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Optimal Dose of Antivenom for Daboia Siamensis Envenomings (ODADS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04210141
Recruitment Status : Not yet recruiting
First Posted : December 24, 2019
Last Update Posted : September 4, 2020
University of Oxford
Mahidol Oxford Tropical Medicine Research Unit
Information provided by (Responsible Party):
Myanmar Oxford Clinical Research Unit

Brief Summary:
The aim of the study is to identify an 'optimal' initial dosing of the new Burma Pharmaceutical Industry (BPI) lyophilized mono-specific antivenom for patients with systemic Daboia siamensis envenoming. The initial dosing will aim to reverse venom-induced coagulopathy (as demonstrated by a negative 20 minutes Whole Blood Clotting Time (20WBCT) at 6 hours in 95% of patients whilst causing less than 5% anaphylactic reaction.

Condition or disease Intervention/treatment Phase
Daboia Siamensis Envenoming Biological: lyophilized BPI viper antivenom Phase 2

Detailed Description:

Snake-bite envenoming (SBE) was re-categorized as a priority neglected tropical disease by the World Health Organization (WHO) in 2017. Antivenom is considered to be one of the most cost effective health interventions. Despite this, due to challenges in manufacture, reliance on cold chain for transport and storage, and geographically remote location of most envenomed patients, many patients do not receive the antivenom they require in a timely manner. The WHO strategy for a globally coordinated response to SBE highlighted the need to prioritize clinical research into the safety and effectiveness of antivenoms.

Myanmar is a country with a high incidence of snake-bite with an estimated 25,000 snake-bites and 1250 deaths per year. Daboia siamensis (Eastern Russell's viper) is responsible for 85% of snake-bites presenting to hospitals in Myanmar. Given their natural habitat and abundance of prey within the paddy fields, envenoming predominantly occurs in rural areas affecting agricultural workers.

Following a recent 4-year collaborative initiative between institutions in Myanmar and Australia entitled the Myanmar Snakebite project, antivenom production facilities have improved resulting in the production of a new monospecific lyophilized F(ab)'2 antivenom (Viper antivenom BPI). The new lyophilized antivenom has replaced the former liquid antivenom and has been distributed countrywide. The current dosing strategy is based on unpublished results of pre-clinical testing and stratified into two doses according to absence or presence of clinical features of severity at presentation (80 mL and 160 mL, respectively). No clinical trial data or post marketing data has been published to support the efficacy or toxicity of these recommended doses. This lack of robust clinical evidence to support dosing of antivenom is mirrored across the world with few well conducted trials to determine the safety and efficacy of antivenoms.

This paper presents a novel phase 2, model based, Bayesian adaptive design to determine optimal antivenom dosing for Russell's viper envenoming. In this context there are two concurrent considerations for dose optimality. Firstly, the efficacy of the dose, defined in this context as restoration of blood coagulation within 6 hours; secondly, the dose-related toxicity, defined as the occurrence of an anaphylactic reaction within 180 minutes post antivenom administration. The model based design estimates dose-response curves for both the efficacy outcome and the toxicity outcome, and thus derives a user-defined 'optimal dose'. Patients will be randomized at a ratio of 4:1 to either adaptive dose or standard of care respectively.

The study team will perform a number of nested studies within the dose finding trial:

  • An assessment of the pharmacokinetic properties of Daboia siamensis venom pre and post antivenom administration.
  • A parallel observation study of severely envenomed patients who will be administered 160mL (current standard of care).
  • Sensitivity and specificity analysis of the 20WBCT and point of care International Normalized Ratio at detecting coagulopathy.
  • A prospective follow up of envenomed patients to define the envenoming sequelae of Daboia siamensis envenoming.
  • An assessment of ferryl-haem derivatives in urine of envenomed patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized adaptive design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Adaptive Clinical Trial to Determine the Optimal Initial Dose of Lyophilized, Species Specific Monovalent Antivenom for the Management of Systemic Envenoming by Daboia Siamensis (Eastern Russell's Viper) in Myanmar
Estimated Study Start Date : February 1, 2021
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : September 1, 2023

Arm Intervention/treatment
Active Comparator: Standard of care
Patients will receive an initial antivenom dose of 80mL lyophilized BPI viper antivenom, as per current national guidelines
Biological: lyophilized BPI viper antivenom

Experimental: Adaptive arm
Patients will receive an initial dose of lyophilized BPI viper antivenom determined by the adaptive model.
Biological: lyophilized BPI viper antivenom

Primary Outcome Measures :
  1. Blood Coagulation [ Time Frame: within 24 hours of patient recruitment ]
    Blood coagulation at 6 hours as measured by the 20 minute WBCT (binary outcome)

  2. Anaphylaxis [ Time Frame: within 24 hours of patient recruitment ]
    Anaphylaxis as defined by the European Academy of Allergy and Immunology within 180 minutes of antivenom administration

Secondary Outcome Measures :
  1. Time to restoration of blood coagulability as determined by the 20 WBCT. [ Time Frame: within 24 hours of patient recruitment ]
  2. International normalized ratio (INR) determined by the POC INR meter. [ Time Frame: within 24 hours of patient recruitment ]
  3. Blood coagulability as determined by PT and fibrinogen [ Time Frame: within 24 hours of patient recruitment ]
  4. Occurrence of any serious adverse events [ Time Frame: within 24 hours of patient recruitment ]
  5. The occurrence of envenoming sequelae at 3 month follow up [ Time Frame: within 6 months of patient recruitment ]
  6. The occurrence of detectable ferryl-haem derivatives in urine samples [ Time Frame: within 6 months of patient recruitment ]
  7. The occurrence of Capillary Leak Syndrome [ Time Frame: within 2 weeks of patient recruitment ]

Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients suspected of systemic envenoming with DS
  2. Incoagulable blood by 20-minute WBCT
  3. Antivenom naïve
  4. Age ≥ 15

Exclusion Criteria:

  1. Receiving anticoagulant therapy e.g. warfarin
  2. Known bleeding disorder e.g. haemophilia
  3. Decompensated liver disease
  4. Severely envenomed patients (as defined in the Myanmar National Guidelines)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04210141

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Contact: Thomas Lamb, MBCHB +951544537
Contact: Htet Htet Aung, BA +951544537

Sponsors and Collaborators
Myanmar Oxford Clinical Research Unit
University of Oxford
Mahidol Oxford Tropical Medicine Research Unit
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Responsible Party: Myanmar Oxford Clinical Research Unit Identifier: NCT04210141    
Other Study ID Numbers: OXTREC 63-19
First Posted: December 24, 2019    Key Record Dates
Last Update Posted: September 4, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: For ethics purposes, there is no current plans to share IPD with other researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Immunologic Factors
Physiological Effects of Drugs