Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 4 - June 1994
Derek Link

The plans for the trial were greeted with substantial criticism by the activists in New York, many of whom regarded the potential for finding a "home-run" treatment from any of the proposed combinations as negligible. The critics questioned whether the trials would produce meaningful data to clearly determine whether any of these combinations have a more modest benefit in treating HIV infection.

Trial Design

The protocol, designed as a pilot study, will enroll 100 asymptomatic patients with 200 to 500 CD4 cells and no prior HIV treatment in each study arm. The study will sequentially enroll patients. The first 100 patients will receive the first combination regimen, the next 100 patients will receive the second regimen, and so forth. The ICC initially will use two approved drugs and one unapproved drug to create the three-drug combinations.

The ICC will begin with four triple-drug regimens, enrolling patients at "10 to 20" sites nationwide. Sites have not yet been selected, but accrual could begin sometime this summer.

The four regimens selected for earliest evaluation are:

Arm 1: AZT + ddC + Saquinavir (the Roche protease inhibitor) Arm 2: AZT + ddI + Nevirapine Arm 3: AZT + ddI + 3TC Arm 4: AZT + ddC + Nevirapine

All drugs will be used at standard monotherapy doses. Dr. Barry anticipates that accrual into each regimen will take two to three months. If a "home-run" effect occurs, it could be noted as early as 26 weeks into the study because regular interim analyses are planned.

Although the ICC hopes to score a home-run with this strategy, it recognizes that a less dramatic therapeutic effect may also occur. Thus a graded scale has been developed to record a range of therapeutic responses that fall short of a home run. Four types of response will be examined: immunological markers, HIV levels, adverse effects and emergence of drug-resistant HIV strains. Each of these areas will be graded. For immunological markers, a "Grade A" response is CD4 cells returning to normal (above 800) in 90 percent of patients. A "Grade D" response is no CD4 effect at all.

Criticisms of the Trial Design

The first criticism of this trial design concerns randomization, the process by which patients in a clinical trial are "randomly" assigned to different treatments. Randomization minimizes the differences among groups by equally distributing people with particular characteristics among all the arms. It also allows for certain statistical methods to be applied to the data.

But the ICC master protocol is not randomized. The failure to randomize the study means that the data generated by it will lack both confidence and sophistication. It may be open to substantial bias if the different groups do not have equivalent characteristics that affect their response to therapy.

Then too, the study has no "control arm" (e.g. a placebo or even a standard therapy regimen) against which the effect of triple-drug combination is compared. Instead, the master protocol will compare triple-drug combination to an historical control - i.e., surrogate marker data from similar patients in previous studies.

Historical controls do have some advantages. Fewer patients are required for a study, resulting in easier recruitment. The trials also are much cheaper and simpler to conduct. Historical controls have some significant disadvantages, though. In the specific case of anti-HIV therapies, little is known about two-drug combination therapy in patients who have never before taken anti-HIV drugs. It is hard to imagine how the ICC can arbitrarily establish standard comparison data for this patient group. Not only are immunological markers, such as CD4 cell counts, open to considerable uncertainty for these people, but the effect of antiviral drugs on newer virological markers (like PCR or branched-chain DNA assay) has not been established.

In general, trials utilizing historical controls tend to over-estimate the therapeutic effect of treatment. Uncontrolled studies generally yield a much higher percentage of positive results than controlled studies.[1,2] All criticisms of the trial are not scientific. Only "nucleoside analog naive" volunteers (no history of taking AZT, ddI, ddC, etc.) are eligible for the study, which raises a difficult issue. People who have faithfully followed government, industry and (in some cases) community recommendations that "it's never too early" to start nucleoside analog treatment now find that the presumed cutting edge of research is unavailable to them. Is this anyway to treat one's best customers?

The most significant criticism of the trial is the drugs themselves. Three of the four regimens selected for initial investigation include only reverse transcriptase inhibitors, with the combination of AZT, ddI and 3TC being particularly dubious. Few virologists believe that a "home-run" is possible with a regimen that includes just reverse transcriptase inhibitors or even any of the drugs currently available. The trial appears in some respects to be a renamed repeat of the notorious "convergent combination therapy." The obvious, sad reality is that there are few new drugs to plug into the master protocol. This situation underscores the desperate need for new agents. Accordingly, the ICC must open up membership to the biotechnology industry, which is at the cutting-edge of drug discovery.

Strengths of the Trial

The master protocol has some important strengths that should not be overlooked. For treatment-naive asymptomatic patients, this trial represents a new option that some may find highly desirable. Despite the study design's scientific weaknesses, the protocol is probably adequate to detect a "home-run" treatment. A dramatic "cure," a treatment that brings patients back to normal and eliminates viral replication, is not difficult to observe. The problem, of course, is that treatments up to now have not shown such a dramatic, overwhelming effect.

The ICC protocol is a good sign that the drug industry is serious about cooperation. By explicitly going after a home- run strategy, the industry also has taken an important step toward defining its role in clinical research of HIV disease. Up to this point, no research group (government, industry or academic) has so clearly defined its mission. One hopes that other organizations, particularly those that are publicly funded, will follow the ICC's example and clarify their own missions.

And here's a final point not to be dismissed lightly: ICC members are spending their own money on these trials.

References:

1. Sacks H, et al. American Journal of Medicine, 1982; 72(2):233-40.

2. Sacks H, et al. Archives of Internal Medicine, 1983; 143(4):753-5.

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