Safety and Efficacy Trial of Zavegepant* Intranasal for Hospitalized Patients With COVID-19 Requiring Supplemental Oxygen

Study Overview
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Brief Summary
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The purpose of this study is to determine if a CGRP receptor antagonist may potentially blunt the severe inflammatory response at the alveolar level, delaying or reversing the path towards oxygen desaturation, Acute respiratory distress syndrome (ARDS), requirement for supplemental oxygenation, artificial ventilation or death in patients with COVID-19 on supplemental oxygen. * BHV-3500, formerly vazegepant, is now referred to as zavegepant (za ve' je pant). The World Health Organization (WHO) International Nonproprietary Names (INN) Expert Committee revised the name to zavegepant which was accepted by the United States Adopted Names (USAN ) Council for use in the U.S. and is pending formal adoption by the INN for international use.

Official Title
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BHV3500-203: Double-Blind, Randomized, Placebo Controlled, Safety and Efficacy Trial of Zavegepant* (BHV-3500) Intranasal (IN) for Hospitalized Patients With COVID-19 Requiring Supplemental Oxygen

Conditions
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COVID-19 Infection

Intervention / Treatment
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* Drug: Zavegepant (BHV-3500)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must provide informed consent in accordance with requirements of the study center's institutional review board (IRB) or eithics committee prior to the initiation of any protocol-required procedures Subjects must agree to provide all requested demographic information (i.e. gender, race) Subjects must be able to read and understand English or Spanish Subjects must be over the age of 18 years Subjects must have laboratory-confirmed SARS-CoV-2 infection as determined by PCR-based commercial or public health assay Subjects must have symptoms that require hospitalization with supplemental oxygen and / or non-invasive ventilation as determined by the admitting physician. The maximum nasal cannula O2 concentration should be determined by the treating clinician and the limitations of the specific equipment Subjects must be willing and able to comply with study-related procedures/assessments Exclusion Criteria: Subjects in immediate need of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Subjects with an eGFR < 30 mL/min, at the Screening Visit Prisoners or subjects who are involuntarily incarcerated Subjects who are participating in any other investigational clinical trial while participating in this clinical trial Subjects who are under the age of 18 years Subjects who are pregnant (all potential female enrollees need to have a negative pregnancy test prior to IP administration) Subjects with multi-organ failure Subjects who have received more than 48 hours of supplemental oxygen prior to randomization Subjects with prior significant pulmonary disease (e.g., severe COPD/ILD/CHF/IPF) are excluded Subjects receiving investigational therapies as part of a formal clinical trial for the treatment of COVID-19. During the course of this study, investigational therapies that may become standard of care to treat COVID-19, but are not part of a clinical trial, are allowed Subjects who are on long-acting CGRP monoclonal antibodies will be excluded including Aimovig (erenumab), Emgality (galcanezumab), Ajovy (fremanezumab), and Vyepti (eptinezumab). Additionally, the investigational oral CGRP receptor antagonist, atogepant, that is taken daily will also be excluded. Oral CGRP receptor antagonists, Nurtec ODT (rimegepant) and Ubelvy (ubrogepant) that are typically used PRN infrequently will not be excluded as long the subject was not taking them on a daily basis and does not take them during the current study Subjects who are unlikely to survive for more than 48 hours from the Screening Visit Subjects with any of the following abnormal laboratory values at screening: aspartate AST or ALT greater than 5x ULN or bilirubin greater than 2x ULN Subjects with known active TB, history of incompletely treated TB, suspected or known extrapulmonary TB Subjects with suspected or known systemic bacterial or fungal infections. However, empiric antibiotics are permitted. Subjects who have participated in any clinical research study evaluating an IP or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit Subjects with any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the subject by their participation in the study

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zavegepant<br>Zavegepant (BHV-3500) 10 mg intranasal (IN) dosed every 8 hours (3 times/day) (Q8h) for 14 days | Drug: Zavegepant (BHV-3500)<br>* 10 mg intranasal (IN) for 14 days<br>|
| Placebo Comparator: Placebo<br>Placebo Q8h for 14 days Subjects dosed every 8 hours; 3 times/day (Q8h) | Drug: Placebo<br>* Placebo Q8h for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the efficacy of zavegepant (BHV-3500) to placebo in subjects hospitalized with COVID-19 infection requiring supplemental oxygen, using a six-point rating scale at Day 15. . | a. Efficacy will be measured by the difference between groups in the meah 6-point severity rating at Day 15. The severity ratings are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized | Baseline to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who have a 6-point severity rating of 5 or 6, are alive, and do not use supplemental oxygen as a procedure at Day 29. |  | Baseline to Day 29 | 
| Proportion of subjects who have a 6-point severity rating of 2 or 3, or use any ventilation or high-flow nasal cannula as procedures, on any day through Day 29. |  | Baseline to Day 29 | 
| Proportion of subjects admitted into an ICU on any day through Day 29 from AE eCRFs. |  | Baseline to Day 29 | 
| Number of subjects with deaths, SAEs, severe AEs, and Grade 3 or 4 laboratory test abnormalities at any time on study. |  | Screening to Day 60 | 
| Number and percentage of subjects with severe or life-threatening bacterial, invasive fungal, or opportunistic infections at any time through Day 29 from AE/SAE eCRFs. |  | Baseline to Day 29 | 
| Number and percentage of subjects with intranasal administration reactions at any time through Day 29 from AE/SAE eCRFs. |  | Baseline to Day 29 | 
| Proportion of subjects with ≥ 50% reduction in eGFR from baseline at any time on study from laboratory test eCRFs. |  | Baseline to Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, COVID, Coronavirus, Biohaven, Intranasal, SARS-CoV-2, BHV-3500, Zavegepant