Acute Treatment Trial in Adult Subjects With Migraines

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the safety and efficacy of three different intranasal dose levels of zavegepant (BHV-3500), relative to placebo, in the acute treatment of moderate to severe migraine.

Official Title
-----------------
Phase II/III: Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Trial of BHV-3500 for the Acute Treatment of Migraine

Conditions
-----------------
Migraine

Intervention / Treatment
-----------------
* Drug: Zavegepant
* Drug: Zavegepant matching placebo
* Device: Intranasal Aptar Pharma Unit Dose System


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Key Inclusion Criteria: 1. Participants have at least 1-year history of migraines (with or without aura), consistent with a diagnosis according to the International Classification of Headache Disorder, 3rd Edition, including the following: Migraine attacks present for more than 1 year with the age of onset prior to 50 years of age. Migraine attacks, on average, lasting about 4-72 hours if untreated. Not more than 8 attacks of moderate to severe intensity per month within the last 3 months. At least 2 consistent migraine headache attacks of moderate or severe intensity in each of the 3 months prior to the Screening Visit and throughout the Screening Period. Less than 15 days with headache (migraine or non-migraine) per month in each of the 3 months prior to the Screening Visit and throughout the Screening Period. Participants on prophylactic migraine medication are permitted to remain on therapy provided they have been on a stable dose for at least 3 months prior to Screening Visit and the dose is not expected to change during the course of the study. Participants with contraindications for use of triptans may be included provided they meet all other study entry criteria. Exclusion Criteria: Key Exclusion Criteria: Participant with a history of basilar migraine or hemiplegic migraine. Participant with a history of human immunodeficiency virus (HIV) disease. Participant history with current evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and cerebral ischemia. Participants with myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke or transient ischemic attack during the 6 months prior to screening. Uncontrolled hypertension (high blood pressure), or uncontrolled diabetes (however subjects can be included who have stable hypertension and/or diabetes for at least 3 months prior to being enrolled). Participant has a current diagnosis of major depression, other pain syndromes, psychiatric conditions (for example, schizophrenia), dementia, or significant neurological disorders (other than migraine) that, in the Investigator's opinion might interfere with study assessments. Participant has a history of gastric, or small intestinal surgery (including gastric bypass, gastric banding, gastric sleeve, gastric balloon, etc.), or has disease that causes malabsorption. The participant has a history of current or evidence of any significant and/ or unstable medical conditions (for example, history of congenital heart disease or arrhythmia, known suspected infection, hepatitis B or C, or cancer) that, in the Investigator's opinion, would expose them to undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial. History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 months or subjects who have met Diagnostic and Statistical Manual of Mental Disorders Fifth edition (DSM-V) criteria for any significant substance use disorder within the past 12 months from the date of the Screening Visit. History of nasal surgery in the 6 months preceding the Screening Visit. Participation in any other investigational clinical trial while participating in this clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zavegepant 5 mg<br>Participants administered a single intranasal dose of zavegepant 5 mg on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar Unidose System (UDS) liquid spray device. | Drug: Zavegepant<br>* A single dose of zavegepant<br>* Other names: BHV3500;Device: Intranasal Aptar Pharma Unit Dose System<br>* A single-dose intranasal device<br>|
| Experimental: Zavegepant 10 mg<br>Participants administered a single intranasal dose of zavegepant 10 mg on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar UDS liquid spray device. | Drug: Zavegepant<br>* A single dose of zavegepant<br>* Other names: BHV3500;Device: Intranasal Aptar Pharma Unit Dose System<br>* A single-dose intranasal device<br>|
| Experimental: Zavegepant 20 mg<br>Participants administered a single intranasal dose of zavegepant 20 mg on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar UDS liquid spray device. | Drug: Zavegepant<br>* A single dose of zavegepant<br>* Other names: BHV3500;Device: Intranasal Aptar Pharma Unit Dose System<br>* A single-dose intranasal device<br>|
| Placebo Comparator: Placebo<br>Participants administered a single intranasal dose of zavegepant-matching placebo on occurrence of migraine that reached moderate or severe intensity within 45 days after randomization. The dose was administered using Aptar UDS liquid spray device. | Drug: Zavegepant matching placebo<br>* A single dose of placebo matched to zavegepant<br>Device: Intranasal Aptar Pharma Unit Dose System<br>* A single-dose intranasal device<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Freedom From Pain at 2 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the electronic clinical outcome assessment (eCOA) handheld device. Pain freedom was defined as pain level of none post-dose. | 2 hours post-dose | 
| Percentage of Participants With Freedom From Most Bothersome Symptom (MBS) at 2 Hours Post-dose | MBS was reported as nausea, photophobia, or phonophobia at migraine onset using the eCOA handheld device. Symptom status (absent, present) was assessed post-dose using the eCOA handheld device separately for nausea, photophobia, and phonophobia. Freedom from MBS was defined as MBS reported at on-study migraine attack onset that was absent post-dose. | 2 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pain Relief at 2 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Pain relief was defined as pain level of none or mild. | 2 hours post-dose | 
| Percentage of Participants Who Were Able to Function Normally at 2 Hours Post-dose | Functional disbaility level was assessed on a 4-point scale (normal function, mildly impaired, severely impaired, requires bedrest) using the eCOA handheld device. Normal function was defined as a functional disability level of normal post-dose in the subset of participants with functional disability (mildly impaired, severely impaired, requires bedrest) at on-study migraine attack onset. | 2 hours post-dose | 
| Percentage of Participants With Rescue Medication Use Within 24 Hours Post-dose | Participants who did not experience relief of their migraine headache at the end of 2 hours after dosing with study medication (and after the 2-hour assessments had been completed on the eCOA handheld device) were permitted to use the following rescue medications: aspirin, ibuprofen, acetaminophen up to 1000 mg/day (this includes Excedrin® Migraine), naproxen (or any other type of nonsteroidal anti-inflammatory drug), antiemetics (for example, metoclopramide or promethazine), or baclofen. The participant's use of rescue medication was recorded by the site on a case report form. | Through 24 hours post-dose | 
| Percentage of Participants With Freedom From Photophobia at 2 Hours Post-dose | Photophobia (sensitivity to light) status was measured as absent or present in the eCOA handheld device. Freedom from photophobia was defined as photophobia absent post-dose in the subset of participants with photophobia present at on-study migraine attack onset. | 2 hours post-dose | 
| Percentage of Participants With Freedom From Phonophobia at 2 Hours Post-dose | Phonophobia (sensitivity to sound) status was measured as absent or present in the eCOA handheld device. Freedom from phonophobia was defined as phonophobia absent post-dose in the subset of participants with phonophobia present at on-study migraine attack onset. | 2 hours post-dose | 
| Percentage of Participants With Pain Relief at 60 Minutes Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Pain relief was defined as pain level of none or mild. | 60 minutes post-dose | 
| Percentage of Participants Who Were Able to Function Normally at 60 Minutes Post-dose | Functional disbaility level was assessed on a 4-point scale (normal function, mildly impaired, severely impaired, requires bedrest) using the eCOA handheld device. Normal function was defined as a functional disability level of normal post-dose in the subset of participants with functional disability (mildly impaired, severely impaired, requires bedrest) at on-study migraine attack onset. | 60 minutes post-dose | 
| Percentage of Participants With Pain Relief at 30 Minutes Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Pain relief was defined as pain level of none or mild. | 30 minutes post-dose | 
| Percentage of Participants Who Were Able to Function Normally at 30 Minutes Post-dose | Functional disbaility level was assessed on a 4-point scale (normal function, mildly impaired, severely impaired, requires bedrest) using the eCOA handheld device. Normal function was defined as a functional disability level of normal post-dose in the subset of participants with functional disability (mildly impaired, severely impaired, requires bedrest) at on-study migraine attack onset. | 30 minutes post-dose | 
| Percentage of Participants With Sustained Pain Relief From 2 to 24 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Sustained pain relief was defined as pain level of none or mild at 2 hours up to 24 hours post-dose. | From 2 hours up to 24 hours post-dose | 
| Percentage of Participants With Sustained Pain Freedom From 2 to 24 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Sustained pain freedom was defined as pain level of none at 2 hours up to 24 hours post-dose. | From 2 hours up to 24 hours post-dose | 
| Percentage of Participants With Sustained Pain Relief From 2 to 48 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Sustained pain relief was defined as pain level of none or mild at 2 hours up to 48 hours post-dose. | From 2 hours up to 48 hours post-dose | 
| Percentage of Participants With Sustained Pain Freedom From 2 to 48 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Sustained pain freedom was defined as pain level of none at 2 hours up to 48 hours post-dose. | From 2 hours up to 48 hours post-dose | 
| Percentage of Participants With Freedom From Nausea at 2 Hours Post-dose | Nausea status was measured as absent or present in the eCOA handheld device. Freedom from nausea was defined as nausea absent post-odse in the subset of participants with nausea present at on-study migraine attack onset. | 2 hours post-dose | 
| Percentage of Participants With Pain Relapse From 2 to 48 Hours Post-dose | Pain levels were assessed on a 4-point scale (none, mild, moderate, severe) using the eCOA handheld device. Pain relapse was defined as pain level of mild, moderate, or severe after 2 hours up to 48 hours post-dose in the subset of participants with pain level of none at 2 hours post-dose. | From 2 hours up to 48 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Migraine, phonophobia, photophobia, nausea