Purpose of this Document

This document provides information on the results of a clinical trial that compared the standard dose of clarithromycin (500 mg bid) with a higher dose (1000 mg bid) for treatment of HIV-infected patients with disseminated infection by Mycobacterium avium Complex (MAC). Based on the study findings of poorer survival associated with the high dose compared to the standard dose, NIAID recommends that treatment of these patients with clarithromycin should not exceed the approved dose of 500 mg twice daily. The study was conducted by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), a clinical research network sponsored by the National Institute of Allergy and Infectious Diseases. NIAID is providing this preliminary information to you as a health care provider while the investigators are preparing a manuscript for submission to a peer-reviewed medical journal.

Study Design

The CPCRA MAC treatment study was an open-label randomized trial comparing the safety and efficacy of four three-drug regimens for the treatment of patients with DMAC. All patients received a standard dose of ethambutol and were randomized to receive either standard-dose (500 mg bid) or high-dose (1000 mg bid) clarithromycin, and either rifabutin (300 mg/day) or clofazimine (100 mg/day). The primary endpoint of the study was death due to any cause. The study opened in March 1995 with a planned accrual of 400 patients.

Results

Closure of the high-dose clarithromycin arm
After review of the first interim analysis on Feb. 6, 1996, the NIAID Data and Safety Monitoring Board (DSMB) recommended termination of the clarithromycin dose comparison because of poorer survival in patients randomized to receive high-dose clarithromycin. Study enrollment ended immediately, and investigators and patients were informed of the results. All patients in the high-dose group were placed on the standard clarithromycin dose, and study follow-up was continued.

Primary endpoint
The interim analysis cutoff date was December 15, 1995. Through that date, 69 patients were randomized: 36 to receive 500 mg bid and 33 to receive 1000 mg bid of clarithromycin with a median follow-up of 3.3 months. As of December 15, 1995, five deaths had occurred in the standard dose group and 13 deaths in the high-dose group. In the analysis stratified by study site, the relative risk (RR) for death in the high-dose group compared to the standard-dose group was 1.94 (95% CI = 0.63 to 5.93, p = 0.24). Comparing the doses without stratifying by study site (a more efficient analysis due to the small numbers of events) the RR for death was 3.07 (95% CI = 1.09 to 8.65, p = 0.02). At the time of the DSMB review, 85 patients had been randomized, and seven deaths (16%) in the standard-dose arm and 17 deaths (43%) in the high-dose arm had been reported; the unstratified RR for death was 3.32 (95% CI = 1.37 to 8.03, p = 0.005).

Subsequent analysis with more complete data through Feb. 6, 1996, the discontinuation date for the dose comparison, revealed that 10 deaths occurred in the standard-dose arm and 17 deaths occurred in the high-dose arm (RR = 2.43, 95% CI = 1.11 to 5.43, p = 0.02).

Other analyses
Although the number of patients randomized to each dose group was relatively small, no baseline imbalances were detected, and adjusting for baseline covariates did not alter the relative risk of death. There was no indication that the higher dose was more or less effective than the standard dose in clearing bacteremia or relieving symptoms.

Reports of adverse events did not significantly differ between the doses. There were no types of toxicity consistently associated with the deaths. It is unlikely that the excess deaths were related to premature discontinuation of study therapy, since patients in both arms actually received study therapy during approximately 90% of time on the trial. Overall, no reason for the higher mortality in the high-dose arm compared to the standard-dose arm could be identified.

Other Dose Comparison Studies of Clarithromycin

Different doses of clarithromycin have been compared previously, in ACTG Study 157 and Abbott Protocol M91-577. ACTG 157 (Chaisson et al, Ann Intern Med, 121:905-911, 1994) was a dose-ranging study comparing 2000 mg bid, 1000 mg bid and 500 mg bid as monotherapy for patients with disseminated MAC. The Abbott M91-577 expanded access randomized dosing study (data presented at the FDA Advisory Panel Meeting, May 1993) compared 500 mg bid and 1000 mg bid for 12 weeks with the option to continue therapy.

In ACTG 157, the 1000 mg bid dose resulted in a more rapid clearance of MAC bacteremia than the 500 mg dose through 12 weeks. Both studies found a statistically significant poorer survival in the high-dose groups as compared to the standard-dose groups at early stages (12 - 16 weeks) of patient follow-up. However, based on a Kaplan-Meier survival analysis for the entire study period of ACTG 157, the difference between the 500 mg bid and the 1000 mg bid groups was not statistically significant. Unlike the ACTG study, the poorer survival in the high-dose arm continued throughout the Abbott M91-577 study, although it did not increase after the first 16 weeks.

The FDA analysis of these two data sets concluded that both studies demonstrated an excess of deaths early in the course of therapy among patients receiving 1000 mg bid, but extensive analyses did not identify the reasons. The FDA Advisory Committee, as well as the subsequent publication of ACTG 157 and its accompanying editorial, recommended that additional trials be done to compare different doses of clarithromycin and assess survival.

Conclusions

The standard dose (500 mg bid) is the only clarithromycin dosing regimen approved for the treatment of patients with DMAC and is an essential component of a recommended first-line treatment regimen for DMAC. Combination therapy including the standard dose clarithromycin has proven to be highly effective in decreasing MAC bacteremia and improving symptoms, and it has been proven to significantly reduce mortality in comparison to a regimen not including a macrolide. The results of the CPCRA MAC Treatment Trial provide further indication that doses of clarithromycin exceeding 500 mg twice daily should not be utilized for the treatment of MAC disease in HIV-infected patients. The explanation for the poorer survival associated with the high dose of clarithromycin compared to the standard dose has not been determined.

For more information concerning the CPCRA MAC Treatment Trial, please call 1-800-TRIALS-A.