Snake BitesPhase 4RADIANSNCT02570347
Routine Antibiotic vs. Directed Antibiotic Treatment in Snake Bite
A Phase 4 study testing Co-amoxiclav and Tetanus toxoid in people with Snake Bites, run by Jawaharlal Institute of Postgraduate Medical Education & Research at 1 site in India.
Trial summary
Clinicians tend to overuse antibiotics in snake bite despite evidence from three previous clinical trials that failed to show a benefit. But, none of these trials was done in India. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Snake Bites
- What is being tested?
- Co-amoxiclav and Tetanus toxoid
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 66 participants
- Where
- 1 siteIndia
- Study dates
- 3 May 2016to 31 Mar 2020
- Phase
- Phase 4
- 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 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-65 years
- History of snake bite with features of local envenomation with/without systemic features
- Less than 24 hours since bite, AND
- No prior antibiotic treatment
Who cannot join
- Upper limb bites
- Multiple (> 1) bites
- Wound manipulation
- Extensive local necrosis or blebs
- Seriously-ill patients with hypotension/capillary leak/life threatening bleeding.
- Suspected cobra bite, OR
- Pregnant/breast-feeding women
Trial locations and contacts
1 site in 1 country.
India1 site
Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research
Puducherry, Puducherry, 605006
About this study
Official title: Routine vs. Clinically-Directed Antibiotic Treatment in Snake Bite With Local Envenomation: a Randomised Controlled Trial
Clinicians tend to overuse antibiotics in snake bite despite evidence from three previous clinical trials that failed to show a benefit. But, none of these trials was done in India. Further, the species of snake in two of these trials was quite different from that seen in the Indian setting limiting generalization of these findings. Hence, home-grown evidence is needed to persuade clinicians to use antibiotics rationally.
Read the detailed description
Snake bite is a common clinical problem in India and elsewhere, affecting agricultural workers and rural population, resulting in thousands of deaths every year. Apart from causing systemic manifestations such as coagulopathy, acute renal failure, and neuroparalysis, local effects of the venom manifest as swelling of the bitten limb. Despite administration of adequate antivenom, the limb swelling progresses in the first 48-72 hours accompanied by considerable pain. Often the limb swelling is accompanied by formation of blebs and gangrenous skin changes. At times, the limb swelling is severe enough to result in compartment syndrome, necessitating surgical interventions such as fasciotomy and debridement. Animal bites are typically associated with a risk of infection by the oral flora. Likewise, apart from releasing the venom, inoculation of oral flora as a result of snake bite could result in local infectious complications adding to the deleterious effects of the snake venom.
Observational studies suggest that the risk of infection following simple bites on the lower limbs is much less than what is often believed, and evidence from clinical trials also does not support routine use of antibiotics in snake bite. For this reason, clinical practice guidelines do not recommend routine prophylactic use of antibiotics in snake bite. But, in reality, many clinicians continue to use antibiotics routinely in all venomous snake bites hoping to prevent a local infection. While such a strategy may not reduce the risk of infection, it would result in overuse of antibiotics promoting antimicrobial resistance and escalating treatment costs.
The investigators hypothesize that clinically-directed use of antibiotics would be non-inferior to routine use in preventing local infectious complications of snake bite, while being superior in reducing the antibiotic consumption. Non-inferiority would be inferred if the one-sided 95% CI of the difference does not exceed 10% in favour of the routine use arm.
- Conditions
- Snake Bites
- Being tested
- Co-amoxiclav, Tetanus toxoid
- Keywords
- Snake Envenomation, Antibiotic Prophylaxis, Viperidae
- Medical subject headings
- Snake Bites
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Co-amoxiclavDrug
Also called Augmentin
Injection Co-amoxiclav 1.2 g intravenously q8h for a minimum of 48-72 hours; switched to oral Co-amoxiclav 625 mg b.i.d. when clinically appropriate.
Tetanus toxoidBiological
Injection Tetanus toxoid 0.5 ml intramuscularly Stat
| Study group | Role | What they receive |
|---|---|---|
| Routine use arm | Active comparator | All participants allocated to this arm will be given
* Injection Tetanus toxoid 0.5 ml intramuscularly Stat
* Antibiotic (Co-amoxiclav) will be given to all patients for a minimum duration of 5 days.
* Daily clinical assessment would be done. Change of antibiotics is allowed if clinical failure occurs.
Use of antibiotics for emergent indications unrelated to the bitten limb such as nosocomial infections would be allowed at the treating physician's discretion. Receives: Drug: Co-amoxiclav; Biological: Tetanus toxoid |
| Clinically-directed use arm | Experimental | Participants allocated to this arm will be given
* Injection Tetanus toxoid 0.5 ml intramuscularly Stat
* Daily clinical assessment would be done. Antibiotic (Co-amoxiclav) will be started only if clinical failure occurs.
Use of antibiotics for emergent indications unrelated to the bitten limb such as nosocomial infections would be allowed at the treating physician's discretion. Receives: Drug: Co-amoxiclav; Biological: Tetanus toxoid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical failure
Defined as occurrence of any one of the following on daily assessments - Abscess formation at any point of time; Surgical debridement/fasciotomy at any time; Worsening limb swelling beyond 72-96 hours or appearance of necrosis or blebs along with any one of the following: fever, persistent or worsening leucocytosis, or global deterioration on clinical assessment.
Measured: up to 4 weeks
Antibiotic consumption
Defined as the total amount of all antibiotics consumed regardless of clinical indication expressed in terms of defined daily doses (DDD).
Measured: up to 4 weeks
Secondary outcomes (5)
Length of hospital stay
Number of days from hospital admission until discharge
Measured: up to 4 weeks
Anti-snake venom consumption
The total number of vials of the anti-venom administered including doses received prior to being brought to JIPMER.
Measured: up to 4 weeks
New-onset organ failure
This includes acute kidney injury (AKI) defined as peak serum creatinine > 2 mg/dL, shock defined as systolic blood pressure < 90 mm Hg requiring use of vasopressors; bleeding from any site necessitating transfusion of blood/blood products; and capillary leak syndrome.
Measured: up to 4 weeks
Death/need for surgical intervention
This would be a composite measure of death and/or need for surgical intervention. Death indicates in-hospital death due to any cause during the index hospitalisation. Surgical intervention would include need for any surgical intervention such as incision and drainage of abscess, wound debridement for necrosis or gangrene, fasciotomy for compartment syndrome, etc.
Measured: up to 4 weeks
Drug-related adverse events
Any suspected or confirmed adverse drug reaction
Measured: up to 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2015 (estimated)
- Study start3 May 2016
- Primary completion24 Oct 2019
- Study completion31 Mar 2020
Why it stopped: Slower than anticipated recruitment and emergent COVID-19 situation
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Snake BitesStudies 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 66 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jawaharlal Institute of Postgraduate Medical Education & Research
- Sponsor type
- Other government
- Responsible party
- Principal investigator, Tamilarasu Kadhiravan, MD, Jawaharlal Institute of Postgraduate Medical Education & Research
- Investigators
- Tamilarasu Kadhiravan, M.D., Principal investigator, Jawaharlal Institute of Postgraduate Medical Education & Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02570347
- Sponsor's protocol ID
- JIP/IEC/2015/17/649
- Acronym
- RADIANS
- Status last verified
- May 2025
- First submitted
- 5 Oct 2015
- Last updated
- 30 May 2025
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: De-identified individual participant data that underlie the published results (text, tables, figures and appendices).
Publications
Terry P, Mackway-Jones K. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. The use of antibiotics in venomous snake bite. Emerg Med J. 2002 Jan;19(1):48-9. doi: 10.1136/emj.19.1.48.
PubMed 11777875Terry P, Mackway-Jones K. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Antibiotics in non-venomous snakebite. Emerg Med J. 2002 Mar;19(2):142. doi: 10.1136/emj.19.2.142.
PubMed 11904264Jorge MT, Malaque C, Ribeiro LA, Fan HW, Cardoso JL, Nishioka SA, Sano-Martins IS, Franca FO, Kamiguti AS, Theakston RD, Warrell DA. Failure of chloramphenicol prophylaxis to reduce the frequency of abscess formation as a complication of envenoming by Bothrops snakes in Brazil: a double-blind randomized controlled trial. Trans R Soc Trop Med Hyg. 2004 Sep;98(9):529-34. doi: 10.1016/j.trstmh.2003.12.009.
PubMed 15251401Kularatne SA, Kumarasiri PV, Pushpakumara SK, Dissanayaka WP, Ariyasena H, Gawarammana IB, Senanayake N. Routine antibiotic therapy in the management of the local inflammatory swelling in venomous snakebites: results of a placebo-controlled study. Ceylon Med J. 2005 Dec;50(4):151-5. doi: 10.4038/cmj.v50i4.1405.
PubMed 16538909Kerrigan KR, Mertz BL, Nelson SJ, Dye JD. Antibiotic prophylaxis for pit viper envenomation: prospective, controlled trial. World J Surg. 1997 May;21(4):369-72; discussion 372-3. doi: 10.1007/pl00012255.
PubMed 9143566Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, Rodriguez PS, Mishra K, Whitaker R, Jha P; Million Death Study Collaborators. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis. 2011 Apr 12;5(4):e1018. doi: 10.1371/journal.pntd.0001018.
PubMed 21532748Gautam A, Indu MB, Bhardwaj A, Sabitha P, Deepanjali S, Suryanarayana BS, Bammigatti C, Kadhiravan T. Clinically directed initiation versus routine use of amoxicillin-clavulanate and the risk of local complications among patients with haemotoxic snakebite envenomation treated at a teaching hospital in southern India: a randomised, non-inferiority trial. BMJ Open. 2025 Jun 23;15(6):e094409. doi: 10.1136/bmjopen-2024-094409.
PubMed 40550712
Study at a glance
From the registry record, last updated by the sponsor on 30 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Routine vs. Clinically-Directed Antibiotic Treatment in Snake Bite With Local Envenomation: a Randomised Controlled Trial
- ClinicalTrials.gov ID
- NCT02570347
- Acronym / sponsor ID
- RADIANS / JIP/IEC/2015/17/649
- Conditions
- Snake Bites
- Keywords
- Snake Envenomation, Antibiotic Prophylaxis, Viperidae
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Slower than anticipated recruitment and emergent COVID-19 situation
- Enrolment
- 66 participants (actual)
- Lead sponsor
- Jawaharlal Institute of Postgraduate Medical Education & ResearchOther government
- Study start
- 3 May 2016 (actual)
- Primary completion
- 24 Oct 2019 (actual)
- Study completion
- 31 Mar 2020 (actual)
- First posted
- 7 Oct 2015 (estimated)
- 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.
Clinicians tend to overuse antibiotics in snake bite despite evidence from three previous clinical trials that failed to show a benefit. But, none of these trials was done in India. Further, the species of snake in two of these trials was quite different from that seen in the Indian setting limiting generalization of these findings. Hence, home-grown evidence is needed to persuade clinicians to use antibiotics rationally.
Detailed description
Snake bite is a common clinical problem in India and elsewhere, affecting agricultural workers and rural population, resulting in thousands of deaths every year. Apart from causing systemic manifestations such as coagulopathy, acute renal failure, and neuroparalysis, local effects of the venom manifest as swelling of the bitten limb. Despite administration of adequate antivenom, the limb swelling progresses in the first 48-72 hours accompanied by considerable pain. Often the limb swelling is accompanied by formation of blebs and gangrenous skin changes. At times, the limb swelling is severe enough to result in compartment syndrome, necessitating surgical interventions such as fasciotomy and debridement. Animal bites are typically associated with a risk of infection by the oral flora. Likewise, apart from releasing the venom, inoculation of oral flora as a result of snake bite could result in local infectious complications adding to the deleterious effects of the snake venom.
Observational studies suggest that the risk of infection following simple bites on the lower limbs is much less than what is often believed, and evidence from clinical trials also does not support routine use of antibiotics in snake bite. For this reason, clinical practice guidelines do not recommend routine prophylactic use of antibiotics in snake bite. But, in reality, many clinicians continue to use antibiotics routinely in all venomous snake bites hoping to prevent a local infection. While such a strategy may not reduce the risk of infection, it would result in overuse of antibiotics promoting antimicrobial resistance and escalating treatment costs.
The investigators hypothesize that clinically-directed use of antibiotics would be non-inferior to routine use in preventing local infectious complications of snake bite, while being superior in reducing the antibiotic consumption. Non-inferiority would be inferred if the one-sided 95% CI of the difference does not exceed 10% in favour of the routine use arm.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Routine use arm | Active comparator | Drug: Co-amoxiclav, Biological: Tetanus toxoidAll participants allocated to this arm will be given * Injection Tetanus toxoid 0.5 ml intramuscularly Stat * Antibiotic (Co-amoxiclav) will be given to all patients for a minimum duration of 5 days. * Daily clinical assessment would be done. Change of antibiotics is allowed if clinical failure occurs. Use of antibiotics for emergent indications unrelated to the bitten limb such as nosocomial infections would be allowed at the treating physician's discretion. |
| Clinically-directed use arm | Experimental | Drug: Co-amoxiclav, Biological: Tetanus toxoidParticipants allocated to this arm will be given * Injection Tetanus toxoid 0.5 ml intramuscularly Stat * Daily clinical assessment would be done. Antibiotic (Co-amoxiclav) will be started only if clinical failure occurs. Use of antibiotics for emergent indications unrelated to the bitten limb such as nosocomial infections would be allowed at the treating physician's discretion. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age 18-65 years
- History of snake bite with features of local envenomation with/without systemic features
- Less than 24 hours since bite, AND
- No prior antibiotic treatment
Key exclusion criteria (7 listed)
- Upper limb bites
- Multiple (> 1) bites
- Wound manipulation
- Extensive local necrosis or blebs
- Seriously-ill patients with hypotension/capillary leak/life threatening bleeding.
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 |
|---|---|---|
| Co-amoxiclavAlso: AugmentinInjection Co-amoxiclav 1.2 g intravenously q8h for a minimum of 48-72 hours; switched to oral Co-amoxiclav 625 mg b.i.d. when clinically appropriate. | Drug | Clinically-directed use arm, Routine use arm |
| Tetanus toxoidInjection Tetanus toxoid 0.5 ml intramuscularly Stat | Biological | Clinically-directed use arm, Routine use arm |
Primary outcome
Clinical failure
Time frame: up to 4 weeks
Defined as occurrence of any one of the following on daily assessments - Abscess formation at any point of time; Surgical debridement/fasciotomy at any time; Worsening limb swelling beyond 72-96 hours or appearance of necrosis or blebs along with any one of the following: fever, persistent or worsening leucocytosis, or global deterioration on clinical assessment.
Antibiotic consumption
Time frame: up to 4 weeks
Defined as the total amount of all antibiotics consumed regardless of clinical indication expressed in terms of defined daily doses (DDD).
5 secondary outcomes
Length of hospital stay
Time frame: up to 4 weeks
Anti-snake venom consumption
Time frame: up to 4 weeks
New-onset organ failure
Time frame: up to 4 weeks
Death/need for surgical intervention
Time frame: up to 4 weeks
Drug-related adverse events
Time frame: up to 4 weeks
Results and safety
The study was stopped early (reason given: Slower than anticipated recruitment and emergent COVID-19 situation). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 May 2025.
- Background: PubMed 11777875Terry P, Mackway-Jones K. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. The use of antibiotics in venomous snake bite. Emerg Med J. 2002 Jan;19(1):48-9. doi: 10.1136/emj.19.1.48.
- Background: PubMed 11904264Terry P, Mackway-Jones K. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Antibiotics in non-venomous snakebite. Emerg Med J. 2002 Mar;19(2):142. doi: 10.1136/emj.19.2.142.
- Background: PubMed 15251401Jorge MT, Malaque C, Ribeiro LA, Fan HW, Cardoso JL, Nishioka SA, Sano-Martins IS, Franca FO, Kamiguti AS, Theakston RD, Warrell DA. Failure of chloramphenicol prophylaxis to reduce the frequency of abscess formation as a complication of envenoming by Bothrops snakes in Brazil: a double-blind randomized controlled trial. Trans R Soc Trop Med Hyg. 2004 Sep;98(9):529-34. doi: 10.1016/j.trstmh.2003.12.009.
- Background: PubMed 16538909Kularatne SA, Kumarasiri PV, Pushpakumara SK, Dissanayaka WP, Ariyasena H, Gawarammana IB, Senanayake N. Routine antibiotic therapy in the management of the local inflammatory swelling in venomous snakebites: results of a placebo-controlled study. Ceylon Med J. 2005 Dec;50(4):151-5. doi: 10.4038/cmj.v50i4.1405.
- Background: PubMed 9143566Kerrigan KR, Mertz BL, Nelson SJ, Dye JD. Antibiotic prophylaxis for pit viper envenomation: prospective, controlled trial. World J Surg. 1997 May;21(4):369-72; discussion 372-3. doi: 10.1007/pl00012255.
- Background: PubMed 21532748Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, Rodriguez PS, Mishra K, Whitaker R, Jha P; Million Death Study Collaborators. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis. 2011 Apr 12;5(4):e1018. doi: 10.1371/journal.pntd.0001018.
- Derived from this study: PubMed 40550712Gautam A, Indu MB, Bhardwaj A, Sabitha P, Deepanjali S, Suryanarayana BS, Bammigatti C, Kadhiravan T. Clinically directed initiation versus routine use of amoxicillin-clavulanate and the risk of local complications among patients with haemotoxic snakebite envenomation treated at a teaching hospital in southern India: a randomised, non-inferiority trial. BMJ Open. 2025 Jun 23;15(6):e094409. doi: 10.1136/bmjopen-2024-094409.
- Individual participant dataSharing planned: Yes. De-identified individual participant data that underlie the published results (text, tables, figures and appendices).
Related trials for Snake Bites
RecruitingObservational study
Mapping Snakebite Risk in Ghana and Rwanda
Snakebite, Snake Envenomation
RecruitingObservational study
Predictive Accuracy of the Snakebite Severity Score (SSS) in Identifying Syndrome-Specific Core Outcome Parameters Among Envenomated Patients Presenting to the Emergency Department
Snake Bite
Not yet recruitingObservational study
Point-of-care Ultrasound in the Assessment of Snake Bite
Rattlesnake Bite (Diagnosis)
RecruitingObservational study
Polyvalent Antivenom (Premium-PANAF) for Snakebite Envenoming in Ethiopia
Snake Envenomation
Enrolling by invitationObservational study
Multicenter Application Verification and Effect Evaluation of Artificial Intelligence-Based Snake Species Identification System in the Diagnosis and Treatment of Snakebites
Snake Bite
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.
Tamilarasu Kadhiravan, M.D. principal investigator
Jawaharlal Institute of Postgraduate Medical Education & Research
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Co-amoxiclav and Tetanus toxoid in people with Snake Bites, run by Jawaharlal Institute of Postgraduate Medical Education & Research at 1 site in India.
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 7 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: stopped early, as of the sponsor's last update on 30 May 2025. 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 India. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Slower than anticipated recruitment and emergent COVID-19 situation). 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?
Clinical failure (time frame: up to 4 weeks). 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 NCT02570347, which also lists 7 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 30 May 2025.