Non-inferiority Trial of Two Snake Antivenoms in CAR (PAVES) (PAVES)

Randomized, Double-blind, Non-inferiority Trial of Two Antivenoms for the Treatment of Snakebite With Envenoming

Interventional, individually randomized, double (e.g. investigator and participant) blinded, parallel two-arm, non-inferiority trial to assess the efficacy of EchiTabPlus-ICP compared to FAV-Africa for the treatment of snakebite with envenoming.

Study Overview

• Status: Withdrawn
• Conditions: Snake Bites
• Intervention / Treatment: Biological: FAV-Africa; Biological: EchiTabPlus-ICP

Detailed Description

The study is designed as a randomized, double-blind, non-inferiority trial among patients suffering envenoming following snakebite in Paoua, Central African Republic. The primary aim of the study is to assess the non-inferiority of EchiTabPlus-ICP compared to FAV-Africa, at preventing a composite primary endpoint consisting of death from any cause, need for blood transfusion or need for a third dose of antivenom.

A total of 196 patients will be individually randomized in a 1:1 ratio to receive FAV-Africa or EchiTabPlus-ICP.

The first dose of intervention antivenom will be administered at study enrollment, and the need for further doses will be judged by clinical exam and the 20 minute WBCT, following the protocol. All other necessary medical care will be provided as per routine in the Paoua Prefectural Hospital. Study followup and surveillance for adverse events and serious adverse events will continue until 28 days after the initial dose of antivenom.

Unique identification numbers will be allocated by an individual independent of the study team using a computer-generated random number list using permuted blocks of random sizes. Block sizes will not be disclosed to reduce predictability of the random sequence and ensure allocation concealment. The Site Principal Investigator who will oversee randomization will be given a set of sequentially numbered silver coated booklets. The Site Principal Investigator will be instructed to assign the next sequential randomization code noted in the booklet to each eligible participant as (s)he is enrolled.

Study antivenoms will be prepared by the unblinded study pharmacist, and will be provided to the clinical staff in identical presentations. Group assignment will remain concealed from study personnel, investigators, and participants for the entire study period. The Data and Safety Monitoring Board (DSMB) will also be masked to the group assignment. The DSMB will remain masked unless otherwise deemed necessary by the DSMB members for any safety related issues. Investigators conducting the final analysis will remain masked to the group assignment until the end of the analysis.

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• present within 72 hours of snakebite
• have signs and symptoms of grade 2 envenoming (oedema beyond the elbows or knees, bleeding at site of bite, bleeding from the gums or hematuria) or grade 3 envenoming (oedema to the shoulders or hips, or serious bleeding - epistaxis, hemoptysis, gastrointestinal bleeding)
• lack of coagulation of blood at 20 minutes in a dry vacutainer tube (abnormal 20 minute WBCT)

Exclusion Criteria:

• known allergy to horses or heterologous proteins of equine origins
• pregnancy
• have received antivenom since the snakebite

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FAV-Africa; FAV-Africa infusion at enrollment, and then at two and six hours after enrollment, if necessary. To be given as unblinded rescue dose at twelve hours if fourth dose of antivenom necessary.	Biological: FAV-Africa; Polyspecific antivenom immunoglobulin F(ab)'2 fragments of equine origin manufactured by Sanofi Pasteur, S.A., Lyon, France. Per undiluted 1 ml, the multivalent serum contains ≥25 times the LD50 for mice exposed to venom of Bitis gabonica, Bitis arietans, Echis leucogaster, Echis ocellatus, Naja haje, Dendroaspis polylepis, Dendroaspis viridis, and Dendroaspis jamesoni, as well as ≥20 times the LD50 for mice exposed to venom of Naja melanoleuca and Naja nigricollis.
Experimental: EchiTabPlus-ICP; EchiTabPlus-ICP infusion at enrollment, and then at two and six hours after enrollment, if necessary.	Biological: EchiTabPlus-ICP; Polyspecific antivenom immunoglobulin of equine origin manufactured by the Clodomiro Picado Institute, San Jose, Costa Rica. Each 10 ml of undiluted antivenom contains enough antibody fragments to neutralize 30 mg of Echis ocellatus venom, 20 mg of Bitis arietans venom and 5 mg of Naga nigricollis venom.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of patients needing a third dose of antivenom, needing a blood transfusion, or dying	28 days after enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death from any cause		28 days after enrolment
Need for blood transfusion		Will be evaluated at 2, 6, 12, and 24 hours after enrolment and at hospital discharge
Need for third dose of antivenom		Will be evaluated at 2, 6, 12, and 24 hours after enrolment and at hospital discharge
Normalization of coagulopathy as measured by the 20 minute whole blood clotting test	Using 20 min whole blood clotting test	Will be evaluated at 2, 6, 12, and 24 hours after enrolment

Collaborators and Investigators

• Sponsor: Epicentre
• Collaborators: Medecins Sans Frontieres, Netherlands
• Investigators: Study Director: Rebecca Grais, PhD, Epicentre

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2016
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: February 17, 2016
• First Submitted That Met QC Criteria: February 24, 2016
• First Posted (Estimate): March 1, 2016

Study Record Updates

• Last Update Posted (Actual): June 2, 2017
• Last Update Submitted That Met QC Criteria: June 1, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Wounds and Injuries; Poisoning; Bites and Stings; Snake Bites
• Other Study ID Numbers: EPICENTRE CAR 2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No