A Comparison of Three Drug Combinations Containing Clarithromycin in the Treatment of Mycobacterium Avium Complex (MAC) Disease in Patients With AIDS

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00001058

Collaborator

(none)

246

Enrollment

Locations

7.2

Patients Per Site

Study Details

Study Description

Brief Summary

To compare the efficacy and safety of clarithromycin combined with rifabutin, ethambutol, or both in the treatment of disseminated Mycobacterium avium Complex (MAC) disease in persons with AIDS, including individuals who have or have not received prior MAC prophylaxis.

It is believed that effective therapy for MAC disease in patients with AIDS requires combinations of two or more antimycobacterial agents in order to overcome drug resistance and the unfavorable influence of the profound immunosuppression associated with AIDS. Data suggest that clarithromycin may have substantial activity in two- or three-drug combination regimens with clofazimine, rifamycin derivatives, ethambutol, or the 4-quinolones.

Condition or Disease	Intervention/Treatment	Phase
Mycobacterium Avium-intracellulare Infection HIV Infections	Drug: Indinavir sulfate Drug: Ritonavir Drug: Ethambutol hydrochloride Drug: Clarithromycin Drug: Rifabutin	Phase 2

Detailed Description

Patients are randomized to one of three treatment arms containing clarithromycin in combination with ethambutol, rifabutin, or both. Clarithromycin alone is taken on days 1 through 3 to determine tolerance and rifabutin and/or ethambutol is added on day 3. AS PER AMENDMENT 7/2/97: Patients may elect to add ritonavir or indinavir to their treatment regimen. Treatment continues daily for 48 weeks. In the absence of a dose-limiting toxicity, those patients who are determined to be complete or partial responders continue on the regimen to which they were originally assigned. Patients who have failed or relapsed on originally assigned MAC therapy, must have their therapy amended to receive clarithromycin and at least two other drugs not included in their originally assigned regimen. Patients are followed twice in the first week, then every 2 weeks for the first 2 months, then monthly for the next 4 months, and then every 2 months thereafter until the end of 12 months. PER AMENDMENT 10/10/96: NOTE: Any patient who develops a toxicity to rifabutin or ethambutol after week 12 or thereafter will be offered the option of being registered to a salvage regimen of 2 new drugs not previously received, plus clarithromycin to continue for the study duration.

Study Design

Study Type:

Interventional

Primary Purpose:

Treatment

Official Title:

A Phase II/III Prospective, Multicenter, Randomized, Controlled Trial Comparing the Safety and Efficacy of Three Clarithromycin-Containing Combination Drug Regimens for the Treatment of Disseminated Mycobacterium Avium Complex (MAC) Disease in Persons With AIDS

Actual Study Completion Date :

Jan 1, 1999

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Concurrent Medication:

Allowed:

Antiretroviral therapy.
Maintenance or prophylactic therapy for other opportunistic infections (with the exception of specifically excluded drugs).
Carbamazepine or theophylline.
Isoniazid for TB prophylaxis.

PER AMENDMENT 10/10/96:

Therapy for acute infectious processes, other than MAC, provided that the patient is stable on the therapy.
Fluconazole therapy for maintenance or suppression of fungal infections, providing the patient has been on a stable dose for at least 4 weeks.

PER AMENDMENT 7/02/97:

If a patient elects to receive indinavir, ORTHO/NOVUM 1/35 is an acceptable means of birth control.

Patients must have:

HIV infection.
Disseminated MAC disease.
Life expectancy of at least 8 weeks.
Consent of parent or guardian if under 18 years of age.

NOTE:

This protocol is approved for prisoner participation.

Prior Medication:

Allowed:

PER AMENDMENT 10/10/96:

Therapy for acute infectious processes, other than MAC, prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

Active mycobacterial infection other than MAC that requires treatment, with the exception of isoniazid used solely for TB prophylaxis.

Concurrent Medication:

Excluded:

Other antimycobacterial drugs (with the exception of isoniazid for TB prophylaxis).
Other investigational drugs unless approved by protocol chair.

PER AMENDMENT 7/2/97:

For patients who elect to receive indinavir or ritonavir:
Terfenadine, astemizole, cisapride, triazolam, or midazolam.
For patients who elect to receive ritonavir:
alprazolam, amiodarone, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine, ergotamine, estazolam, encainide, flecainide, flurazepam, meperidine, pimozide, piroxicam, propafenone, propoxyphene, quinidine or zolpidem.
For patients who elect to receive indinavir:
oral contraceptives other than ORTHO/NOVUM as a sole form of birth control.
For patients randomized to a rifabutin-containing arm:
oral contraceptives or Norplant as a sole form of birth control.

Patients with the following prior condition are excluded:

History of severe hypersensitivity to erythromycin, clarithromycin, azithromycin, ethambutol, rifampin, or rifabutin (including Type 1 hypersensitivity reaction, Stevens-Johnson syndrome, hepatitis, optic neuritis, or exfoliative dermatitis).

Prior Medication:

Excluded:

Empiric or presumptive antimycobacterial therapy prior to study entry if > 14 days, within 90 days prior to entry.

NOTE:

Patients unwilling to discontinue presumptive therapy or empiric therapy may be enrolled with the permission of the protocol chairs, however, if they are without a MAC positive blood culture at baseline, they will have study medications discontinued (AS PER AMENDMENT 7/2/97).

PER AMENDMENT 10/10/96:

Treatment with clarithromycin or ethambutol within 4 days of initiation of study medications.
Treatment with rifabutin or rifampin within 7 days of initiation of study medications.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Therapeutics CRS	Birmingham	Alabama	United States	35294
2	USC CRS	Los Angeles	California	United States	90033
3	UCLA CARE Center CRS	Los Angeles	California	United States	90035
4	Ucsd, Avrc Crs	San Diego	California	United States	92103
5	Ucsf Aids Crs	San Francisco	California	United States	94110
6	Harbor-UCLA Med. Ctr. CRS	Torrance	California	United States	90502
7	University of Colorado Hospital CRS	Aurora	Colorado	United States	80045
8	The Ponce de Leon Ctr. CRS	Atlanta	Georgia	United States	30308
9	Queens Med. Ctr.	Honolulu	Hawaii	United States	96813
10	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii	United States	96816
11	Northwestern University CRS	Chicago	Illinois	United States	60611
12	Cook County Hosp. CORE Ctr.	Chicago	Illinois	United States	60612
13	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois	United States	60612
14	Weiss Memorial Hosp.	Chicago	Illinois	United States	60640
15	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana	United States	46202
16	Indiana Univ. School of Medicine, Wishard Memorial	Indianapolis	Indiana	United States	46202
17	Methodist Hosp. of Indiana	Indianapolis	Indiana	United States	46202
18	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland	United States	21287
19	Bmc Actg Crs	Boston	Massachusetts	United States	02118
20	Beth Israel Deaconess - East Campus A0102 CRS	Boston	Massachusetts	United States	02215
21	Hennepin County Med. Ctr., Div. of Infectious Diseases	Minneapolis	Minnesota	United States	55415
22	University of Minnesota, ACTU	Minneapolis	Minnesota	United States	55455
23	Washington U CRS	Saint Louis	Missouri	United States	63110
24	St. Louis ConnectCare, Infectious Diseases Clinic	Saint Louis	Missouri	United States	63112
25	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York	United States	14260
26	Beth Israel Med. Ctr. (Mt. Sinai)	New York	New York	United States	10003
27	NY Univ. HIV/AIDS CRS	New York	New York	United States	10016
28	Univ. of Rochester ACTG CRS	Rochester	New York	United States	14642
29	Unc Aids Crs	Chapel Hill	North Carolina	United States	27514
30	Univ. of Cincinnati CRS	Cincinnati	Ohio	United States	45267
31	The Ohio State Univ. AIDS CRS	Columbus	Ohio	United States	43210
32	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania	United States	19104
33	University of Washington AIDS CRS	Seattle	Washington	United States	98104
34	Mbeya Med. Research Program, Mbeya Referral Hosp. CRS	Mbeya		Tanzania