Trial of Oral Community SVMP INhibitors for Snakebite (TOCSINS)

A Phase 2 Randomised Placebo-controlled Platform Trial of Snake Venom Metalloproteinase Inhibitors for Snakebite Envenoming in Brazil and Ghana

Bites by venomous snakes can cause disability and can be life-threatening. We are doing research in adult patients to try and find medications that can be administered orally and can help to reduce disability and death due to snakebite. We do not know whether the drugs in this study work in humans and we aim to discover this.

In Stage A, we will provide a new drug or placebo (inactive medication) in community locations, such as rural health clinics, in Brazil and Ghana. Neither the patient nor the clinical team will know which treatment option has been allocated. If a drug were to show signs of working as a treatment during Stage A, it will progress to Stage B. In Stage B, we will provide the drug or antivenom (the current approved treatment for snakebite) in a hospital setting. During Stage B, the patient and the clinician will know which treatment has been received. The purpose of Stage B is to discover whether the drug might hold promise as an alternative treatment to antivenom in the future. Participants will be monitored closely during Stage B and 'rescue antivenom' will be given if they become unwell.

The medications being considered were developed for other health conditions, like cancer, so have been given to patients across the world before. The medications may prove effective at inhibiting the damaging effects of snake venom. Each of the trial drugs could be taken by mouth (oral) in community clinics and ambulances, much sooner than the current treatment for snakebite injuries (antivenom), which is only given within hospitals. They may have other advantages too, like reduced cost and less chance of side effects, including severe allergic reaction. Before a medication is included in the trial it will be reviewed and approved by a group of experts. Before a medication is included in Stage B of the trial it will be reviewed for whether it is safe and effective enough (from Stage A results) to be compared against antivenom.

Stage A Participants will be recruited in the field when they attend a community clinic or ambulance. They will be randomly assigned to receive either a study drug or a placebo. When they arrive at hospital, all participants will receive standard of care antivenom. Participants will continue to take study medication (or matching placebo) for 24 hours, and have frequent blood samples collected during their treatment. Once 20 participants have received the drug and twenty have received the placebo, recruitment for this drug will cease. The difference in the improvement in blood clotting studies (how long it takes to clot) will be compared between the participants receiving the drug and the placebo. If the drug shows an improvement in the clotting studies, then it will proceed to Stage B. If the drug fails to improve the clotting studies, or if it is found to cause unsafe side effects, then it will be rejected from progressing to Stage B.

Stage B Participants will be recruited upon arrival at the hospital site and randomly assigned to receive either a study drug shown to be effective in Stage A or standard-of-care antivenom. Study drugs will be administered for 24 hours, during which all participants will undergo frequent blood sampling. Recruitment for each study drug will stop once 48 participants have received the drug and 48 have received antivenom. The primary comparison will be the improvement in blood clotting parameters between the intervention and control groups. If the study drug is safe and achieves a similar improvement to antivenom - allowing for up to a three-hour delay in effect due to oral absorption compared with intravenous antivenom - it will be considered a promising alternative therapy.

Following a planned 3-day stay in hospital, all participants from Stage A and B will be followed up at 2 and 6 weeks. These follow-up visits can be conducted by telephone, outpatient hospital visit, or home visit, depending on what is most suitable for that individual. The end of study visit will take place at the 6-week visit.

Study Overview

• Status: Not yet recruiting
• Conditions: Snakebite
• Intervention / Treatment: Drug: Oral placebo capsules; Drug: Antivenom Snakes; Drug: 2,3-dimercapto-1-propanesulfonic acid; Drug: marimastat

• Study Type: Interventional
• Enrollment (Estimated): 504
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: TOCSINS Trial Management; Phone Number: +44(0)1517053100; Email: tocsins@lstmed.ac.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Snakebite in the preceding 12 hours (Stage A & B)
• Aged ≥18-years (Stage A & B)
• Residing in the Amazonas region of Brazil or the Upper West region of Ghana (Stage A & B)
• Capable of giving informed consent (Stage A & B)
• Are eligible for antivenom treatment according to local guidelines (Stage B only)

Exclusion Criteria:

• individual with severe envenoming (defined in the protocol) (Stage A & B)
• concomitant anticoagulation (heparins, coumarin anticoagulants such as warfarin, or direct oral anticoagulants such as apixaban) (Stage A & B)
• pregnant or breastfeeding (Stage A & B)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Oral Placebo Stage A	Drug: Oral placebo capsules; Oral placebo
Active Comparator: Stage B IV Antivenom	Drug: Antivenom Snakes; Standard of care IV antivenom recommended in country
Experimental: Stage A & B Oral DMPS	Drug: 2,3-dimercapto-1-propanesulfonic acid; Oral administration; Other Names: unithiol; DMPS
Experimental: Stage A & B Oral Marimastat	Drug: marimastat; oral administration
Experimental: Stage B IV Marimastat	Drug: marimastat; oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean time until lab INR is less than 50% of the baseline value (efficacy)	Stage A and B - The mean time until the lab INR is <50% of the baseline value (or less than 1.4 if the baseline value is <2.8) on two consecutive measurements per treatment arm. Time is measured starting from randomisation. Time is measured until the first of the two consecutive measurements being <50% or <1.4. Baseline INR sample is defined as blood collected day 0 post-consent and prior to treatment administration.	From randomisation until end of admission
Incidence (cumulative) of safety events (safety)	Stage A and B- Incidence (cumulative) of any AE, non-serious AE, SAE, SAR, SUSAR. Cumulative incidence is calculated as the number (%) of participants who experience at least one AE in the pre-specified groups.	From informed consent until 42 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage A- Assess the effect of pre-hospital treatment on INR improvement based on travel time to hospital.	Stage A- Assess the effect of pre-hospital treatment on INR improvement based on travel time to hospital. Amongst participants with baseline INR ≥1.4, the log change in INR, from pre-hospital baseline to hospital arrival, will be analysed using a linear regression model with treatment group, travel time, and their interaction	Day 0 clinic and hospital
Stage A- Assess the effect of pre-hospital treatment on fibrinogen improvement based on travel time to hospital.	Stage A- Assess the effect of pre-hospital treatment on fibrinogen improvement based on travel time to hospital. Amongst participants with baseline INR ≥1.4, the log change in fibrinogen from pre-hospital baseline to 12 hours after randomisation, will be analysed using a linear regression model with treatment group, travel time, and their interaction.	Day 0 clinic and hospital
Stage A and B- To determine the acceptability of the intervention between treatment arms in terms of quality of life.	Stage A and B- to determine the acceptability of the intervention between treatment arms as a patient-reported outcome of functioning. Assessed using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0), a 12-item validated scale measuring disability across six life domains (cognition, mobility, self-care, interpersonal interaction, life activities, and participation). Scores range from 0 to 48, where higher scores indicate greater disability. Unit of Measure: Units on a scale (0-48)	Day 14, Day 42 (Stage A and B)
Stage A and B- To determine the acceptability of the intervention between treatment arms as patient-reported outcomes of functioning.	Assessed using the Patient Specific Functional Scale (PSFS), in which participants rate their ability to perform up to three self-nominated activities on a numerical scale from 0 to 10, where 0 indicates inability to perform the activity and 10 indicates full pre-injury ability. Higher scores indicate better function. Unit of Measure: Units on a scale (0-10).	Day 14 and Day 42 post-randomisation (Stage A and B)
Stage A and B- To evaluate the reach of the intervention (Participant refusal rate)	Stage A and B- To evaluate the reach of the intervention. Monitor enrolment data based on % refusal. Measurement: Percentage of eligible patients who decline participation Unit of measure: Percentage (%)	Day 0 clinic (Stage A) or hospital (Stage B)
Stage A and B- To evaluate the reach of the intervention (Exclusion rate)	Stage A and B- To evaluate the reach of the intervention. Monitor enrolment data based on % exclusion. Measurement: Percentage of screened patients excluded due to protocol-defined exclusion criteria. Unit of measure: Percentage (%)	Day 0 clinic (Stage A) or hospital (Stage B)
Stage A and B- To evaluate the reach of the intervention (Time between bite and treatment received)	Stage A and B- To evaluate the reach of the intervention. Monitor enrolment data based on time between bite and treatment received. Measurement: Time elapsed between reported snakebite and receipt of study treatment. Unit of measure: Hours	Day 0 clinic (Stage A) or hospital (Stage B)
Stage A and B-To evaluate the reach of the intervention based on recruitment rate across the study catchment area (Recruitment rate)	Stage A and B- To evaluate the reach of the intervention. Monitor enrolment data based recruitment rate across the study catchment area. Measurement: Rate of participant enrolment across the study catchment area. Unit of measure: Participants per site per month	Day 0 clinic (Stage A) or hospital (Stage B)
Stage A and B- Identify benefits of and barriers for future implementation of the intervention.	Stage A and B- Identify benefits of and barriers for future implementation of the intervention. Mixed-methods following the Consolidated Framework Implementation Research interviewing participants and health care providers	Day 42
Stage A- To determine differences in resolution of clinically relevant non-serious bleeding events.	Stage A- To determine differences in resolution of clinically relevant non-serious bleeding events. Amongst all participants with non-major bleeding (epistaxis, gingival bleeding, or bleeding from a venepuncture site for >5 min) at randomisation, proportion with cessation of bleeding on arrival to the hospital site per treatment arm.	Day 0 clinic and hospital
Stage B- Assess the effect of time to treatment on INR improvement (based on estimated time from bite until administration of the treatment).	Stage B- Assess the effect of time to treatment on INR improvement (based on estimated time from bite until administration of the treatment). Amongst participants with baseline INR ≥1.4, change in INR from baseline to 6 hours, analysed using a linear regression model with treatment group, estimated time from bite to treatment, and their interaction	Day 0 hospital
Stage B- Assess the effect of time to treatment on fibrinogen improvement (based on estimated time from bite until administration of the treatment).	Stage B- Assess the effect of time to treatment on fibrinogen improvement (based on estimated time from bite until administration of the treatment). Amongst participants with baseline INR ≥1.4, change in fibrinogen from baseline to 12 hours, analysed using a linear regression model with treatment group, estimated time from bite to treatment, and their interaction	Day 0 hospital
Stage B- To determine differences in resolution of clinically relevant non-serious bleeding events.	Stage B- To determine differences in resolution of clinically relevant non-serious bleeding events. Amongst all participants with non-major bleeding (epistaxis, gingival bleeding, or bleeding from a venepuncture site for >5 min) at randomisation, proportion with cessation of bleeding at 3 hours after randomisation per treatment arm.	Day 0 hospital

Collaborators and Investigators

• Sponsor: Liverpool School of Tropical Medicine
• Collaborators: Kumasi Centre for Collaborative Research (KCCR); Coefficient Giving (Formerly Open Philanthropy); Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD)

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: envenoming
• Additional Relevant MeSH Terms: Wounds and Injuries; Chemically-Induced Disorders; Poisoning; Bites and Stings; Snake Bites; Sulfur Compounds; Organic Chemicals; Sulfhydryl Compounds; Dimercaprol; Unithiol; marimastat
• Other Study ID Numbers: 25-033-310

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified IPD and related documents will be shared via a trial repository.
• IPD Sharing Time Frame: After primary results have been published and within 12 months of study completion.
• IPD Sharing Access Criteria: Requests will be assessed and shared per the study Data Management Plan.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No