Preliminary safety and activity evaluation of new agents for the treatment of HIV-1 infection: Recommended guidelines for trial design

The Primary Infection Committee Phase l/II Studies Working Group of the AIDS Clinical Trials Group has authored a working document entitled “Recommended Guidelines for the Phase I/II Study of Drug X in HIV Infected Patients.” The guidelines represent the evolving consensus on optimal Phase I Clinical Trial design for agents directed against Human lmmunodeficiency Virus-l (HIV-l) in adult patients. Three sequential Phase I stages should efficiently yield data necessary to guide subsequent decisions on drug development. Phase I-A studies are single administration, dose ranging studies to determine preliminary safety and pharmacokinetic parameters in human subjects. Phase I-B studies are multiple administration, dose escalation trials of at least 8 weeks per cohort designed to bracket a range of tolerated as well as biologically active dose regimens. Phase I-C/IIA trials entail randomization to 2 2 tolerated and active dosages from a Phase I-B study in order to choose a dose regimen with the best therapeutic index for further comparative efficacy evaluation. Randomization at this phase is recommended to overcome disparities seen between group characteristics in sequential Phase I enrollment. Sample sizes for Phase I-B trials are based on demonstration of anti-HIV activity (e.g. reduction in HIV-l p24 antigen) in a sufficient proportion per group so as to significantly exceed the background level of variability seen in untreated controls from other ACTG studies. Thus, of 8 to 10 patients per dose groups, z 6 would be required to be p24 Ag positive at entry. Sample sizes in Phase I-B are sufficient for enumerating the most serious toxicities which would define the maximally tolerated dose. In Phase I-B and I-C trials, extended dosing of the tolerated and antivirally active arms would be offered to patients in order to gain valuable information on long-term toxicity and duration of activity early in a given agents development. The consensus guidelines will be periodically modified as new anti-HIV agents and biological assays enter clinical trials.