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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00001058
• Other study ID #: ACTG 223
• Secondary ID: 11200
• Status: Completed
• Phase: Phase 2
• Est. completion date: January 1999

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 246
• Est. completion date: January 1999
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Communicable Diseases
• HIV Infections
• Infections
• Mycobacterium avium-intracellulare Infection
• Mycobacterium Infections

Intervention

Drug:
• Indinavir sulfate

• Ritonavir

• Ethambutol hydrochloride

• Clarithromycin

• Rifabutin

Locations

Country	Name	City	State
Tanzania	Mbeya Med. Research Program, Mbeya Referral Hosp. CRS	Mbeya
United States	The Ponce de Leon Ctr. CRS	Atlanta	Georgia
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland
United States	Alabama Therapeutics CRS	Birmingham	Alabama
United States	Beth Israel Deaconess - East Campus A0102 CRS	Boston	Massachusetts
United States	Bmc Actg Crs	Boston	Massachusetts
United States	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York
United States	Unc Aids Crs	Chapel Hill	North Carolina
United States	Cook County Hosp. CORE Ctr.	Chicago	Illinois
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois
United States	Weiss Memorial Hosp.	Chicago	Illinois
United States	Univ. of Cincinnati CRS	Cincinnati	Ohio
United States	The Ohio State Univ. AIDS CRS	Columbus	Ohio
United States	Queens Med. Ctr.	Honolulu	Hawaii
United States	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii
United States	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana
United States	Indiana Univ. School of Medicine, Wishard Memorial	Indianapolis	Indiana
United States	Methodist Hosp. of Indiana	Indianapolis	Indiana
United States	UCLA CARE Center CRS	Los Angeles	California
United States	USC CRS	Los Angeles	California
United States	Hennepin County Med. Ctr., Div. of Infectious Diseases	Minneapolis	Minnesota
United States	University of Minnesota, ACTU	Minneapolis	Minnesota
United States	Beth Israel Med. Ctr. (Mt. Sinai)	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	St. Louis ConnectCare, Infectious Diseases Clinic	Saint Louis	Missouri
United States	Washington U CRS	Saint Louis	Missouri
United States	Ucsd, Avrc Crs	San Diego	California
United States	Ucsf Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	Harbor-UCLA Med. Ctr. CRS	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Tanzania, 

References & Publications (2)

Benson CA, Williams PL, Currier JS, Holland F, Mahon LF, MacGregor RR, Inderlied CB, Flexner C, Neidig J, Chaisson R, Notario GF, Hafner R; AIDS Clinical Trials Group 223 Protocol Team. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. Clin Infect Dis. 2003 Nov 1;37(9):1234-43. Epub 2003 Oct 3. — View Citation

Flexner C, Noe D, Benson C, Currier J, Andrade A, Shaver A. Adherence patterns in patients with symptomatic Mycobacterium avium complex (MAC) infection taking a twice-daily clarithromycin regimen. ACTG 223 Study Team. Int Conf AIDS. 1998;12:585 (abstract no 32324)