The design and implementation of A5146, a prospective trial assessing the utility of therapeutic drug monitoring using an inhibitory quotient in antiretroviral-experienced HIV-infected patients

Abstract

The AIDS Clinical Trials Group designed and implemented a prospective, randomized, strategy trial in antiretroviral-experienced, HIV-infected patients to evaluate the virologic impact of protease inhibitor dose escalation in response to therapeutic drug monitoring (TDM) with an inhibitory quotient, which integrates both drug exposure and viral drug resistance. In the process of developing this clinical trial, several unique challenges were identified that required innovative solutions. The major challenge was the need to integrate resistance testing, pharmacokinetic data, medication adherence, toxicity data, clinical assessments, randomization assignment, and protocol-specified clinical management in a way that could be utilized in real time by the protocol team, communicated promptly to the clinical sites, and transmitted accurately to the study database. In addition, the protocol team had to address the relative lack of commercially available TDM laboratories in the United States that were experienced in antiretroviral drug assays and a lack of familiarity with the principles of pharmacokinetic monitoring at participating clinical sites. This article outlines the rationale for the design of this strategy trial, specific barriers to implementation that were identified, and solutions that were developed with the hope that these experiences will facilitate the design and conduct of future trials of TDM.

Figure 1. Study design of A5146

The four phases of A5146 (screening, Steps 1, 2, and 3) are illustrated schematically. During the process of screening for study eligibility, a resistance test was obtained on the failing antiretroviral regimen, and used to design a new regimen. During Step 1, the new salvage antiretroviral regimen was begun at entry, and a PI trough sample was obtained 2 weeks later. The NIQ was calculated as outlined in the text, using the screening fold-change in IC₅₀ for the PI(s) in the A5146 antiretroviral regimen and the week 2 trough PI concentration measured in patient plasma. Entry into Step 2 was dependent on the value of the NIQ. If it was ≤ 1, the subject was randomized to the TDM or SOC arms. If the NIQ was > 1, the subject entered Step 2 on the observational arm or discontinued study, if the accrual goal of the observational arm had been met. Subjects who developed virologic failure at or after 20 weeks post-randomization in any of the 3 arms of Step 2 could enter Step 3 to receive a repeat resistance test and TDM followed by dose escalation on a new salvage regimen. Maximum follow-up on study was 48 weeks after Step 1 entry.

Figure 2. Calculation of the Normalized Inhibitory Quotient (NIQ)

The method for calculating an NIQ is illustrated. The NIQ is the ratio of the patient's IQ to a reference IQ, which was obtained from a population of patients that was expected to achieve virologic success (180 in this example). The patient's IQ is the ratio of the week 2 plasma trough concentration of the PI being taken (in this case, saquinavir) and the fold-change in IC₅₀ for the same PI obtained at the screening visit. In this example, the NIQ is greater than one, and the study patient would either enter the Observational arm, or discontinue the study. SQV, saquinavir; FC IC50, fold-change in the 50% inhibitory quotient for the patient's virus; CCO1, 1^st clinical cutoff (threshold below which one would expect maximal virologic response); CCO2, 2^nd clinical cutoff (threshold above which one would expect little or no virologic response). If the fold-change in IC50 is between CCO1 and CCO2, a reduced, but detectable virologic response would be expected). For protease inhibitors that have only a single cutoff (such as atazanavir and tipranavir in this specific example), this represents a biological cutoff for resistance, rather than a clinical cutoff.

Figure 3. Real-time communications required for Step 2 entry

The diagram illustrates the real-time interdisciplinary communications that were needed before a study subject could enter Step 2. Dotted arrows represent communications that occurred during screening; solid arrows represent those that occurred at or near the week 2 visit; and double-lined arrows represent communications that occurred at or near the time of randomization, for those subjects with an NIQ ≤ 1. SDMC, Statistical and Data Management Center; UB PSL, University of Buffalo pharmacology support laboratory.

Figure 4. A5146 accrual

The graph illustrates the accrual, by month, of study subjects into A5146. X-axis, month of accrual; Y-axis, number of study subjects. Gray bars, Step 1 accrual; black bars, Step 2 accrual. Arrow points to the month in which the revised protocol with liberalized entry criteria was released to the sites. The lag in time to increased rates of accrual was due in large part to the time needed for each site to obtain IRB approval.