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

Phase 3TerminatedNCT04346615

Pfizer47 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

COVID-19 Infection

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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 2. Subjects must agree to provide all requested demographic information (i.e. gender, race) 3. Subjects must be able to read and understand English or Spanish 4. Subjects must be over the age of 18 years 5. Subjects must have laboratory-confirmed SARS-CoV-2 infection as determined by PCR-based commercial or public health assay 6. 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 7. Subjects must be willing and able to comply with study-related procedures/assessments Exclusion Criteria: 1. Subjects in immediate need of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 2. Subjects with an eGFR \< 30 mL/min, at the Screening Visit 3. Prisoners or subjects who are involuntarily incarcerated 4. Subjects who are participating in any other investigational clinical trial while participating in this clinical trial 5. Subjects who are under the age of 18 years 6. Subjects who are pregnant (all potential female enrollees need to have a negative pregnancy test prior to IP administration) 7. Subjects with multi-organ failure 8. Subjects who have received more than 48 hours of supplemental oxygen prior to randomization 9. Subjects with prior significant pulmonary disease (e.g., severe COPD/ILD/CHF/IPF) are excluded 10. 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 11. 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 12. Subjects who are unlikely to survive for more than 48 hours from the Screening Visit 13. 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 14. Subjects with known active TB, history of incompletely treated TB, suspected or known extrapulmonary TB 15. Subjects with suspected or known systemic bacterial or fungal infections. However, empiric antibiotics are permitted. 16. 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 17. 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

Locations (6)

Georgetown University Hospital Research Pharmacy

Washington D.C., District of Columbia, United States

Georgetown University Hospital

Washington D.C., District of Columbia, United States

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, United States

Jefferson Torresdale Hospital

Philadelphia, Pennsylvania, United States

Roper Hospital

Charleston, South Carolina, United States

Outcomes

Primary Outcomes

Mean 6 Point Ordinal Severity Rating Scale (6POSRS) Score at Day 15

The 6POSRS score was used to assess severity and ranged from 1 to 6 where: 1= Death; 2= Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), 3= Hospitalized, on non-invasive ventilation or high-flow oxygen devices; 4= Hospitalized, requiring supplemental oxygen; 5= Hospitalized, not requiring supplemental oxygen and 6= not hospitalized. A higher score indicated a better outcome.

Time frame: Day 15

Secondary Outcomes

Percentage of Participants With a 6-Point Severity Rating of 5 or 6, Who Were Alive and Off Supplemental Oxygen at Day 29

Percentage of participants who were alive and had a 6POSRS rating of 5 (Hospitalized, not requiring supplemental oxygen) or 6 (not hospitalized) and did not use supplemental oxygen at Day 29 were reported in this outcome measure. Participants with missing 6POSRS rating at Day 29 had the last on-study 6POSRS rating before Day 29 used. Participants with \>= 1 procedure day of supplemental oxygen use before Day 29 for an ongoing procedure were considered failures, i.e., not alive or not off of oxygen at Day 29. 95% confidence interval (CI) was based on exact Clopper and Pearson method.

Time frame: Day 29

Percentage of Participants With a 6-Point Severity Rating of 2 or 3 or Required Initiation of Invasive Mechanical Ventilation, Non-Invasive Ventilation, or a High-Flow Nasal Cannula Through Day 29

Percentage of participants who had a 6POSRS rating of 2 (Hospitalized, on invasive mechanical ventilation or ECMO) or 3 (Hospitalized, on non-invasive ventilation or high-flow oxygen devices) or \>= 1 procedure day of ventilation or high-flow nasal cannula use on study through Day 29 were reported in this outcome measure. Participants with missing 6POSRS rating at Day 29 had all available on-study 6POSRS ratings before Day 29 used. 95% CI was based on exact Clopper and Pearson method.

Time frame: Up to Day 29

Percentage of Participants Admitted Into an Intensive Care Unit (ICU) Through Day 29

Percentage of participants admitted into an ICU on any day through Day 29 were reported in this outcome measure. 95% CI was based on exact Clopper and Pearson method

Time frame: Up to Day 29

Number of Participants With On-Treatment Deaths, Serious Adverse Events (SAEs) and Severe Adverse Events (AEs)

An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that did not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; was life-threatening; required prolongation of existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect; other important medical events. Severe AEs were AEs that interrupted usual activities of daily living, significantly affected clinical status, or required intensive therapeutic intervention. On-treatment was defined as the time on study drug.

Time frame: From first dose of study treatment on Day 1 until Day 15

Number of Participants With Grade 3 or 4 On-Treatment Laboratory Test Abnormalities

The following laboratory parameters were assessed: eosinophils, hemoglobin, leukocytes, lymphocytes (high and low), neutrophils, platelets, alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bicarbonate, bilirubin, calcium (high and low), creatine kinase, creatinine, glomerular filtration rate (GFR) estimated Modification of Diet in Renal Disease (MDRD), glucose (high and low), lactate dehydrogenase, potassium (high and low), sodium (high and low), urate, glucose (urine) and protein (urine). Laboratory abnormalities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5 for all parameters except glucose and uric acid. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 was used for grading glucose and uric acid. Grade 3=severe and grade 4=potentially life threatening. Number of participants with grade 3 or 4 laboratory abnormalities is reported.

Time frame: From first dose of study treatment on Day 1 until Day 15

Number of Participants With Severe or Life-Threatening Bacterial, Invasive Fungal, or Opportunistic Infections Through Day 29

Number of participants with any severe or life-threatening bacterial, invasive fungal, or opportunistic infections through Day 29 is reported in this outcome measure. Severe= interrupted usual activities of daily living, significantly affected clinical status, or required intensive therapeutic intervention. Life threatening=Participant was at immediate risk of death from the event as it occurred; i.e., it did not include a reaction that if it had occurred in a more serious form might have caused death.

Time frame: Up to Day 29

Number of Participants With Intranasal Administration Reactions Through Day 29

Time frame: Up to Day 29

Percentage of Participants With >= 50% Reduction in Estimated Glomerular Filtration Rate (eGFR) From Baseline

Percentage of participants with \>=50% reduction in eGFR from Baseline during on-treatment phase were reported in this outcome measure.

Time frame: From Baseline (Day 1) up to Day 15