Study to Determine Safety and Efficacy of B244 in Subjects With Episodic Migraine

This is a Prospective, Randomized, Vehicle-controlled, Double-blind, Multi-center, 3-arm study assessing the safety, tolerability, and efficacy of B244 delivered as an intranasal spray for preventive treatment in subjects with episodic migraine.

At Screening and Baseline, all subjects must experiences 4-14 migraine days per month and 3-14 migraine attacks per month and no more than 14 headache days per month in the 3 months prior to screening.

The total duration of the study will be approximately 16 weeks. Participants will report for a Screening visit and if all inclusion criteria are met, subjects will go through a one month baseline period prior to randomization. Subjects will come in for visits at Day 28 (Week 4), Day 56 (Week8), Day 84 (Week12), and Day 112 (Week 16).

Efficacy will be assessed by change in migraine attacks, days, and hours. Blood and urine samples will be collected for standard safety laboratory testing and the effect of the drug on inflammatory biomarkers. Safety will be monitored throughout the study.

Investigators plan to enroll 303 total subjects. Subjects will be randomized 1:1:1 so that an equal number of subjects will be treated in each arm of the study.

• B244 (Biological): B244 Suspension
• Vehicle (Biological): Vehicle Suspension

Primary outcomes

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 [Baseline to Day 112]: Safety and tolerability endpoints will consist of all adverse events reporting during the study duration.

Secondary outcomes

• Mean Change in Monthly Migraine Days. [Baseline to Day 84]: Subjects made daily entries to include recordings of migraine frequency, duration, and severity that included information on migraine days (experiencing migraine with or without aura in a given day).
• Mean Change in Monthly Migraine Attacks. [Baseline to Day 84]: Subjects made daily entries to include recordings of migraine frequency, duration, and severity that included information on migraine attacks (an episode of any qualified migraine headache. To distinguish an attack of long duration from two attacks or to distinguish between attacks and relapses: A migraine attack that is interrupted by sleep, or temporarily remits, and then recurs within 48 hours (i.e., <48 hours between the start of the migraine attack to the time of the recurrence) will be considered as one attack and not two. -An attack treated successfully with medication but with relapse within 48 hours (i.e., <48 hours between the start of the migraine attack to the time of recurrence) will be considered as one attack.)
• Proportion of Subjects Experiencing a 50%, 75%, and 100% Reduction in Monthly Migraine Days. [Baseline to Day 112]: Subjects made daily entries to include recordings of migraine frequency, duration, and severity that included information on migraine days (experiencing migraine with or without aura in a given day).
• Mean Change in Monthly Acute Migraine Specific Medication Days. [Baseline to Day 84]: Subjects made daily entries to include recordings of migraine frequency, duration, and severity that included use of rescue (acute migraine specific) medications and dosing administration.
• Mean Change in Monthly Headache Days. [Baseline to Day 84]: Subjects made daily entries to include recordings of migraine frequency, duration, and severity that included information on headache days (a non-migraine headache day)
• Mean Change From Baseline to 12 Weeks of Treatment in Disability, as Measured by the Migraine Disability Assessment (MIDAS) [Baseline to Day 84]: The Migraine Disability Assessment (MIDAS) questionnaire was administered to study examine the relationship between the impact of migraine and quality of life where subjects scored 5 questions on a scale of 0 to 21+ (0-5=little or no disability, 6-10=mild disability, 11-20=moderate disability, 21+=severe disability). The total score ranges from 0 to 90.
• Mean Change From Baseline to 12 Weeks of Treatment in Monthly Headache Impact Test-6 (HIT-6) Questionnaire [Baseline to Day 84]: The Headache Impact Test-6 (HIT-6) questionnaire was administered to examine the relationship between impact of migraine and quality of life. The total score ranges from 36 to 78 where a higher score indicates a greater impact on quality of life (Class I: 36-49, Class II: 50-55, Class III: 56-59, Class IV: 60+).
• Mean Change From Baseline to 12 Weeks of Treatment in Monthly Migraine Specific Quality of Life Questionnaire (MSQL) [Baseline to Day 84]: The Migraine Specific Quality of Life (MSQL) questionnaire was used to examine the impact of migraine on health-related quality of life across three domains: Role Function-Restrictive (7 questions) examines the degree to which performance of daily activities is limited by migraine; Role Function-Preventive (4 questions) examines the degree to which performance of daily activities is prevented by migraine; Emotional Function (3 questions) examines feelings of frustration and helplessness due to migraine. Total score for each domain ranges from 0 to 100, where a higher score indicates greater severity.

Other outcomes

• Mean Change in Days Where Subject Recorded Migraine Associated Symptoms: Nausea/Vomiting, Photophobia and Sonophobia. [Baseline to Day 112]: Subjects made daily entries to include recordings of migraine frequency, duration, and severity that included information on migraine associated symptoms: nausea/vomiting, photophobia and sonophobia.

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

* Males and Females, 18 to 65 years of age.
* In good general health as determined by a thorough medical history and physical examination, and vital signs.
* At least a 1-year history of migraine with or without aura that began before the age of 50 years old and consistent with a diagnosis of migraine with or without aura according to the International Classification of Headache Disorders, 3rd edition, beta version.
* Experiences 4-14 migraine days per month and 3-14 migraine attacks per month and no more than 14 headache days per month (including migraine and non-migraine headache days) in the 3 months prior to screening.
* Experiences 4-14 migraine headache days per month during the baseline period.
* Ability and willingness to abstain from taking medications not allowed by the protocol or administering any foreign substance intranasally.
* Ability and willingness to complete a migraine-history diary from screening to treatment with study drug and a migraine-treatment diary from prevention treatment through the remainder of the follow-up period.

Exclusion Criteria:

* Headache on greater than 14 days/month in any of the three months (90 days) preceding entry into the study.
* Use of acute migraine-specific medications (e.g., ergotamine, triptan) on more than 10 days per month in the previous 3 months and during study.
* Use of intranasal migraine medications during study.
* Use of any intranasally administered over-the-counter product or nasal irrigation (e.g., neti pot) during study.
* Opioids/barbiturates used on more than 4 days per month in the previous 3 months and throughout the duration of the study.
* Use of analgesics (including acetaminophen, nonsteroidal anti-inflammatory drugs \[NSAIDs\], acetylsalicylic acid, or combination analgesics) for migraine and non-migraine headaches on more than 14 days per month in the - Use of migraine prevention medication within two months prior to study and throughout the duration of the study.
* Botulinum toxin injection within 3 months prior to screening or during study.
* Anti-CGRP monoclonal antibody (e.g., erenumab, fremanezumab, galcanezumab, and eptinezumab) injection or infusion within 4 months prior to screening or during study.
* Small molecule anti-CGRP medications in the 30 days prior to the screening visit.
* Use of systemic antibiotics during study.
* Pregnancy or breast-feeding.
* Female of childbearing potential not using adequate contraceptive measures.
* Inability to give informed consent.
* History of neurological, psychiatric, or any other medical condition that in the opinion of the investigator may compromise the subject's ability to safely participate in the study.
* Subjects with any significant clinical abnormalities which may interfere with study participation.
* Prior use of AO+ Mist.
* Subjects with immunodeficiencies, nasal lesions, nasal polyps, or sinus infections.
* Subjects who have participated in an investigational drug trial in the 30 days prior to the screening visit.
* Inability to maintain at least 80% diary compliance during the study from baseline to follow-up.

Participant flow

Outcome results

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 (Primary), Count of participants, Participants: B244 Dose 1 18; B244 Dose 2 13; Vehicle 17
• Mean Change in Monthly Migraine Days. (Secondary), Mean, days per month: B244 Dose 1 -3.2 +/- 4.53; B244 Dose 2 -3.0 +/- 4.04; Vehicle -3.4 +/- 3.77
• Mean Change in Monthly Migraine Attacks. (Secondary), Mean, attacks: B244 Dose 1 -2.0 +/- 2.83; B244 Dose 2 -2.1 +/- 2.43; Vehicle -2.0 +/- 2.69
• Proportion of Subjects Experiencing a 50%, 75%, and 100% Reduction in Monthly Migraine Days. (Secondary), Count of participants, Participants: B244 Dose 1 31; B244 Dose 2 36; Vehicle 32
• Mean Change in Monthly Acute Migraine Specific Medication Days. (Secondary), Mean, days: B244 Dose 1 -2.0 +/- 5.62; B244 Dose 2 -2.5 +/- 3.70; Vehicle -2.9 +/- 4.26
• Mean Change in Monthly Headache Days. (Secondary), Mean, days: B244 Dose 1 -3.5 +/- 4.66; B244 Dose 2 -3.4 +/- 3.96; Vehicle -4.2 +/- 3.79
• Mean Change From Baseline to 12 Weeks of Treatment in Disability, as Measured by the Migraine Disability Assessment (MIDAS) (Secondary), Mean, score on a scale: B244 Dose 1 -10.0 +/- 24.83; B244 Dose 2 -18.0 +/- 39.43; Vehicle -13.8 +/- 23.82
• Mean Change From Baseline to 12 Weeks of Treatment in Monthly Headache Impact Test-6 (HIT-6) Questionnaire (Secondary), Mean, score on a scale: B244 Dose 1 -4.3 +/- 6.72; B244 Dose 2 -6.2 +/- 7.68; Vehicle -5.7 +/- 7.54
• Mean Change From Baseline to 12 Weeks of Treatment in Monthly Migraine Specific Quality of Life Questionnaire (MSQL) (Secondary), Mean, score on a scale: B244 Dose 1 15.5 +/- 18.00; B244 Dose 2 22.7 +/- 23.69; Vehicle 22.3 +/- 24.53
• Mean Change in Days Where Subject Recorded Migraine Associated Symptoms: Nausea/Vomiting, Photophobia and Sonophobia. (Other pre specified), Mean, days: B244 Dose 1 -2.3 +/- 4.68; B244 Dose 2 -2.8 +/- 3.49; Vehicle -2.9 +/- 3.56

Adverse events

Time frame: Baseline to Day 112

Serious adverse events by term

Other adverse events by term

71 more terms not shown.

• Study Protocol (PDF, 2018-06-22)
• Statistical Analysis Plan (PDF, 2019-03-18)

• Judith Ng-Cashin, MD, Study director, Chief Medical Officer