title: Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design.
abstract: BACKGROUND
  Many 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  By 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Richert
authors.forename: Adélaïde
authors.initials: A
authors.lastname: Doussau
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Lelièvre
authors.forename: Vincent
authors.initials: V
authors.lastname: Arnold
authors.forename: Véronique
authors.initials: V
authors.lastname: Rieux
authors.forename: Amel
authors.initials: A
authors.lastname: Bouakane
authors.forename: Yves
authors.initials: Y
authors.lastname: Lévy
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chêne
authors.affiliation: Université Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, F-33000, France. rodolphe.thiebaut@isped.u-bordeaux2.fr.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiébaut
mesh_terms: D016915:AIDS Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003198:Computer Simulation; D003661:Decision Support Techniques; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D015337:Multicenter Studies as Topic / Q000379:methods*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016915:AIDS Vaccines