Elsevier

Annals of Emergency Medicine

Volume 74, Issue 3, September 2019, Pages 439-449
Annals of Emergency Medicine

Toxicology/original research
The Efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial

Presented at the North American Congress of Clinical Toxicology annual meeting, September 2016, Boston, MA.
https://doi.org/10.1016/j.annemergmed.2019.02.007Get rights and content

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 (P=.019). Differences in pain intensity 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.

Introduction

There are 5 species of widow spiders (Latrodectus) in North America, with 1,330 bites reported to US poison centers in 2016.1 The active component of Latrodectus venom is latrotoxin, a neurotoxin that is highly conserved among widow spiders worldwide. Latrotoxin causes latrodectism, which was aptly described by Maretic2: “Cramping pains in the thighs, lumbar region, abdomen or thorax are often present. The patient may also feel pressure and tightness in these areas. From time to time, contraction in the large muscle masses may occur, culminating in paroxysms of pain. This myopathic syndrome of latrodectism is often manifested by hypertonicity of the musculature, with rigidity of the abdomen, trismus, muscle fibrillations, tonic contractions and tremor.” The pain can mimic acute abdominal conditions and acute myocardial infarction. Although considered a nonfatal condition, rare but well-documented instances of death have been reported.3 The syndrome is most severe for the first 12 to 24 hours and then gradually resolves during several days; persistent symptoms may result in repeated visits to the emergency department (ED).

Editor’s Capsule Summary

What is already known on this topic

Latrodectus (black widow) spider bite may cause a painful systemic myopathic syndrome (latrodectism). Existing immunoglobulin-based antivenom is limited in supply and associated with anaphylaxis.

What question this study addressed

Is a newer antibody-based antivenom (antivenin Latrodectus equine immune F[abʹ]2) safe and efficacious in the treatment of black widow spider envenomation?

What this study adds to our knowledge

In this multicenter randomized trial of 60 patients, F(abʹ)2 was associated with fewer treatment failures (<13-mm visual analog scale pain scale decrease, need for commercial antivenom, or need for prescription analgesia) than placebo (51.7% versus 77.4%). Adverse event rates were similar.

How this is relevant to clinical practice

F(abʹ)2 offers a potential new treatment for Latrodectus envenomation. Larger series are needed to verify its safety and effectiveness. Future studies must develop improved methods for defining latrodectism cases and treatment outcomes.

Few clinical trials have addressed the treatment of Latrodectus envenomation. In the United States, treatment of latrodectism typically includes opioid analgesics and benzodiazepines.4 However, these measures have been associated with prolonged illness and higher rates of hospital admission.4

Antivenin (Latrodectus mactans) (Merck & Co, Inc, Whitehouse Station, NJ) was introduced in the 1950s and contains equine whole immunoglobin, as well as other constituents of horse serum. It is considered effective, but has been associated with anaphylaxis and 2 reported fatalities from allergic reactions.4, 5 For many years, the supplier has restricted availability of the antivenom because of insufficient supply. This creates an untenable clinical position: patients in severe pain have to wait 24 to 48 hours or more for antivenom. This prolongs pain and increases health care expense. High doses of benzodiazepines and opioids may be used, but have well-known risks and prolong the duration of illness.4 In contrast, antivenom binds latrotoxin and prevents its interaction with presynaptic membranes. Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2 is an experimental equine Fab2 antibody preparation purified to reduce nonimmunizing serum components such as albumin.6

This study was a phase 3 trial to evaluate the efficacy and safety of Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2.

Section snippets

Study Design

A multicenter, randomized, double-blind, placebo-controlled trial was performed comparing the efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2 with placebo for reduction of pain intensity caused by latrodectism (Figure 1). The study was approved by the institutional review board at the central coordinating center and at each participating site.

Setting

Subjects were enrolled in the ED at 16 adult, pediatric, and mixed academic and community-based EDs in the United States between

Characteristics of Study Subjects

A total of 66 subjects at 11 sites provided consent. Six patients were subsequently excluded because of a VAS score of less than 40 mm at the baseline measurement. Demographic and clinical characteristics were similar between groups, with most subjects reporting local discomfort at the bite site, radiation of pain from the bite site to larger muscle groups, muscle cramps, and weakness (Tables 1 and 2). Localized erythema with diaphoresis and piloerection was the most commonly observed clinical

Limitations

It is likely that some of our patients did not have latrodectism because there are no pathognomonic signs, symptoms, or tests to establish the diagnosis unequivocally. This misclassification produces bias toward the null hypothesis (no effect of antivenom). Furthermore, placebo effect affects all research involving the treatment of pain. The effect can be large and generally also biases toward the null hypothesis. The external validity of our results is unknown because our study was performed

Discussion

We found that administration of an investigational black widow spider antivenom was followed by fewer treatment failures than placebo treatment. Secondary endpoints also supported efficacy. No patient developed symptoms consistent with an acute allergic reaction. These results support the feasibility of Antivenin Latrodectus (Black Widow) Equine Immune F(abʹ)2 as a treatment for latrodectism.

The patients enrolled in our study appeared similar to those in previous reports, with a predominance of

References (20)

There are more references available in the full text version of this article.

Cited by (0)

Please see page 440 for the Editor’s Capsule Summary of this article.

Supervising editor: Henry E. Wang, MD, MS. Specific detailed information about possible conflict of interest for individual editors is available at https://www.annemergmed.com/editors.

Author contributions: RCD, JM, and WG-U designed the trial. RCD obtained research funding and supervised the conduct of the trial and data collection. RIB provided statistical analysis. RCD and VEA drafted the article, and all authors contributed to its revision. RCD takes responsibility for the paper as a whole.

All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). Financial support for conduct of the trial was provided to the coordinating clinical site (Rocky Mountain Poison and Drug Center [RMPDC]) by Rare Disease Therapeutics, Nashville, TN; and Instituto Bioclon S.A. de C.V., Tlalpan, Mexico. Dr. Dart, Mr. Burnham, and Ms. Anderson were employed by RMPDC and received standard salary throughout the duration of the conduct of the trial. Drs. McNally and Garcia-Ubbelohde are employed by Instituto Bioclon S.A. de C.V. and Rare Disease Therapeutics, Inc., respectively, and received standard salary throughout the duration of the conduct of the trial. Drs. Bush, Heard, Arnold, Sutter, Campagne, Holstege, Seifert, Lo, Quan, Borron, and Meurer received funds from RMPDC to cover administration and procedural costs associated with the conduct of the trial at their respective investigative sites. No RMPDC employee received direct compensation for his or her role in this trial.

Trial registration number: NCT00657540

The trial sponsor did not have possession of the research data and did not participate in collection, management, or analysis of data.

A podcast for this article is available at www.annemergmed.com.

View full text