Clinical trial NCT04996264: Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Snakebites
Envenoming
Envenoming, Snake
Envenomation, Snake
Keywords: envenoming
venom
snakebite
snakebite severity score
varespladib
snake
antidote
LY333013
sPLA2
Lead sponsor: Ophirex, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Premier Research Group plc
First posted: 2021-08-09
Enrollment: 96
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Change in the combined pulmonary, cardiovascular, hematologic, and nervous system subscores of the snakebite severity score (SSS)
timeFrame: Baseline to 6 and 9 hours after first dose
Secondary outcomes:
measure: Area under the curve (AUC) of the pulmonary, cardiovascular, hematologic symptoms, renal, and nervous system sections of the SSS
timeFrame: Baseline through Day 7
measure: Total antivenom requirement
timeFrame: Baseline through Day 28
measure: Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)
timeFrame: From Baseline through Day 3
measure: Clinician Global Impression - Improvement
timeFrame: Day 2
measure: Complete SSS scores
timeFrame: Baseline through Day 7
measure: Percent of patients with hematological abnormalities
timeFrame: Baseline through Day 7
measure: Hemolysis markers: percent of patients for each visual hemolysis score level and abnormal lactate dehydrogenase (LDH)
timeFrame: Baseline through Day 3
measure: Hemolysis markers: quantitative hemolysis score occurrence
timeFrame: Baseline through Day 3
measure: Levels of myonecrosis marker, creatine kinase (CK)
timeFrame: Baseline through Day 3
measure: Patients requiring ventilatory support
timeFrame: Baseline through Day 28
measure: Total duration of ventilatory support
timeFrame: Baseline through Day 28
measure: Total duration of Intensive Care Unit (ICU) stay
timeFrame: Baseline through Day 28
measure: Total duration of hospitalization
timeFrame: Baseline through Day 28
measure: All-cause mortality
timeFrame: Baseline through Day 60
measure: Clinical Global Impression - Improvement (CGI-I) and Patient Global Impression of Change (PGIC) responders
timeFrame: Baseline through Day 7
measure: Patient-Specific Functional Scale (PSFS) total score
timeFrame: Day 1 through Day 28
measure: Numeric Pain Rating Scale (NPRS) score
timeFrame: Baseline through Day 28
measure: Kidney function markers: blood urea nitrogen (BUN) and creatinine
timeFrame: Baseline through Day 28
measure: Snakebite severity score
timeFrame: Baseline through day 3
Other outcomes:
measure: Snakebite severity score
timeFrame: Baseline through Day 28 after first dose
measure: Grip strength
timeFrame: Baseline through Day 28
measure: Analgesic use
timeFrame: Baseline through Day 28
measure: PGIC scores through Day 28
timeFrame: Baseline through Day 28
measure: Kidney function markers: estimated glomerular filtration rate (eGFR)
timeFrame: Baseline through Day 28
measure: Kidney function markers: urinalysis
timeFrame: Baseline through Day 28
measure: Complete blood count (CBC)
timeFrame: Baseline through Day 28
measure: Transfusion requirement
timeFrame: Enrollment through Day 28
measure: C-reactive protein (CRP) levels
timeFrame: Baseline through Day 14
measure: D-dimer levels
timeFrame: Baseline through Day 14
measure: Levels of myonecrosis marker (CK)
timeFrame: Baseline through Day 3
measure: Secretory phospholipase A₂ (sPLA₂) activity in serum
timeFrame: Days 1 to 7
measure: Pharmacokinetic (PK) parameters of varespladib-methyl in plasma: area under the curve
timeFrame: Days 1, 3, and 7
measure: PK parameters of varespladib-methyl in plasma: maximum serum plasma concentration
timeFrame: Days 1, 3, and 7
measure: PK parameters of varespladib-methyl in plasma: time of Cmax (Tmax)
timeFrame: Days 1, 3, and 7
measure: PK parameters of varespladib-methyl in plasma: apparent first order terminal elimination half-life (t1/2)
timeFrame: Days 1, 3, and 7
measure: PK parameters of varespladib-methyl in plasma: apparent terminal phase rate constant (λz)
timeFrame: Days 1, 3, and 7
measure: Incidence and severity of adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation of Investigational Product (IP)
timeFrame: After obtaining informed consent until 28 days after the last day of study participation
measure: Number of reported treatment-emergent adverse events (TEAEs)
timeFrame: Beginning of treatment until last Follow-Up Visit/Telephone call at Day 28
measure: Rates of reported TEAEs
timeFrame: Beginning of treatment until last Follow-Up Visit at Day 28
measure: Number of patients with a treatment-related SAE
timeFrame: Beginning of treatment until last Follow-Up Visit/Telephone call at Day 28
measure: Clinical laboratory evaluations
timeFrame: Baseline through Day 28
measure: 12-lead electrocardiogram (ECG)
timeFrame: Baseline through Day 28
measure: Concomitant medications and analgesics
timeFrame: Baseline through Day 28
measure: Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Baseline through Day 28
measure: Snakebite Severity score
timeFrame: Baseline through day 7
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Jacksonville
country: United States
facility: University of Florida Health
state: Florida
city: Augusta
country: United States
facility: Agusta University Medical Center
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Shreveport
country: United States
facility: LSU LA Poison Control Center
state: Louisiana
city: Jackson
country: United States
facility: University of Mississippi Medical Center - Jackson
state: Mississippi
city: Durham
country: United States
facility: Duke University Hospital Durham, NC
state: North Carolina
city: Kozhikode
country: India
facility: Government medical College
state: Calicut
city: Mangalore
country: India
facility: Father Muller medical College Hospital
state: Karnataka
city: Mysore
country: India
facility: K R Hospital Mysore medical College and Research Institute
state: Karnataka
city: Thrissur
country: India
facility: Jubilee Mission Medical College and Research Institute
state: Kerala
city: Pondicherry
country: India
facility: Jawaharlal Institute of Postgraduate Medical Education & Research
state: Puducherry
city: Bikaner
country: India
facility: S.P. Medical College Snakebite Research Cell
state: Rajasthan
city: Kolkata
country: India
facility: Calcutta National Medical College
state: West Bengal
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research
Study officials:
affiliation: Ophirex, Inc.
name: Matthew Lewin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ophirex, Inc.
name: Timothy F Platts-Mills, MD, MSc
role: PRINCIPAL_INVESTIGATOR
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