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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 95
- 试验地点
- 16
- 主要终点
- Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
All subjects, Investigators, and study personnel involved in the conduct of the study, including data management, will be blinded to treatment assignment except for a specified unblinded statistician and programmer from the study contract research organization who will have access to the randomization code. The unblinded study personnel will not participate in study procedures or data analysis prior to unblinding of the study data to all study-related personnel upon database lock. If an interim analysis is conducted, then unblinded personnel who are not otherwise involved in the study will prepare the data for review.
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- •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.
研究组 & 干预措施
Varespladib-methyl
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.
干预措施: Varespladib Methyl (Drug)
Varespladib-methyl
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.
干预措施: Standard of care (SOC) (Drug)
Placebo
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.
干预措施: Placebo (Drug)
Placebo
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.
干预措施: Standard of care (SOC) (Drug)
结局指标
主要结局
Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS)
时间窗: Baseline to 6 and 9 hours after first dose
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.
次要结局
- Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS(Baseline through Day 7)
- Clinician Global Impression - Improvement(Day 2)
- Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)(From Baseline through Day 3)
- All-cause Mortality(Baseline through Day 28)
- Patient-Specific Functional Scale (PSFS) Score(Day 7)
- Numeric Pain Rating Scale (NPRS) Score(Baseline through Day 28)