Dose-Finding Designs for HIV Studies

Abstract

We present a class of simple designs that can be used in early dose-finding studies in HIV. Such designs, in contrast with Phase I designs in cancer, have a lot of the Phase II flavor about them. Information on efficacy is obtained during the trial and is as important as that relating to toxicity. The designs proposed here sequentially incorporate the information obtained on viral reduction. Initial doses are given from some fixed range of dose regimens. The doses are ordered in terms of their toxic potential. At any dose, a patient can have one of three outcomes: inability to take the treatment (toxicity), ability to take the treatment but insufficient reduction in viral load (viral failure), and ability to take the treatment as well as a sufficient reduction of viral load (success). A clear goal for some class of designs would be the identification of the dose leading to the greatest percentage of successes. Under certain assumptions, which we identify and discuss, we can obtain efficient designs for this task. Under weaker, sometimes more realistic assumptions, we can still obtain designs that have good operating characteristics in identifying a level, if such a level exists, having some given or greater success rate. In the absence of such a level, the designs will come to an early closure, indicating the ineffectiveness of the new treatment.

Flexible Link Continual Reassessment Methods for Trivariate Binary Outcome Phase I/II Trials

“…Therefore, it would be wise to collect and utilize as much relevant information, including early efficacy data, as possible. Thus a better dose-finding approach may be to incorporate both toxicity and efficacy in a blended phase I/II fashion, an approach investigated by Gooley et al (1994), O'Quigley et al (2001), Braun (2002), and Thall and Cook (2004). One class of approaches actually transform bivariate binary outcomes to univariate trinomial outcomes: no efficacy or toxicity, efficacy without toxicity, and toxicity with or without efficacy (Thall and Russell, 1998;Fan and Chaloner, 2004;Zhang et al, 2006), then a proportional odds model or a continuation-ratio model is used for the trinomial outcomes.…”

Planning a Bayesian early‐phase phase I/II study for human vaccines in HER2 carcinomas

“…A phase I/II dose allocation scheme was chosen in order to model both dose-toxicity and dose-response without toxicity relationships, using an hybrid design combining a Bayesian inference and an 'up-and-down' approach based on either dose de-escalation any time toxicity is observed or dose escalation any time no toxicity and no treatment efficacy are observed [5,6]. The design deals with two binary random variables (0,1), Y and V where, Y = 1 denotes a toxicity, Y = 0 a non-toxicity, V = 1 a response, and V = 0 a non-response.…”

“…Stopping rules: As the trial proceeds and information is gathered about the success at the dose level d j , a decision is taken based on a sequential probability ratio test (SPRT) [32] to stop the trial for either the efficacy at the dose level estimated to be the MSD or for the inefficacy of all dose levels as proposed in O'Quigley et al [6]. It should be noted that, due to the dependence among doses and multiple hypotheses under study, probability of type I and type II error could be higher than the nominal level; some work has been done in this direction to adjust significance levels [33,34], but its direct link to the actual dose-finding procedure is still lacking.…”

Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment

“…Further, Bayesian model‐based designs have been developed for phase I trials with dual endpoints, efficacy and toxicity, 10 and to allow for non‐monotonicity in the dose‐response curve 11. O'Quigley et al 12 discuss adaptive designs for early dose‐finding studies in HIV‐disease, incorporating information on efficacy as well as toxicity. Their work was motivated by clinical trials designed to evaluate new antiretroviral treatments for children infected with HIV in general, rather than a specific trial.…”