Comparison of F(ab’)₂ versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

Abstract

Background. Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab’)₂ immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab’)₂ antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. Methods. We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab’)₂ with maintenance doses [F(ab’)₂/F(ab’)₂], or F(ab’)₂ with placebo maintenance doses [F(ab’)₂/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm³, fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. Results. 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab’)₂/F(ab’)₂ cohort and 2/38 (5.3%, p < 0.05) in the F(ab’)₂/placebo cohort. The lowest heterologous protein exposure was with F(ab’)₂/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. Conclusions. In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab’)₂ antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation.

Keywords:

• Snakes
• Antivenins
• Toxinology

Author contributions and responsibilities

LVB, WG-U, and AA designed the study; SPB, A-MR, LVB, SAS, DLM, BJL, TCA, RFC, WJM, EAT, SWB, GRF, DRS, FMS, RW, IDC, and DQ collected the data; SPB, LVB, A-MR, SAS, RDG analyzed the data; SPB, LVB, A-MR, and SAS were the primary authors of the manuscript with final editing and approval by all coauthors, and all authors vouch for the accuracy and completeness of the reported analyses.

Acknowledgments

We thank Joanne Mallie, who assisted with study administration and coordinated data management from 4 sites in Tucson; Lisbeth Gaf, who set up and coordinated central data management; Pieter D’Arnaud, who assisted with statistical analysis; Angela Padilla-Jones, RN, research nurse and study coordinator at Banner Good Samaritan Medical Center; Frank Watkins, study coordinator at Vidant Medical Center; “Team Venom” at Loma Linda University Medical Center, Susan D. Smith, Tammy H. Phan, Sarah R. Pearl, Sarang Kim, and Alyssa Flores-Cuevas; and Ramona Gee.

In memoriam: The authors acknowledge with respectful memory the work of John F. Haynes, Jr., MD, whose participation as clinical investigator was essential to this study.

Declaration of interest

Rare Disease Therapeutics, Inc. (RDT) sponsored this study through contracts with the authors’ affiliated institutions, and Instituto Bioclon, SA de CV manufactures the F(ab’)₂ antivenom in this study. Drs. Bush, Ruha, and Quan report receiving remuneration for educational presentations related to the medical management of North American Crotalinae bites with Fab antivenom from BTG international Inc (BTG). Drs. Bush, Ruha, and Seifert participated in an expert panel sponsored by BTG that developed a treatment algorithm for pit viper envenomation. Drs. Bush, Ruha, and Siefert report being investigators in phase 2 and/or 3 clinical trials of a black widow spider antivenom manufactured by Instituto Bioclon, and their institution(s) contracted with Rocky Mountain Poison & Drug Center (RMPDC) to conduct these studies. Drs. Ruha and Boyer report being investigators in phase 2 and/or 3 clinical trials of a scorpion antivenom manufactured by Instituto Bioclon. Dr. Ruha reports having received remuneration from RDT for providing presentations about scorpion antivenom. Dr. Alagón reports that he had grant support from Instituto Bioclon at the time of the study, as well as past consultancy for Instituto Bioclon. Dr. Garcia reports being a full-time employee of Instituto Bioclon. Dr. Boyer reports that she had grant support from RDT for management of patients in the study, as well as a grant from Instituto Bioclon for development of North African antivenom. The authors alone are responsible for the content and writing of the paper.

Notice of Correction

Since the online publication of this article the following has been corrected in Table 1, “3.Oil.51” has been changed to “3.0±1.51.