Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design

Abstract

BackgroundMany candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic.MethodsWe explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial.ResultsWe propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative.ConclusionsBy combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.

Multi-arm, multi-stage randomised controlled trials for evaluating therapeutic HIV cure interventions

“…Adaptive trial designs are attractive and becoming increasingly popular in an effort to accelerate clinical development (32). The use of MAMS is a promising design strategy to evaluate complex therapeutic strategies aimed at curing HIV infection, particularly where there are multiple agents or combinations of agents to be examined and where short-term endpoints, such as viral rebound during ATIs, are to be used in the evaluation of treatment success.…”

“…There have been calls for adaptive designs to be more readily used in the evaluation of HIV-1 vaccines (29,30) and they have been employed in a handful of prophylactic HIV vaccine trials (29)(30)(31)(32), however to-date an adaptive design has not been used in the evaluation of therapeutic HIV agents. A number of methodological and practical considerations are needed in order to adapt the MAMS design to evaluate immune-based therapeutic interventions for HIV cure.…”

A Bayesian design for phase I cancer therapeutic vaccine trials

“…This point has been reflected in the recent early phase (cancer) vaccine clinical trial design literature. For example, randomized phase I study designs have been proposed for optimizing the dose level or the schedule of therapeutic cancer vaccines . In a nonrandomized setting, Zohar et al proposed a Bayesian “up‐and‐down” phase I design for a cancer vaccine that makes dose level escalation decisions after each patient …”

Recent developments in clinical trial designs for HIV vaccine research

“…52 Nevertheless, all currently established designs for early stage HIV vaccine trials, be they comparative or not, rely on the definition of a single immunogenicity primary endpoint. 43 Secondary immunogenicity endpoints thus play an important role in these designs.…”

“…This is achieved by a sequential analyses of an early safety endpoint of the concerned vaccine with the aim to stop the vaccine before the boost phase should it be unsafe. 43 The applicability of the integrated phase I evaluation relies on prior knowledge of the safety of similar vaccines and quick participant accrual in the trial.…”