Subject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists/administration & dosage , Cognitive Dysfunction/drug therapy , HIV Infections/complications , Imidazoles/pharmacokinetics , Anti-HIV Agents/cerebrospinal fluid , Anti-HIV Agents/therapeutic use , Cognition/drug effects , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/etiology , HIV Infections/cerebrospinal fluid , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/genetics , HIV-1/isolation & purification , Humans , Imidazoles/cerebrospinal fluid , Imidazoles/therapeutic use , RNA, Viral/cerebrospinal fluid , SulfoxidesABSTRACT
The design of phase I studies is often challenging, because of limited evidence to inform study protocols. Adaptive designs are now well established in cancer but much less so in other clinical areas. A phase I study to assess the safety, pharmacokinetic profile and antiretroviral efficacy of C34-PEG4 -Chol, a novel peptide fusion inhibitor for the treatment of HIV infection, has been set up with Medical Research Council funding. During the study workup, Bayesian adaptive designs based on the continual reassessment method were compared with a more standard rule-based design, with the aim of choosing a design that would maximise the scientific information gained from the study. The process of specifying and evaluating the design options was time consuming and required the active involvement of all members of the trial's protocol development team. However, the effort was worthwhile as the originally proposed rule-based design has been replaced by a more efficient Bayesian adaptive design. While the outcome to be modelled, design details and evaluation criteria are trial specific, the principles behind their selection are general. This case study illustrates the steps required to establish a design in a novel context. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Bayes Theorem , Clinical Trials, Phase I as Topic/methods , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , Endpoint Determination , HIV Envelope Protein gp41 , HIV Fusion Inhibitors/administration & dosage , Humans , Peptide FragmentsABSTRACT
The aim of this randomised controlled trial was to see if the addition of 4 mg/ml DNA-C priming given by the intramuscular route at weeks 0 and 4 to NYVAC-C at weeks 20 and 24, safely increased the proportion of participants with HIV-specific T-cell responses measured by the interferon (IFN)-gamma ELISpot assay at weeks 26 and/or 28 compared to NYVAC-C alone. Although 2 individuals discontinued after the first DNA-C due to adverse events (1 vaso-vagal; 1 transient, asymptomatic elevation in alanine transaminase), the vaccines were well tolerated. Three others failed to complete the regimen (1 changed her mind; 2 lost to follow-up). Of the 35 that completed the regimen 90% (18/20) in the DNA-C group had ELISpot responses compared to 33% (5/15) that received NYVAC-C alone (p=0.001). Responses were to envelope in the majority (21/23). Of the 9 individuals with responses to envelope and other peptides, 8 were in the DNA-C group. These promising results suggest that DNA-C was an effective priming agent, that merits further investigation.
