The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming

Rebecca W Carter; Charles J Gerardo; Stephen P Samuel; Surendra Kumar; Suneetha D Kotehal; Partha P Mukherjee; Farshad M Shirazi; Peter D Akpunonu; Chanaveerappa Bammigatti; Ashish Bhalla; Neeraj Manikath; Timothy F Platts-Mills; Matthew R Lewin; BRAVO Study Group

doi:10.3390/toxins15010022

The BRAVO Clinical Study Protocol: Oral Varespladib for Inhibition of Secretory Phospholipase A2 in the Treatment of Snakebite Envenoming

Toxins (Basel). 2022 Dec 28;15(1):22. doi: 10.3390/toxins15010022.

Affiliations

¹ Ophirex, Inc., Corte Madera, CA 94295, USA.
² Department of Emergency Medicine, Duke University, Durham, NC 27708, USA.
³ Department of Medicine, Sardar Patel Medical College, PBM Hospital, Bikaner 334001, India.
⁴ Department of Medicine, Mysore Medical College and Research Institute, Mysore 570001, India.
⁵ Department of General Medicine, Calcutta National Medical College, Kolkata 700014, India.
⁶ Arizona Poison & Drug Information Center, College of Pharmacy and University of Arizona College of Medicine, University of Arizona, Tucson, AZ 85721, USA.
⁷ Department of Emergency Medicine and Medical Toxicology, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
⁸ Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India.
⁹ Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
¹⁰ Department of Emergency Medicine, Government Medical College, Kozhikode 673008, India.

Abstract

Introduction: Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A₂ (sPLA₂) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies.

Methods and analysis: BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite) is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl plus standard of care (SoC) vs. SoC plus placebo in patients presenting with acute SBE by any venomous snake species. Male and female patients 5 years of age and older who meet eligibility criteria will be randomly assigned 1:1 to varespladib-methyl or placebo. The primary outcome is the Snakebite Severity Score (SSS) that has been modified for international use. This composite outcome is based on the sum of the pulmonary, cardiovascular, nervous, hematologic, and renal systems components of the updated SSS.

Ethics and dissemination: This protocol was submitted to regulatory authorities in India and the US. A Clinical Trial No Objection Certificate from the India Central Drugs Standard Control Organisation, Drug Controller General-India, and a Notice to Proceed from the US Food and Drug Administration have been obtained. The study protocol was approved by properly constituted, valid institutional review boards or ethics committees at each study site. This study is being conducted in compliance with the April 1996 ICH Guidance for Industry GCP E6, the Integrated Addendum to ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study is conducted. The trial is registered on Clinical trials.gov, NCT#04996264 and Clinical Trials Registry-India, 2021/07/045079 000062.

Keywords: BRAVO; clinical trial; direct toxin inhibitor; protocol; snakebite; snakebite severity score; varespladib.

Publication types

Clinical Trial Protocol
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Clinical Trials, Phase II as Topic
Female
Humans
Male
Multicenter Studies as Topic
Phospholipases A2, Secretory*
Randomized Controlled Trials as Topic
Snake Bites* / drug therapy

Substances

varespladib
tetrachloroisophthalonitrile
varespladib methyl
Phospholipases A2, Secretory

Grants and funding

This work was supported by the Defense Health Agency, administered by US Army Medical Materiel Development Activity under SBIR 3 Award No. W81XWH20C0017. Work was also supported by the Wellcome Trust, Award No. 222964/Z/21/Z. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense or the Wellcome Trust.