A Review of the Ring Trial Design for Evaluating Ring Interventions for Infectious Diseases

Abstract

In trials of infectious disease interventions, rare outcomes and unpredictable spatiotemporal variation can introduce bias, reduce statistical power, and prevent conclusive inferences. Spillover effects can complicate inference if individual randomization is used to gain efficiency. Ring trials are a type of cluster-randomized trial that may increase efficiency and minimize bias, particularly in emergency and elimination settings with strong clustering of infection. They can be used to evaluate ring interventions, which are delivered to individuals in proximity to or contact with index cases. We conducted a systematic review of ring trials, compare them with other trial designs for evaluating ring interventions, and describe strengths and weaknesses of each design. Of 849 articles and 322 protocols screened, we identified 26 ring trials, 15 cluster-randomized trials, 5 trials that randomized households or individuals within rings, and 1 individually randomized trial. The most common interventions were postexposure prophylaxis (n = 23) and focal mass drug administration and screening and treatment (n = 7). Ring trials require robust surveillance systems and contact tracing for directly transmitted diseases. For rare diseases with strong spatiotemporal clustering, they may have higher efficiency and internal validity than cluster-randomized designs, in part because they ensure that no clusters are excluded from analysis due to zero cluster incidence. Though more research is needed to compare them with other types of trials, ring trials hold promise as a design that can increase trial speed and efficiency while reducing bias.

Keywords: disease elimination; emerging infections; postexposure prophylaxis; randomized controlled trials; reactive interventions; ring trials; ring vaccination; targeted interventions.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for systematic review screening and inclusion. All registrations from ClinicalTrials.gov were reviewed in a single stage of full-text review, and records overlapped. “Total included studies” refers to research projects for which 1 or more records were included. Records of studies include trial registrations, published trial protocols, and original research articles.

Figure 2

Types of ring intervention trial designs. A) Ring trial design. B) Ring-stratified randomized trial. C) Cluster-randomized trial of ring intervention. The dotted line separates cluster 1 (left) from cluster 2 (right). Whereas all participants in cluster 1 were assigned to the intervention group, only participants inside the 4 rings received the intervention.