Item #22: HIVNET 012 Not Placebo Controlled

HIVNET 012, according to its original 1997 protocol, was intended to be a four-arm, Phase III, randomized, placebo-controlled trial.6 Its sole sponsor was listed as the National Institute of Allergy and Infectious Diseases (NIAID), though one of the investigators was a Boehringer employee. The “sample size” was to be 1,500 HIV-1 infected Ugandan women more than thirty-two weeks pregnant. The four arms they would be divided into were 1) A single dose of 200mg nevirapine at onset of labor and a single 2mg dose to the infant forty-eight to seventy-two hours post-delivery, and 2) a corresponding placebo group; 3) 600mg of AZT at onset of labor and 300mg until delivery, with a 4mg AZT dose for the infant lasting seven days after birth, and 4) a corresponding placebo group. There were to he 500 women in each “active agent” arm and 250 in each placebo arm. The study was to last eighteen months, and its “primary endpoints” were to see how these two regimens would affect rates of HIV transmission from mother to child, and to examine the “proportion of infants who are alive and free of HIV at 18 months of age.” Another primary objective was to test the “safety/tolerance” of nevirapine and AZT. HIVNET's architects estimated that more than 4,200 HIV-positive pregnant women would deliver at Mulago hospital each year, allowing them to enroll eighty to eighty-five women per month. Consent forms were to be signed by either the mother or a guardian, by signature or “mark.” One of the exclusion criteria was “participation during current pregnancy in any other therapeutic or vaccine perinatal trial.”
Although HIVNET was designed to be a randomized, placebo-controlled, double-blind, Phase III trial of 1,500 mother/infant pairs, it wound up being a no-placebo, neither double- nor even single-blind Phase II trial of 626 mother/infant pairs. Virtually all of the parameters outlined for HIVNET 012 were eventually shifted, amended, or done away with altogether, beginning with perhaps the most important—the placebo controls. By a “Letter of Amendment” dated March 9, 1998, the placebo-control arms of HIVNET were eliminated.
The study as reconstituted thus amounted to a simple comparison of AZT and nevirapine.

Farber claims HIVNET 012 was not placebo-controlled.

This statement is true, but Farber fails to explain critical facts that would allow readers to understand that the trial design was appropriate and that the results are meaningful. A short-course AZT regimen had been found in the PACTG 076 trial to be effective at reducing MTCT. The AZT regimen used in HIVNET 012 was a subset of the PACTG 076 regimen and therefore at least as good as placebo (but probably not as good as the regimen used in PACTG 076). In the nevirapine arm the rate of MTCT was reduced by 47% over that in the AZT arm by the end of the of the study. It would have been unethical to compare nevirapine directly to placebo when it was known that AZT could reduce MTCT. Therefore simple logic shows this: (1) HIVNET 012 AZT regimen is better than or equal to placebo. (2) HIVNET 012 nevirapine regimen is better than HIVNET 012 AZT regimen. Therefore HIVNET 012 nevirapine regimen is better than placebo. For more details, see the Cochrane review of antiretroviral regimens for reducing MTCT42 . Note that four AZT regimens have been shown to be effective at reducing MTCT.

One of the lead researchers certainly thought that terminating the placebo arm was a mistake. Quoting from Anne Bennett Swingle’s article “The Pathologist Who Struck Gold” in the Spring/Summer 2001 issue of Hopkins Medical Journal: "Still, Jackson felt strongly that he didn't want to drop the placebo part of his protocol. Testing two drugs against nothing, instead of only against each other, was the only way to make a valid scientific assessment of the worth of both medications."

Although true placebos are unfashionable, there are still scientists who point out that without a placebo it is not possible to state with any degree of certainty that the two arms of a trial, both using different active medications, are either or both better than doing nothing. The Gallo document extrapolates from other trials done in other places, and concludes that, based on a surrogate marker (transmission of signs of HIV), the long term health of the mothers and children will be enhanced, on average if not for all individuals. Two FDA scientists, in a pair of papers [1] [2] note that only a placebo can tell when the study population is producing the apparently good results in both active arms, and describe the benefits of trials using three arms: standard therapy, new therapy and placebo. They state “This design allows a clear distinction…between a drug that does not work (the standard agent is superior to placebo but the new drug is not) and a study that does not work (neither the standard drug nor the new drug is superior to placebo).” The authors do not note that such a trial could also show that the “standard agent” (AZT in this case) is no more effective than placebo.

1. Temple R et al. Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments; Part 1: Ethical and Scientific Issues. Ann Intern Med. 2000 Sep 19; 133(6): 455-63.
2. Ellenberg SS et al. Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments; Part 2: Practical Issues and Specific Cases. Ann Intern Med. 2000 Sep 19; 133(6): 455-63.