Clinical outcomes and outcome measurement tools reported in randomised controlled trials of treatment for snakebite envenoming: A systematic review

Abstract

Background: Snakebite is a priority neglected tropical disease and causes a range of complications that vary depending on the snake species. Randomised clinical trials have used varied outcome measures that do not allow results to be compared or combined. In accordance with the Core Outcomes Measurements in Effectiveness Trials (COMET) initiative, this systematic review aims to support the development of a globally relevant core outcome set for snakebite.

Methods: All randomised controlled trials, secondary analyses of randomised controlled trials and study protocols investigating the efficacy of therapeutics for human snakebite envenoming were eligible for inclusion. Study screening and data extraction were conducted in duplicate by two independent reviewers. All primary and secondary outcome measures were extracted and compiled, as were adverse event outcome measures. Similar outcome measures were grouped into domains. The study was prospectively registered with PROSPERO: CRD42020196160.

Results: This systematic review included 43 randomised controlled trials, two secondary analyses and 13 study protocols. A total of 382 outcome measures were extracted and, after duplicates were merged, there were 153 unique outcomes. The most frequently used outcome domain ('venom antigenaemia') was included in less than one third of the studies. The unique outcomes were classified into 60 outcome domains. Patient-centred outcomes were used in only three of the studies.

Discussion: Significant heterogeneity in outcome measures exists in snakebite clinical trials. Consensus is needed to select outcome measures that are valid, reliable, patient-centred and feasible. The results of this systematic review strongly support the development of a core outcome set for use in snakebite clinical trials.

Fig 1. Study selection strategy.

RCT = randomised controlled trial.

Fig 2. Total number of randomised controlled trial participants by country.

The area of each circle is proportionate to the total number of trial participants randomised per country in studies published between 1946 and 2020. The area of the segments of each circle are proportionate to the sample size of individual RCTs (e.g., there has been one large trial and three small trials conducted in Nigeria). Each circle overlies the country that it refers to. Where circles would overlap they have been moved, and the edge of the circle touches the corresponding country. The key demonstrates the samples size that corresponds to the surface area of two example circles. World map sourced from the Natural Earth project (1:50m resolution version) https://www.naturalearthdata.com.

Fig 3. UpSet plot summarising methods of snake identification used in snakebite randomised controlled trials.

Upper bar chart, x axis: combinations of snake identification methods; y axis: number of randomised controlled trials using each combination of snake identification methods. Lower left bar chart, x axis: total numbers of randomised controlled trials using each individual method of snake identification; y axis: individual methods of snake identification.

Fig 4. Duration of follow-up of outcome measures: grouped by category of envenoming.

Fig 4 depicts the time-period of follow-up of outcome measures within each category. For each outcome measure, the latest time point of follow-up was identified. Time points were grouped as: up to 24 hours; up to 7 days; up to 28 days; up to 3 months; and over 3 months. Within each category, the proportion of outcome measures with follow-up until each time-point is defined. For example, mortality outcome measures were always followed up for over 7 days but were never followed up for more than 28 days. No outcome measures were followed up until between 28 days and 3 months, and therefore this time point is not displayed in Fig 4.