Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial
Introduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral v...
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BMJ Publishing Group
2024-10-01
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| author | Chanaveerappa Bammigatti Timothy F Platts-Mills Ashish Bhalla Harish Kumar Matthew R Lewin Surendra Kumar Charles J Gerardo Rebecca W Carter Farshad M Shirazi Suneetha D Kotehal Peter D Akpunonu Richard B Schwartz Neeraj Manikath Partha P Mukherjee Thomas C Arnold Brian J Wolk Sophia S Sheikh Dawn R Sollee David J Vearrier Samuel J Francis Adiel Aizenberg Madhu K Ravikumar Sujoy Sarkar Taylor Haston Andrew Micciche Suraj C Oomman Jeffery L Owen Brandi A Ritter Stephen P Samuel |
| author_facet | Chanaveerappa Bammigatti Timothy F Platts-Mills Ashish Bhalla Harish Kumar Matthew R Lewin Surendra Kumar Charles J Gerardo Rebecca W Carter Farshad M Shirazi Suneetha D Kotehal Peter D Akpunonu Richard B Schwartz Neeraj Manikath Partha P Mukherjee Thomas C Arnold Brian J Wolk Sophia S Sheikh Dawn R Sollee David J Vearrier Samuel J Francis Adiel Aizenberg Madhu K Ravikumar Sujoy Sarkar Taylor Haston Andrew Micciche Suraj C Oomman Jeffery L Owen Brandi A Ritter Stephen P Samuel |
| author_sort | Chanaveerappa Bammigatti |
| collection | DOAJ |
| description | Introduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes.Methods This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours.Results Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred.Conclusion For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite. |
| format | Article |
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| institution | Kabale University |
| issn | 2059-7908 |
| language | English |
| publishDate | 2024-10-01 |
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| spelling | doaj-art-c2f65f034bc74026a8e5cd8f3ccaacfe2024-11-12T21:45:08ZengBMJ Publishing GroupBMJ Global Health2059-79082024-10-0191010.1136/bmjgh-2024-015985Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trialChanaveerappa Bammigatti0Timothy F Platts-Mills1Ashish Bhalla2Harish Kumar3Matthew R Lewin4Surendra Kumar5Charles J Gerardo6Rebecca W Carter7Farshad M Shirazi8Suneetha D Kotehal9Peter D Akpunonu10Richard B Schwartz11Neeraj Manikath12Partha P Mukherjee13Thomas C Arnold14Brian J Wolk15Sophia S Sheikh16Dawn R Sollee17David J Vearrier18Samuel J Francis19Adiel Aizenberg20Madhu K Ravikumar21Sujoy Sarkar22Taylor Haston23Andrew Micciche24Suraj C Oomman25Jeffery L Owen26Brandi A Ritter27Stephen P Samuel28Jawaharlal Institute of Postgraduate Medical Education, Puducherry, Tamil Nadu, IndiaOphirex, Inc, Corte Madera, California, USAPost Graduate Institute of Medical Education and Research, Chandigarh, Chandigarh, IndiaSardar Patel Medical College, Bikaner, Rajasthan, IndiaOphirex, Inc, Corte Madera, California, USASardar Patel Medical College, Bikaner, Rajasthan, IndiaDuke University School of Medicine, Durham, North Carolina, USAOphirex, Inc, Corte Madera, California, USAUniversity of Arizona Medical Center, University Campus, Tucson, Arizona, USAMysore Medical College and Research Institute, Mysore, Karnataka, IndiaUniversity of Kentucky College of Medicine, Lexington, Kentucky, USAAugusta University Medical College of Georgia, Augusta, Georgia, USAGovernment Medical College Kozhikode, Kozhikode, Kerala, IndiaCalcutta National Medical College and Hospital, Kolkata, West Bengal, IndiaLouisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USALoma Linda University Medical Center, Loma Linda, California, USAUniversity of Florida Health Science Center Jacksonville, Jacksonville, Florida, USAUniversity of Florida College of Medicine, Jacksonville, Jacksonville, Florida, USAThe University of Mississippi Medical Center, Jackson, Mississippi, USADuke University School of Medicine, Durham, North Carolina, USAUniversity of Arizona Medical Center, University Campus, Tucson, Arizona, USAMysore Medical College and Research Institute, Mysore, Karnataka, IndiaCalcutta National Medical College and Hospital, Kolkata, West Bengal, IndiaAugusta University Medical College of Georgia, Augusta, Georgia, USAUniversity of Kentucky College of Medicine, Lexington, Kentucky, USAOphirex, Inc, Corte Madera, California, USAOphirex, Inc, Corte Madera, California, USAOphirex, Inc, Corte Madera, California, USAOphirex, Inc, Corte Madera, California, USAIntroduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes.Methods This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours.Results Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred.Conclusion For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.https://gh.bmj.com/content/9/10/e015985.full |
| spellingShingle | Chanaveerappa Bammigatti Timothy F Platts-Mills Ashish Bhalla Harish Kumar Matthew R Lewin Surendra Kumar Charles J Gerardo Rebecca W Carter Farshad M Shirazi Suneetha D Kotehal Peter D Akpunonu Richard B Schwartz Neeraj Manikath Partha P Mukherjee Thomas C Arnold Brian J Wolk Sophia S Sheikh Dawn R Sollee David J Vearrier Samuel J Francis Adiel Aizenberg Madhu K Ravikumar Sujoy Sarkar Taylor Haston Andrew Micciche Suraj C Oomman Jeffery L Owen Brandi A Ritter Stephen P Samuel Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial BMJ Global Health |
| title | Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial |
| title_full | Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial |
| title_fullStr | Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial |
| title_full_unstemmed | Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial |
| title_short | Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial |
| title_sort | oral varespladib for the treatment of snakebite envenoming in india and the usa bravo a phase ii randomised clinical trial |
| url | https://gh.bmj.com/content/9/10/e015985.full |
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