TOXICOLOGY/ORIGINAL RESEARCH The Efficacy of Antivenin Latrodectus (Black ʹ Widow) Equine Immune F(ab )2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Richard C. Dart, MD, PhD*; Sean P. Bush, MD; Kennon Heard, MD, PhD; Thomas C. Arnold, MD; Mark Sutter, MD; Danielle Campagne, MD; Christopher P. Holstege, MD; Steven A. Seifert, MD; Jean C. Y. Lo, MD; Dan Quan, DO; Stephen Borron, MD; David A. Meurer, MD; Randy I. Burnham, MS; Jude McNally, PharmD; Walter Garcia-Ubbelohde, MD; Victoria E. Anderson, MPH *Corresponding Author. E-mail: [email protected]. Study objective: The antivenom currently available for treatment of systemic black widow envenomation (latrodectism) is composed of equine whole immunoglobin. Although considered effective, it has been associated with anaphylaxis and 2 reported fatalities. We test the efficacy and safety of new equine antivenom composed of purified F(abʹ)2 antibody fragments. Methods: A randomized, double-blind, placebo-controlled trial was conducted at 16 sites across the United States. Subjects aged 10 years or older with moderate to severe pain because of black widow spider envenomation received F(abʹ)2 antivenom or placebo. The primary outcome measure was treatment failure, which was defined as failure to achieve and maintain clinically significant reduction in pain for 48 hours posttreatment. Secondary measures of pain intensity differences and summed pain intensity difference were computed. Adverse events were recorded. Results: Sixty patients were treated (29 antivenom and 31 placebo). The mean age was 39 years and 68% were male. There were 15 treatment failures in the antivenom group and 24 in the placebo group (P¼.019).Differencesinpainintensity difference between groups were lower at each postbaseline point, and the mean summed pain intensity difference was greater for the antivenom group (difference 2,133; 95% confidence interval 177 to 4,090). No deaths or serious drug-related adverse events were detected. Conclusion: The F(abʹ)2 antivenom met the predefined primary outcome of reduced treatment failures. Secondary outcomes of pain intensity difference and summed pain intensity difference also supported efficacy. The rate of symptom improvement in the placebo group was higher than expected, which may be related to enrollment criteria or placebo effect. [Ann Emerg Med. 2019;-:1-11.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2019 by the American College of Emergency Physicians. https://doi.org/10.1016/j.annemergmed.2019.02.007 INTRODUCTION occur, culminating in paroxysms of pain. This Background myopathic syndrome of latrodectism is often manifested There are 5 species of widow spiders (Latrodectus)in by hypertonicity of the musculature, with rigidity of the fi NorthAmerica,with1,330bitesreportedtoUSpoison abdomen, trismus, muscle brillations, tonic ” centers in 2016.1 The active component of Latrodectus contractions and tremor. The pain can mimic acute venom is latrotoxin, a neurotoxin that is highly abdominal conditions and acute myocardial infarction. conserved among widow spiders worldwide. Latrotoxin Although considered a nonfatal condition, rare but well- 3 causes latrodectism, which was aptly described by documented instances of death have been reported. The fi Maretic2: “Cramping pains in the thighs, lumbar region, syndrome is most severe for the rst 12 to 24 hours and abdomen or thorax are often present. The patient may then gradually resolves during several days; persistent also feel pressure and tightness in these areas. From time symptoms may result in repeated visits to the emergency to time, contraction in the large muscle masses may department (ED). Volume -, no. - : - 2019 Annals of Emergency Medicine 1 ʹ Equine F(ab )2 Black Widow Spider Antivenom Dart et al 4 Editor’s Capsule Summary prolong the duration of illness. In contrast, antivenom binds latrotoxin and prevents its interaction with What is already known on this topic presynaptic membranes. Antivenin Latrodectus (Black ʹ Latrodectus (black widow) spider bite may cause a Widow) Equine Immune F(ab )2 is an experimental equine fi painful systemic myopathic syndrome (latrodectism). Fab2 antibody preparation puri ed to reduce 6 Existing immunoglobulin-based antivenom is limited nonimmunizing serum components such as albumin. in supply and associated with anaphylaxis. Goals of This Investigation What question this study addressed This study was a phase 3 trial to evaluate the efficacy and Is a newer antibody-based antivenom (antivenin ʹ safety of Antivenin Latrodectus (Black Widow) Equine Latrodectus equine immune F[ab ]2) safe and ʹ Immune F(ab )2. efficacious in the treatment of black widow spider envenomation? MATERIALS AND METHODS What this study adds to our knowledge Study Design In this multicenter randomized trial of 60 patients, A multicenter, randomized, double-blind, placebo- ʹ F(ab )2 was associated with fewer treatment failures controlled trial was performed comparing the efficacy of (<13-mm visual analog scale pain scale decrease, Antivenin Latrodectus (Black Widow) Equine Immune ʹ need for commercial antivenom, or need for F(ab )2 with placebo for reduction of pain intensity caused prescription analgesia) than placebo (51.7% versus by latrodectism (Figure 1). The study was approved by the 77.4%). Adverse event rates were similar. institutional review board at the central coordinating center How this is relevant to clinical practice and at each participating site. ʹ F(ab )2 offers a potential new treatment for Latrodectus envenomation. Larger series are needed to Setting verify its safety and effectiveness. Future studies must Subjects were enrolled in the ED at 16 adult, pediatric, develop improved methods for defining latrodectism and mixed academic and community-based EDs in the cases and treatment outcomes. United States between October 2009 and October 2014 (Appendix E1, available online at http://www. annemergmed.com). Enrollment, administration of investigational product, and most data collection were completed in the ED. Follow-up interviews in regard to the subjects’ clinical condition were completed by telephone. Importance Few clinical trials have addressed the treatment of Selection of Participants Latrodectus envenomation. In the United States, treatment Patients aged 10 years and older presenting within 24 of latrodectism typically includes opioid analgesics and hours of symptom onset related to presumed black widow benzodiazepines.4 However, these measures have been spider envenomation were eligible for inclusion. Subjects associated with prolonged illness and higher rates of were required to have moderate to severe pain intensity, hospital admission.4 defined as a score greater than 40 mm on the visual analog Antivenin (Latrodectus mactans) (Merck & Co, Inc, scale (VAS) at both the screening and baseline Whitehouse Station, NJ) was introduced in the 1950s and examinations to be eligible. Similar to previous prospective contains equine whole immunoglobin, as well as other studies, the diagnosis of latrodectism was based on clinical constituents of horse serum. It is considered effective, but diagnosis by the site investigator because no validated has been associated with anaphylaxis and 2 reported instruments for the diagnosis of latrodectism exist. To fatalities from allergic reactions.4,5 For many years, the increase the probability of accurate diagnosis, concurrence supplier has restricted availability of the antivenom because with the diagnosis by a physician not associated with the of insufficient supply. This creates an untenable clinical trial was required for inclusion. position: patients in severe pain have to wait 24 to 48 hours Subjects meeting any of the following criteria were or more for antivenom. This prolongs pain and increases excluded: hypersensitivity to fentanyl or equine serum; health care expense. High doses of benzodiazepines and distracting injury with acute pain; inability to make a opioids may be used, but have well-known risks and reliable self-report of pain intensity; history of significant 2 Annals of Emergency Medicine Volume -, no. - : - 2019 ʹ Dart et al Equine F(ab )2 Black Widow Spider Antivenom Patient Consent Screening Exam Not Eligible NO VAS Screen ≥ 40 mm? for Study YES Randomization Baseline Exam Not Eligible NO VAS 0 m ≥ 40 mm? for Study YES Dose 1 (BWS AV or Placebo) VAS 0 m - VAS 30 m < 13 mm Dose 2 (Same Treatment Assignment as YES OR VAS 30 m > 40 mm? Dose 1) NO VAS 0 m – VAS 60 m ≥ 13 mm? NO Treatment Failure YES Repeat Above Steps for VAS 90 m, VAS 120 m, and VAS 150 m (2.5 hours total) Phone Follow-Up with Subjects on Day 2, 10, and 17 Figure 1. Study schematic. BWS AV, Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2. cardiac, respiratory, hepatic, or renal disease, or psychiatric minute washout period after fentanyl administration was disorder or chronic pain syndrome, that in the required, and the baseline VAS score had to be 40 mm or investigator’s valuation could limit the efficacy or safety greater for administration of the study drug. endpoint assessment; history or suspected history of substance abuse; pregnancy or breastfeeding; previous treatment with commercially available antivenom for the Interventions current envenomation; or inability to provide a telephone The study medication was Analatro (Antivenin ʹ number for follow-up interviews. Latrodectus [Black Widow] Equine Immune F[ab ]2), a Subjects