Daboia Siamensis EnvenomingPhase 2ODADSNCT04210141
Optimal Dose of Antivenom for Daboia Siamensis Envenomings
A Phase 2 study testing lyophilized BPI viper antivenom in people with Daboia Siamensis Envenoming, run by Myanmar Oxford Clinical Research Unit at 1 site in Burma.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Daboia Siamensis Envenoming
- What is being tested?
- lyophilized BPI viper antivenom
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 1 siteBurma
- Study dates
- Apr 2025to 1 Nov 2027
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients suspected of systemic envenoming with DS
- Incoagulable blood by 20-minute WBCT
- Antivenom naïve
- Age ≥ 15
Who cannot join
- Receiving anticoagulant therapy e.g. warfarin
- Known bleeding disorder e.g. haemophilia
- Decompensated liver disease
- Severely envenomed patients (as defined in the Myanmar National Guidelines)
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Conditions
- Daboia Siamensis Envenoming
- Being tested
- lyophilized BPI viper antivenom
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
lyophilized BPI viper antivenomBiological
Antivenom
| Study group | Role | What they receive |
|---|---|---|
| Standard of care | Active comparator | Patients will receive an initial antivenom dose of 80mL lyophilized BPI viper antivenom, as per current national guidelines Receives: Biological: lyophilized BPI viper antivenom |
| Adaptive arm | Experimental | Patients will receive an initial dose of lyophilized BPI viper antivenom determined by the adaptive model. Receives: Biological: lyophilized BPI viper antivenom |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood Coagulation
Blood coagulation at 6 hours as measured by the 20 minute WBCT (binary outcome)
Measured: within 24 hours of patient recruitment
Anaphylaxis
Anaphylaxis as defined by the European Academy of Allergy and Immunology within 180 minutes of antivenom administration
Measured: within 24 hours of patient recruitment
Secondary outcomes (7)
Time to restoration of blood coagulability as determined by the 20 WBCT.
Measured: within 24 hours of patient recruitment
International normalized ratio (INR) determined by the POC INR meter.
Measured: within 24 hours of patient recruitment
Blood coagulability as determined by PT and fibrinogen
Measured: within 24 hours of patient recruitment
Occurrence of any serious adverse events
Measured: within 24 hours of patient recruitment
The occurrence of envenoming sequelae at 3 month follow up
Measured: within 6 months of patient recruitment
The occurrence of detectable ferryl-haem derivatives in urine samples
Measured: within 6 months of patient recruitment
The occurrence of Capillary Leak Syndrome
Measured: within 2 weeks of patient recruitment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2019
- Study startApr 2025 (estimated)
- Primary completion1 Feb 2027 (estimated)
- Study completion1 Nov 2027 (estimated)
Why it stopped: due to current political circumstances in study site area.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Daboia Siamensis EnvenomingStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized adaptive design
- Masking
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Myanmar Oxford Clinical Research Unit
- Sponsor type
- University, hospital or other
- Collaborators
- University of Oxford, Mahidol Oxford Tropical Medicine Research Unit
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04210141
- Sponsor's protocol ID
- OXTREC 63-19
- Acronym
- ODADS
- Status last verified
- Oct 2023
- First submitted
- 20 Dec 2019
- Last updated
- 1 Apr 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: For ethics purposes, there is no current plans to share IPD with other researchers.
Publications
Gutierrez 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.
PubMed 28905944Williams 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. No abstract available.
PubMed 30789906Myint-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. doi: 10.1016/s0140-6736(85)91550-8.
PubMed 2866333Alfred 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. No abstract available.
PubMed 31517153Wheeler 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.
PubMed 30658575
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04210141
- Acronym / sponsor ID
- ODADS / OXTREC 63-19
- Conditions
- Daboia Siamensis Envenoming
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: due to current political circumstances in study site area.
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Myanmar Oxford Clinical Research UnitUniversity, hospital or other
- Collaborators
- University of Oxford, Mahidol Oxford Tropical Medicine Research Unit
- Study start
- Apr 2025 (estimated)
- Primary completion
- 1 Feb 2027 (estimated)
- Study completion
- 1 Nov 2027 (estimated)
- First posted
- 24 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Randomized adaptive design
| Arm | Type | Receives |
|---|---|---|
| Standard of care | Active comparator | Biological: lyophilized BPI viper antivenomPatients will receive an initial antivenom dose of 80mL lyophilized BPI viper antivenom, as per current national guidelines |
| Adaptive arm | Experimental | Biological: lyophilized BPI viper antivenomPatients will receive an initial dose of lyophilized BPI viper antivenom determined by the adaptive model. |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- Patients suspected of systemic envenoming with DS
- Incoagulable blood by 20-minute WBCT
- Antivenom naïve
- Age ≥ 15
Key exclusion criteria (4 listed)
- Receiving anticoagulant therapy e.g. warfarin
- Known bleeding disorder e.g. haemophilia
- Decompensated liver disease
- Severely envenomed patients (as defined in the Myanmar National Guidelines)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| lyophilized BPI viper antivenomAntivenom | Biological | Adaptive arm, Standard of care |
Primary outcome
Blood Coagulation
Time frame: within 24 hours of patient recruitment
Blood coagulation at 6 hours as measured by the 20 minute WBCT (binary outcome)
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
7 secondary outcomes
Time to restoration of blood coagulability as determined by the 20 WBCT.
Time frame: within 24 hours of patient recruitment
International normalized ratio (INR) determined by the POC INR meter.
Time frame: within 24 hours of patient recruitment
Blood coagulability as determined by PT and fibrinogen
Time frame: within 24 hours of patient recruitment
Occurrence of any serious adverse events
Time frame: within 24 hours of patient recruitment
The occurrence of envenoming sequelae at 3 month follow up
Time frame: within 6 months of patient recruitment
The occurrence of detectable ferryl-haem derivatives in urine samples
Time frame: within 6 months of patient recruitment
The occurrence of Capillary Leak Syndrome
Time frame: within 2 weeks of patient recruitment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2024.
- Background: PubMed 28905944Gutierrez 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.
- Background: PubMed 30789906Williams 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. No abstract available.
- Background: PubMed 2866333Myint-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. doi: 10.1016/s0140-6736(85)91550-8.
- Background: PubMed 31517153Alfred 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. No abstract available.
- Background: PubMed 30658575Wheeler 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.
- Individual participant dataSharing planned: Undecided. For ethics purposes, there is no current plans to share IPD with other researchers.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing lyophilized BPI viper antivenom in people with Daboia Siamensis Envenoming, run by Myanmar Oxford Clinical Research Unit at 1 site in Burma.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 1 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Burma. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood Coagulation (time frame: within 24 hours of patient recruitment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04210141, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2024.