Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite

Ophirex, Inc.95 enrolled

Overview

This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.

This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of varespladib-methyl, concurrently with SOC, in subjects bitten by venomous snakes. Approximately 110 male and female eligible subjects will be enrolled and randomized to receive active varespladib-methyl or placebo (in addition to SOC) in a 1:1 ratio (approximately 36 per group). There will be no stratification by type of snakebite, though randomization will be stratified by age group (5 to 11 years, 12 to 17 years, and ≥ 18 years) and by the presence or absence of severe neurologic symptoms defined by yes/no neurologic system subscore of the snakebite severity score of ≥ 2. Effective treatments for snakebite envenoming represents a deadly and unmet global medical need. While antivenoms comprise the SOC for treatment of snakebites, they suffer from several limitations including specificity of each antivenom for specific species of snake, limited access to antivenom in rural areas, practical storage requirements, and delays in administration. Treatment of snakebite envenoming with the small-molecule drug varespladib-methyl, which targets secreted phospholipase A₂ (sPLA₂) present in more than 95% of snake venoms, has the potential to overcome several limitations of serum-based antivenoms that underpin traditional SOC. This study in the United States and India will provide coverage of a broad spectrum of venomous snake genera, including elapids, pit vipers, and potentially exotics such as vipers and colubrids if encountered over the course of the study. The study is designed to cover differing geographies and differing sPLA₂ structures. Study sites have been and will be selected based on demonstrated historical incidence of snake bites from species deemed relevant to this study, to ensure a broad range of envenoming toxins are expected to be encountered in potential study subjects. The study design allows for both treatment arms (varespladib-methyl and placebo) to receive SOC (e.g., antivenom) concurrently. Thus, critically ill adult and pediatric subjects may receive emergency treatment in a timely manner while being evaluated for the potential clinical benefit associated with inhibition of venom sPLA₂ and inflammatory sPLA2s by varespladib-methyl. Because subjects with severe snakebites are admitted to emergency departments, this study was designed to screen, enroll, and administer treatment in a single visit at the hospital upon admission. Because varespladib-methyl is administered orally, subjects who demonstrate substantial improvement and are eligible for discharge from the hospital may continue investigational product treatment in an outpatient setting. Risks associated with the control (placebo) arm of this study include the same risks associated with SOC (antivenom).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Snakebites Envenoming Envenoming, Snake Envenomation, Snake

Interventions

Varespladib MethylDRUG

Varespladib-methyl (LY333013) is an IR, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg IR capsules for oral administration.

PlaceboDRUG

The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Placebo for scaled pediatric dosing is supplied as an IR capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.

Standard of care (SOC)DRUG

Eligibility

Sex: ALLMin age: 5 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Is a male or female subject ≥ 5 years of age with venomous snakebite and must present with an initial SSS of * 2 points in any SSS category other than gastrointestinal and 1 or more additional points in any other SSS category other than gastrointestinal or * ≥ 3 in any SSS category other than gastrointestinal. SSS scoring should be performed for inclusion assessment without waiting for receipt of Baseline hematological laboratory results. Gastrointestinal scores should not be used for inclusion. 2. Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment. 3. Must meet one of two categories of inclusion criteria: Category 1: The patient has not yet completed first dose of antivenom: SSS inclusion score\* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system. OR Category 2: The patient has completed an initial dose of antivenom: SSS inclusion score\* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system AND CGI-I score of ≥5 (i.e., minimally worse, much worse, or very much worse). 4. Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures. Exclusion Criteria: 1. Has received antivenom treatment for envenoming prior to enrollment in this study. 2. Is considered by the investigator to have a clinically significant upper GI bleed evidenced by hematemesis, "coffee-ground" emesis or nasogastric aspirate, or hematochezia thought to originate from upper GI tract. 3. Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension. 4. Has known history of inherited bleeding or coagulation disorder. 5. Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bivalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlopidine or another anticoagulant agent not specifically listed, or has used heparin, enoxaparin, fondaparinux, or other low molecular weight heparin or antiarrhythmic drugs within 14 days prior to treatment. 6. Has a history of chronic liver disease such as chronic active viral hepatitis, alcohol-related liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, or autoimmune hepatitis. 7. Reports or has known pre-existing renal impairment or chronic kidney disease (defined as Stage 4 or receiving dialysis or hemofiltration). 8. Has a known allergy or significant adverse reaction to varespladib-methyl or related compounds. 9. Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns. 10. Is pregnant, has a positive serum human chorionic gonadotropin (hCG) pregnancy test or not willing to use a highly effective method of contraception for 14 days after initial treatment, or is breast-feeding.

Locations (16)

University of Arizona

Tucson, Arizona, United States

Loma Linda University Medical Center

Loma Linda, California, United States

Outcomes

Primary Outcomes

Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS)

Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, nervous system, and renal subscores of the SSS. The values from each of these subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on up to 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal system (graded at levels from Grade 0 to Grade 3), local wound, and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The minimum score for the five item SSS is 0 and the maximum score is 16, with the higher score indicating worse symptoms. For the primary outcome we are focusing only on 5 subscores, that does not include the local wound nor the gastrointestinal subscores.

Time frame: Baseline to 6 and 9 hours after first dose

Secondary Outcomes

Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS

Baseline (pre-dosing) through Day 7 in the AUC of the local wound, pulmonary, cardiovascular, hematologic symptoms, nervous, and renal system sections of the SSS. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal effects (graded at levels from Grade 0 to Grade 3), local wound and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The maximum score for the SSS is 23. For this outcome, the maximum score is 20 and if this score was present for the entire first week (168 hours) the maximum AUC is 3,370. The minimum AUC is a score of 3 at baseline and a score of 0 at three hours, which gives an AUC of 5.25.

Time frame: Baseline through Day 7

Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)

Numeric Pain Rating Scale is a scale that goes from 0 to 10 with 10 being the worst possible pain. This measure is an AUC measure that is calculated from 0 to 48 hours using trapezoidal function in which the mean score for any given 2 periods of time is multiplied by the elapsed duration of time between those two periods. Each of these mean scores are summed to calculate the AUC. The minimum score is 0 and the maximum is 480.

Data from ClinicalTrials.gov

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