Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO)

Snakebite Clinical Trial

— BRAVIO  

Official title:

Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Intravenous Varespladib Followed by Oral Varespladib in Addition to Standard of Care in Subjects Bitten by Venomous Snakes

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05717062
• Other study ID #: OPX-PR-03
• Secondary ID: FD-R-7830
• Status: Recruiting
• Phase: Phase 2
• Start date: May 30, 2023
• Est. completion date: November 2024

Study information

• Verified date: September 2023
• Source: Ophirex, Inc.
• Contact: Brandi Ritter PA-C, MPAS
• Phone: 5302184454
• Email: brandi[@]ophirex.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter,randomized,double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of a continuous rate infusion (CRI) of IV varespladib followed by transition to the oral dosage form, varespladib-methyl, concurrently with SOC, in participants bitten by venomous snakes.

Note: Funding Source - FDA-OOPD

Description:

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

Approximately 140 male and female eligible participants will be enrolled and randomized to receive active varespladib or placebo (in addition to SOC)

Randomization will be stratified by the presence or absence of neurotoxicity (SSS nervous system subscore of 0-1 or ≥ 2) at Baseline, and by receipt of antivenom prior to screening, resulting in 4 strata in total.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: November 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA:

1. Is a male or female = 18 years of age with venomous snakebite.

2. Patients must have known or suspected venomous snakebite. In India, enrollment will be restricted to patients bitten by suspected or confirmed Russell's viper (Daboia russelii) or krait (Bungarus spp.) In the U.S., any snakebite that meets all other criteria may be eligible.

3. Participants must meet one of two categories of inclusion criteria:

1. Category 1: The participant is enrolled within 5 hours of venomous snakebite or symptom onset with an SSS score of =2 in one system and =1 in another system (2+1).

OR

2. Category 2: The participant has a suspected or confirmed bite from an elapid and is enrolled within 10 hours of bite or symptom onset with moderate to severe cranial nerve or skeletal muscle weakness.

4. Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures.

EXCLUSION CRITERIA:

1. Has history of or is suspected to have CVA or intracranial bleeding of any kind, acute coronary syndrome, MI, or severe pulmonary hypertension.

2. Has known history of inherited bleeding or coagulation disorder.

3. Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bilvalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlodipine or another anticoagulant agent not specifically listed, or has used heparin, enoxaparin, fondaparinux, or other low molecular weight heparin or any antiarrhythmic drugs within 14 days prior to treatment.

4. 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, autoimmune hepatitis.

5. Reports or has known pre-existing renal impairment or chronic kidney disease.

6. Has a known allergy or significant adverse reaction to varespladib or varespladib-methyl.

7. Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns.

8. 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.

Related Conditions & MeSH terms

• Snake Bites
• Snakebite

Intervention

Drug:
• Varespladib intravenous form
This is a lyophilized drug contained in 100 mg vials to be reconstituted in Water for Injection (WFI), followed by dilution into 0.9% Sodium Chloride Injection.
• varespladib-methyl- oral form
Varespladib-methyl (LY333013) is an immediate-release, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration.
• Placebo intravenous form
The intravenous placebo will be saline (0.9%). Blinding will be ensured by covering the bag containing the investigational product with opaque covers.
• Placebo - oral form
Oral placebo is supplied as a white film-coated oval tablet to match the appearance of the LY333013 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Tech University Health Sciences Center El Paso	El Paso	Texas
United States	Emergency Medicine, University of Kentucky	Lexington	Kentucky
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Desert Regional Medical Center	Palm Springs	California
United States	Banner University Medical Center - Phoenix	Phoenix	Arizona
United States	Antelope Valley Medical Center	Rosamond	California
United States	UT Health San Antonio	San Antonio	Texas
United States	University of South Florida/Tampa General Hospital	Tampa	Florida
United States	Arizona Poison & Drug Information Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Ophirex, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the curve of the composite outcome of the pulmonary, cardiovascular, local wound, hematologic, renal and nervous system sections of the snakebite severity score (SSS) from Baseline (pre-dosing) to Day 7.	The Snakebite Severity Scale is a tool used to measure the severity of envenoming based on 7 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, renal and nervous system effects (graded at levels from Grade 0 to Grade 4).; A higher score indicates worse symptoms. For the primary outcome, 5 body categories (local wound, pulmonary, cardiovascular, hematological, and nervous system) will be included.	Baseline to Day 7
Secondary	Area under the curve of the composite outcome of pulmonary, cardiovascular, local wound, hematologic, renal, and nervous system sections of the SSS from Baseline to Day 7, among patients receiving study drug, 6 hours after bite or symptom onset	The SSS is a tool developed to measure the severity of snakebite envenoming. Each category is graded from 0 to 3 or 4 (depending on the body category) and a higher score indicates worse signs or symptoms.	Baseline to Day 7
Secondary	Change in the composite outcome of pulmonary, cardiovascular, hematologic, renal, and nervous system sections of the SSS from Baseline to the average of the scores 3 and 6 hours after the first dose.	The SSS is a tool developed to measure the severity of snakebite envenoming. Each category is graded from 0 to 3 or 4 (depending on the body category) and a higher score indicates worse signs or symptoms.	Baseline to 3 and 6 hours
Secondary	Pulmonary, cardiovascular, local wound, hematologic, renal, and nervous system sections of the composite Snakebite Severity Scale from Baseline through Day 7.	The SSS is a tool developed to measure the severity of snakebite envenoming. Each category is graded from 0 to 3 or 4 (depending on the body category) and a higher score indicates worse signs or symptoms.	Baseline through Day 7
Secondary	Elapsed time from initiation	IV varespladib treatment until the transition to oral varespladib-methyl.	Baseline to Day 28
Secondary	Complete Snakebite Severity Scale Scores from baseline to Day 7.	The SSS is a tool developed to measure the severity of snakebite envenoming. Each category is graded from 0 to 3 or 4 (depending on the body category) and a higher score indicates worse signs or symptoms.	Baseline through Day 7
Secondary	Coagulation Abnormalities (subject coagulation lab tests: PT, PTT, fibrinogen, INR will be evaluated) from Baseline through Day 7	Each lab value that is outside of the normal reference range will be evaluated by the investigator to determine clinical relevance.	Baseline through Day 7
Secondary	Hemolysis markers (subject hemolysis lab tests: free hemoglobin, haptoglobin, LDH will be evaluated) from Baseline through Day 3	Each lab value that is outside of the normal reference range will be evaluated by the investigator to determine clinical relevance.	Baseline through Day 3
Secondary	Levels of the Myonecrosis Marker, Creatine Kinase (CK) from Baseline through Day 3		Baseline through Day 3
Secondary	Kidney function markers (subject lab tests: creatinine, BUN, eGFR will be evaluated) from Baseline through Day 28	Each lab value that is outside of the normal reference range will be evaluated by the investigator to determine clinical relevance.	Baseline through Day 28
Secondary	Numeric Pain Rating Scale (NPRS) score in patients able to respond pre-dosing through Day 28	The NPRS is an 11-point scale for participants self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain).	Baseline through Day 28
Secondary	Total Antivenom Requirement, measured in number of vials of antivenom administered to the subject, from baseline (pre-dosing) through Day 28		Baseline through Day 28
Secondary	Head Lift duration (measured time of 0 - 5 seconds of subject's ability to lift head off of the bed, to determine neurological weakness) from Baseline through Day 7	Head lift is used to assess subject for neurological weakness.	Baseline through Day 7
Secondary	Time from initiation of ventilatory support to initiation of weaning		Baseline through Day 28
Secondary	Time of ventilatory support from Baseline through Day 28		Baseline through Day 28
Secondary	Time of Intensive Care Unit (ICU) Stay from Baseline through Day 28		Baseline through Day 28
Secondary	Time of Hospitalization from baseline (pre-dosing) through Day 28		Baseline through Day 28
Secondary	All-cause mortality at Day 28		Baseline through Day 28
Secondary	Clinical Global Impression - Improvement (CGI-I) from Baseline through Day 28	Clinical Global Impression - Improvement Scale is 0, not assessed, 1 = very much improved to 7 = very much worse	Baseline through Day 28
Secondary	Patient-Specific Functional Scale (PSFS) total score from Baseline through Day 28	A 3 item instrument administered verbally; 0= unable to perform activity to 10 = able to perform activity at same level as before injury or problem	Baseline through Day 28
Secondary	Patient Global Impression of Change (PGIC) from Baseline through Day 28	Scale is 1 = no change, to 7= a great deal better	Baseline through Day 28