Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of a Multi-Dose Regimen of Oral Varespladib-Methyl in Subjects Bitten by Venomous Snakes

Conditions
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Snakebites, Envenoming, Envenoming, Snake, Envenomation, Snake

Intervention / Treatment
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* Drug: Varespladib Methyl
* Drug: Placebo
* Drug: Standard of care (SOC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment. 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). Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures. Exclusion Criteria: Has received antivenom treatment for envenoming prior to enrollment in this study. 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. Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension. Has known history of inherited bleeding or coagulation disorder. 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. 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. Reports or has known pre-existing renal impairment or chronic kidney disease (defined as Stage 4 or receiving dialysis or hemofiltration). Has a known allergy or significant adverse reaction to varespladib-methyl or related compounds. Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns. 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.

Ages Eligible for Study
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Minimum Age: 5 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: Varespladib-methyl<br>Varespladib-methyl is an immediate-release (IR), oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl are supplied as 50 mg IR capsules for oral administration. Adult subjects will receive an initial loading dose of 500 mg (2 × 250 mg oral tablet) varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib-methyl (1 × 250 mg oral tablet) approximately 12 hours later, and subsequent twice daily (BID) dosing with 1 × 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment period. Tablets may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation. Pediatric subjects (5 to < 18 years) will be administered doses of varespladib-methyl determined by allometric scaling, provided as 50 mg capsules. Age-appropriate capsules may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation. | Drug: Varespladib Methyl<br>* 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.<br>* Other names: LY333013;Drug: Standard of care (SOC)<br>* SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.<br>|
| Placebo Comparator: Placebo<br>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 immediate-release capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate. The dosing of placebo will match that of varespladib-methyl. | Drug: Placebo<br>* 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.<br>Drug: Standard of care (SOC)<br>* SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the combined pulmonary, cardiovascular, hematologic, and nervous system 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, and nervous system subscores of the SSS. The values from each of these 4 subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. | Baseline to 6 and 9 hours after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of the pulmonary, cardiovascular, hematologic symptoms, renal, and nervous system sections of the SSS | Absolute values and change from baseline (pre-dosing) through Day 7 in the AUC of the pulmonary, cardiovascular, hematologic symptoms, and nervous system sections of the SSS. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. | Baseline through Day 7 | 
| Total antivenom requirement | Total amount of antivenom given from baseline (pre-dosing) through Day 28. | Baseline through Day 28 | 
| Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS) | NPRS | From Baseline through Day 3 | 
| Clinician Global Impression - Improvement | CGI focus on improvement for Day 2 | Day 2 | 
| Complete SSS scores | Absolute values and change from baseline (pre-dosing) through Day 7 in the complete SSS. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. | Baseline through Day 7 | 
| Percent of patients with hematological abnormalities | The percent of patients who had an SSS hematology score ≥ 2 at baseline with coagulation abnormalities from baseline (pre-dosing) through Day 7. | Baseline through Day 7 | 
| Hemolysis markers: percent of patients for each visual hemolysis score level and abnormal lactate dehydrogenase (LDH) | The percent of patients for each visual hemolysis score level and abnormal LDH from baseline (pre-dosing) through Day 3. | Baseline through Day 3 | 
| Hemolysis markers: quantitative hemolysis score occurrence | The quantitative hemolysis score occurrence (yes/no) and occurrence of abnormal LDH values (yes/no) from baseline (pre-dosing) through Day 3. | Baseline through Day 3 | 
| Levels of myonecrosis marker, creatine kinase (CK) | Absolute value and change from baseline in CK from baseline (pre-dosing) through Day 3. Only patients with ≥ 2× institutional reference range at Baseline and gross hemolysis at baseline will be included. | Baseline through Day 3 | 
| Patients requiring ventilatory support | The percent of patients requiring ventilatory support from baseline (pre-dosing) through Day 28. | Baseline through Day 28 | 
| Total duration of ventilatory support | Total duration (days) of ventilatory support from baseline (pre-dosing) through Day 28. | Baseline through Day 28 | 
| Total duration of Intensive Care Unit (ICU) stay | Total duration (days) of ICU stay from baseline (pre-dosing) through Day 28. | Baseline through Day 28 | 
| Total duration of hospitalization | Total duration (days) of hospitalization from baseline (pre-dosing) through Day 28. Only hospitalization from baseline through Day 28 will be included. | Baseline through Day 28 | 
| All-cause mortality | The number of patients experiencing the event (death) and the number of patients censored from baseline (pre-dosing) through Day 60. The all-cause mortality will be censored at Day 60. | Baseline through Day 60 | 
| Clinical Global Impression - Improvement (CGI-I) and Patient Global Impression of Change (PGIC) responders | The proportion of patients with a score on the CGI-I and PGIC of 1: very much improved, or 2: much improved from baseline (pre-dosing) through Day 7. The CGI-I and PGIC are 7-point scales depicting a clinician's/patient's rating of overall improvement, with scores ranging from 1 (very much improved) to 7 (very much worse). | Baseline through Day 7 | 
| Patient-Specific Functional Scale (PSFS) total score | Absolute values and change in the PSFS total score from Day 1 through Day 28. The PSFS is a 3-item instrument which assesses functional abilities. The total score ranges from 0 to 10 with a lower score indicating greater functional difficulties. | Day 1 through Day 28 | 
| Numeric Pain Rating Scale (NPRS) score | Absolute values and change from baseline (pre-dosing) through Day 28 in NPRS score in patients able to respond pre-dosing through Day 28. The NPRS is an 11-point scale for patient self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain). | Baseline through Day 28 | 
| Kidney function markers: blood urea nitrogen (BUN) and creatinine | Absolute values and changes from baseline (pre-dosing) through Day 28 in BUN and creatinine levels (mg/dL). | Baseline through Day 28 | 
| Snakebite severity score | SSS neurologic system subscore | Baseline through day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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envenoming, venom, snakebite, snakebite severity score, varespladib, snake, antidote, LY333013, sPLA2