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CPCRA 015 ANTIRETROVIRAL COMBO THERAPY LARGE SIMPLE TRIAL

Executive Summary

CPCRA 015 ANTIRETROVIRAL COMBO THERAPY LARGE SIMPLE TRIAL could begin a phase-in period "soon," National Institute of Allergy and Infectious Diseases Community Programs for Clinical Research on AIDS (CPCRA) statistician James Neaton, PhD, told FDA's Antiviral Drugs Advisory Committee May 11. The pilot phase of the CPCRA trial (protocol 015) will test the methodologies that NIAID hopes to use in the full study. CPCRA 015 is designed to test the effect of immediate versus delayed combination antiretroviral therapy on survival. The phase-in portion of the study is expected to enroll 600 patients within six months, Neaton said. Five CPCRA centers will participate in the pilot study and 10-15 non-CPCRA sites will also be enrolled, Neaton said. The full CPCRA 015 study is planned to enroll 10,000 patients over a one-to-two-year period and follow them for three years. The study will compare initiating therapy with AZT (Burroughs Wellcome's Retrovir/zidovudine) in combination with another nucleoside analog to initiating therapy with AZT alone and adding another nucleoside when patients begin to show signs of deterioration. Several National Institutes of Health representatives briefed the committee on CPCRA 015 and on the concept of large simple trials in general (see preceding T&G). Such studies are designed to enroll large numbers of patients quickly by relying on limited data collection and minimal eligibility criteria. In CPCRA 015, physicians will enroll by calling a toll-free number to register. The only entry criteria for patients will be an ability to tolerate AZT and one of the other antivirals, Bristol-Myers Squibb's Videx (ddI) or Hoffmann-La Roche's Hivid (ddC), and "uncertainty" as to whether combination therapy is indicated. Some baseline data will be recorded and then patients will be randomized to either "immediate" or "deferred" combo therapy groups. Physicians will be left to judge for themselves when a patient in the deferred group should begin combination therapy. At that time, CPCRA will collect additional data on the patient's clinical status, and the physician will either select an add-on therapy or agree to a second randomization to either ddI or ddC. Patients will be stratified into two groups, those with baseline CD4 cell counts above 300 per mm. and those with baseline CD4 counts below 300. The study is powered to detect a mortality difference in the low CD4 group of 10% versus 7.5%, and a difference of 33% versus 25% in the high CD4 group. CPCRA plans to provide the drug free of charge through a centralized distribution center that will help the agency track compliance. However, Lawrence Deyton, MD, NIAID Division of AIDS, told the committee that "we don't have complete buy-in from the pharmaceutical companies at this point." Discussions "are continuing" with Burroughs, Bristol and Roche. The committee was also briefed on a second large simple trial, dubbed COMPACT 1 (the Community Partnership in AIDS/HIV Clinical Trials). Committee member and COMPACT 1 investigator Donald Abrams, MD, San Francisco General Hospital, told the committee that the study is designed to evaluate early antiretroviral therapy versus late therapy. The study will enroll asymptomatic patients who are uncertain whether they should begin antiretroviral therapy or await signs of clinical worsening. COMPACT 1 has begun its pilot phase with funding from the American Federation for AIDS Research, Abrams said. In eight weeks, the study has enrolled 50 patients of a planned 200. The patients have had CD4 counts from 100 to 1,100, Abrams said, showing that "even in San Francisco there is uncertainty about when to begin antiretroviral therapy." However, "I would have hoped we'd have more than 50 patients enrolled at this point," Abrams said. "Its going to take more public relations" to spur enrollment.
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