject]: Percentage of migraine attacks for which freedom from most bothersome symptom other than pain defined as an absence of the most bothersome symptom was achieved at 2 hours post-dose without the use of rescue medication. This was an open-label study with no control group. No statistical analyses were performed.
• Percentage of Migraine Attacks for Which Pain Relief Was Achieved at 2 Hours Post-dose [2 hours for each Migraine, up to 12 months for each subject]: Percentage of migraine attacks for which pain relief defined as an improvement of pain severity (1) to mild (Grade 1) or none (Grade 0) from moderate (Grade 2) or severe (Grade 3) at baseline, or (2) an improvement of pain severity to none (Grade 0) from mild (Grade 1) at baseline, without rescue medication was achieved. Pain severity scale has grades: 0: None, 1: Mild, 2: Moderate, 3: Severe, where lower values represent a better outcome. This was an open-label study with no control group. No statistical analyses were performed.
• Percentage of Migraine Attacks for Which Nausea Freedom Was Achieved at 2 Hours Post-dose [2 hours for each Migraine, up to 12 months for each subject]: Percentage of subjects for which nausea freedom defined as absence of nausea and/or vomiting without the use of rescue medication was achieved at 2 hours post-dose. This was an open-label study with no control group. No statistical analyses were performed.
• Percentage of Migraine Attacks for Which Photophobia Freedom Was Achieved at 2 Hours Post-dose [2 hours for each Migraine, up to 12 months for each subject]: Percentage of migraine attacks for which photophobia freedom defined as an absence of photophobia without the use of rescue medication was achieved at 2 hours post-dose. This was an open-label study with no control group. No statistical analyses were performed.
• Percentage of Migraine Attacks for Which Phonophobia Freedom Was Achieved at 2 Hours Post-dose [2 hours for each Migraine, up to 12 months for each subject]: Percentage of migraine attacks for which phonophobia freedom defined as an absence of phonophobia without the use of rescue medication was achieved at 2 hours post-dose. This was an open-label study with no control group. No statistical analyses were performed.

Sex: All, ages: 18 Years to 75 Years

Main Inclusion Criteria:

1. Women or men 18 to 75 years of age
2. Greater than 1 year history of episodic, migraine (with or without aura) with onset prior to 50 years of age.
3. Migraine history during the prior 6 months must include:

   1. at least 2 migraines per month
   2. no more than 8 migraines per month
   3. no more than 15 headache days per month
4. Women of child-bearing potential must not be pregnant, must agree to avoid pregnancy and use an acceptable double-barrier method of birth control during the trial.
5. Willing and able to treat a minimum of 2 migraines per month with study medication and consistently complete eDiary for up to 12 months.

Main Exclusion Criteria:

1. Contraindication to triptans
2. Use of selective serotonin reuptake inhibitors (drugs like Prozac®) or serotonin or norepinephrine reuptake inhibitors (drugs like Effexor®) or anti-coagulants (drugs like Coumadin®)
3. Known allergy or sensitivity to zolmitriptan or its derivatives or formulations
4. Known allergy or sensitivity to adhesives and/or titanium
5. Women who are pregnant, breast-feeding or plan a pregnancy during this study
6. Three or more of the following cardiovascular risk factors:

   * Current tobacco use
   * Hypertension or receiving anti-hypertensive medication for hypertension
   * Hyperlipidemia or on prescribed anti-cholesterol treatment
   * Family history of premature coronary artery disease
   * Diabetes mellitus
7. History or current abuse or dependence on alcohol or drugs

Participant flow

Outcome results

• Number of Subjects With Any Treatment-emergent Adverse Events (TEAE) Over 12 Months (Primary), Count of participants, Participants: M207 Microneedle System 3.8 mg 323
• Percentage of Migraine Attacks for Which Pain Freedom Was Achieved at 2 Hours Post-dose (Secondary), Count of units, Qualifying migraines with 2 hour data: M207 Microneedle System 3.8 mg 2477
• Percentage of Migraine Attacks for Which Most Bothersome Symptom Freedom Was Achieved at 2 Hours Post-dose (Secondary), Count of units, Qualifying migraines with 2 hr data: M207 Microneedle System 3.8 mg 3315
• Percentage of Migraine Attacks for Which Pain Relief Was Achieved at 2 Hours Post-dose (Secondary), Count of units, Qualifying migraines with 2 hr data: M207 Microneedle System 3.8 mg 4552
• Percentage of Migraine Attacks for Which Nausea Freedom Was Achieved at 2 Hours Post-dose (Secondary), Count of units, Qualifying migraines with 2 hr data: M207 Microneedle System 3.8 mg 4628
• Percentage of Migraine Attacks for Which Photophobia Freedom Was Achieved at 2 Hours Post-dose (Secondary), Count of units, Qualifying migraines with 2 hour data: M207 Microneedle System 3.8 mg 3410
• Percentage of Migraine Attacks for Which Phonophobia Freedom Was Achieved at 2 Hours Post-dose (Secondary), Count of units, Qualifying migraines with 2 hour data: M207 Microneedle System 3.8 mg 3563

Adverse events

Time frame: 0-12 months

Serious adverse events by term

Other adverse events by term

• Results publication: Nahas SJ, Hindiyeh N, Friedman DI, Elbuluk N, Kellerman DJ, Foreman PK, Schmidt P. Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine. J Headache Pain. 2021 May 17;22(1):37. doi: 10.1186/s10194-021-01249-z. PMID 34001002

• Statistical Analysis Plan (PDF, 2018-11-30)
• Study Protocol (PDF, 2018-04-06)

• Don Kellerman, Pharm.D., Study director, Zosano Pharma Corporation