Randomised Controlled Double-Blind Non-Inferiority Trial of Two Antivenoms for Saw-Scaled or Carpet Viper (Echis ocellatus) Envenoming in Nigeria

Abstract

BackgroundIn West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358).MethodsIn a randomised, double-blind, controlled, non-inferiority trial, “EchiTAb Plus-ICP” (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to “EchiTAb G” (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions.FindingsInitial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively.ConclusionAt these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria.Trial RegistrationCurrent Controlled Trials ISRCTN01257358

Medically important differences in snake venom composition are dictated by distinct postgenomic mechanisms

“…Thus, the antivenom EchiTAbG (manufactured from the IgG of sheep hyperimmunized with E. ocellatus venom; ref. 4) is equally effective at neutralizing the lethal effects of venom from E. ocellatus, E. coloratus, and E. p. leakeyi in vivo (12). These results emphasize that a certain degree of venom variation does not render a monospecific antivenom ineffective, so long as there are sufficient species-common toxin epitopes present to ensure the cross-reactive efficacy of antivenom antibodies.…”

“…Of all venomous animals, snakes are the most wellknown because of their medical importance: As many as 90,000 people die each year as the result of snakebite, with the majority of those inhabiting rural poor regions of the tropics (2,3). This substantial mortality burden of snakebite victims is surprising because antivenom treatment (immunoglobulins from venom-immunized horses/sheep) can be highly effective at neutralizing the toxic components present in snake venom (4,5). However, the efficacy of these therapies is largely restricted to the snake species whose venom was used in manufacture.…”

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

“…13,32 IgG aggregates can be formed by F(ab)-F(ab) or Fc-Fc interactions and occur after prolonged storage times, increasing the immunogenicity and modifying the physical properties of antivenoms. 33 Low-molecular mass proteins were also detected in reduced samples, but they did not correspond to Ig degradation products, which was shown by the Western blot reactions; thus, they were considered protein contaminants.…”

Snakebite Envenoming: A Public Health Perspective

“…This is then followed by phase III clinical trials in which a new antivenom is compared with an existing antivenom of known efficacy and safety (see for example the studies of I.S. Abubakar et al, 2010;Cardoso et al, 1993;Otero et al, 1999;Otero-Patiño et al, 1998;Smalligan et al, 2004;Warrell et al, 1974). Clinical trials should use robust clinical and laboratory end points for the assessment of therapeutic success.…”