Optimal Dose of Antivenom for Daboia Siamensis Envenomings (ODADS)

• ClinicalTrials.gov Identifier: NCT04210141
• Recruitment Status: Not yet recruiting
• First Posted: December 24, 2019
• Last Update Posted: September 4, 2020
• Sponsor: Myanmar Oxford Clinical Research Unit
• Collaborators: University of Oxford; Mahidol Oxford Tropical Medicine Research Unit
• Information provided by (Responsible Party): Myanmar Oxford Clinical Research Unit

Study Description

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.

Study Design

• 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

Arms and Interventions

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; 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; Antivenom

Outcome Measures

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 ]

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Contacts

Contact: Thomas Lamb, MBCHB; +951544537; thomas.lamb@ndm.ox.ac.uk

Contact: Htet Htet Aung, BA; +951544537; htethtetaung.mocru@gmail.com

Sponsors and Collaborators

Myanmar Oxford Clinical Research Unit

University of Oxford

Mahidol Oxford Tropical Medicine Research Unit

More Information

Publications:

Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017 Sep 14;3:17063. doi: 10.1038/nrdp.2017.63. Review. Erratum in: Nat Rev Dis Primers. 2017 Oct 05;3:17079.

Williams DJ, Faiz MA, Abela-Ridder B, Ainsworth S, Bulfone TC, Nickerson AD, Habib AG, Junghanss T, Fan HW, Turner M, Harrison RA, Warrell DA. Strategy for a globally coordinated response to a priority neglected tropical disease: Snakebite envenoming. PLoS Negl Trop Dis. 2019 Feb 21;13(2):e0007059. doi: 10.1371/journal.pntd.0007059. eCollection 2019 Feb.

Myint-Lwin, Warrell DA, Phillips RE, Tin-Nu-Swe, Tun-Pe, Maung-Maung-Lay. Bites by Russell's viper (Vipera russelli siamensis) in Burma: haemostatic, vascular, and renal disturbances and response to treatment. Lancet. 1985 Dec 7;2(8467):1259-64.

Alfred S, Bates D, White J, Mahmood MA, Warrell DA, Thwin KT, Thein MM, Sint San SS, Myint YL, Swe HK, Kyaw KM, Zaw A, Peh CA. Acute Kidney Injury Following Eastern Russell's Viper (Daboia siamensis) Snakebite in Myanmar. Kidney Int Rep. 2019 May 29;4(9):1337-1341. doi: 10.1016/j.ekir.2019.05.017. eCollection 2019 Sep.

Wheeler GM, Mander AP, Bedding A, Brock K, Cornelius V, Grieve AP, Jaki T, Love SB, Odondi L, Weir CJ, Yap C, Bond SJ. How to design a dose-finding study using the continual reassessment method. BMC Med Res Methodol. 2019 Jan 18;19(1):18. doi: 10.1186/s12874-018-0638-z.

• Responsible Party: Myanmar Oxford Clinical Research Unit
• ClinicalTrials.gov Identifier: NCT04210141
• Other Study ID Numbers: OXTREC 63-19
• First Posted: December 24, 2019
• 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.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Antivenins; Immunologic Factors; Physiological Effects of Drugs