Evaluation by simulation of clinical trial designs for evaluation of treatment during a viral haemorrhagic fever outbreak

BACKGROUND: Viral haemorrhagic fevers are characterized by irregular outbreaks with high mortality rate. Difficulties arise when implementing therapeutic trials in this context. The outbreak duration is hard to predict and can be short compared to delays of trial launch and number of subject needed (NSN) recruitment. Our objectives were to compare, using clinical trial simulation, different trial designs for experimental treatment evaluation in various outbreak scenarios. METHODS: Four type of designs were compared: fixed or group-sequential, each being single- or two-arm. The primary outcome was 14-day survival rate. For single-arm designs, results were compared to a pre-trial historical survival rate p(H). Treatments efficacy was evaluated by one-sided tests of proportion (fixed designs) and Whitehead triangular tests (group-sequential designs) with type-I-error = 0.025. Both survival rates in the control arm p(C) and survival rate differences Δ (including 0) varied. Three specific cases were considered: “standard” (fixed p(C), reaching NSN for fixed designs and maximum sample size N(Max) for group-sequential designs); “changing with time” (increased p(C) over time); “stopping of recruitment” (epidemic ends). We calculated the proportion of simulated trials showing treatment efficacy, with K = 93,639 simulated trials to get a type-I-error PI(95%) of [0.024;0.026]. RESULTS: Under H(0) (Δ = 0), for the “standard” case, the type-I-error was maintained regardless of trial designs. For “changing with time” case, when p(C) > p(H,) type-I-error was inflated, and when p(C) < p(H) it decreased. Wrong conclusions were more often observed for single-arm designs due to an increase of Δ over time. Under H(1) (Δ = + 0.2), for the “standard” case, the power was similar between single- and two-arm designs when p(C) = p(H). For “stopping of recruitment” case, single-arm performed better than two-arm designs, and fixed designs reported higher power than group-sequential designs. A web R-Shiny application was developed. CONCLUSIONS: At an outbreak beginning, group-sequential two-arm trials should be preferred, as the infected cases number increases allowing to conduct a strong randomized control trial. Group-sequential designs allow early termination of trials in cases of harmful experimental treatment. After the epidemic peak, fixed single-arm design should be preferred, as the cases number decreases but this assumes a high level of confidence on the pre-trial historical survival rate. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12874-021-01287-w.