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	Treatment or Intervention	Phase
Mycobacterium avium-intracellulare Infection HIV Infections	Drug: Indinavir sulfate  Drug: Ritonavir  Drug: Ethambutol hydrochloride  Drug: Clarithromycin  Drug: Rifabutin	Phase II

Further Study Details: 

Expected Total Enrollment:  246

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.

Ages Eligible for Study:  13 Years and above,  Genders Eligible for Study:  Both

Criteria

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.

Alabama
      Univ of Alabama at Birmingham, Birmingham,  Alabama,  35294,  United States
California
      Univ of California / San Diego Treatment Ctr, San Diego,  California,  921036325,  United States
      San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States
      UCLA CARE Ctr, Los Angeles,  California,  90095,  United States
      Univ of Southern California / LA County USC Med Ctr, Los Angeles,  California,  900331079,  United States
      Harbor UCLA Med Ctr, Torrance,  California,  90502,  United States
      Olive View Med Ctr, Sylmar,  California,  91342,  United States
      USC Univ Hosp & Ambulatory Hlth Care Ctr / USC Med Ctr, Los Angeles,  California,  900334508,  United States
Colorado
      Univ of Colorado Health Sciences Ctr, Denver,  Colorado,  80262,  United States
      Kaiser Permanente Franklin Med Ctr, Denver,  Colorado,  80262,  United States
      Rose Med Ctr, Denver,  Colorado,  80262,  United States
Florida
      Med Ctr Clinic, Pensacola,  Florida,  325241151,  United States
      Regional Oncology Ctr, Daytona Beach,  Florida,  32015,  United States
      St Petersburg Med Clinics, St. Petersburg,  Florida,  33705,  United States
      Miami Veterans Administration Med Ctr, Miami,  Florida,  33125,  United States
Georgia
      Emory Univ, Atlanta,  Georgia,  30308,  United States
Hawaii
      Queens Med Ctr, Honolulu,  Hawaii,  96816,  United States
      Univ of Hawaii, Honolulu,  Hawaii,  96816,  United States
Illinois
      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States
      Rush Presbyterian - Saint Luke's Med Ctr, Chicago,  Illinois,  60612,  United States
      Cook County Hosp, Chicago,  Illinois,  60612,  United States
      Louis A Weiss Memorial Hosp, Chicago,  Illinois,  60640,  United States
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States
      Methodist Hosp of Indiana / Life Care Clinic, Indianapolis,  Indiana,  46202,  United States
      Division of Inf Diseases/ Indiana Univ Hosp, Indianapolis,  Indiana,  46202,  United States
      Wishard Hosp / Indiana Univ Hosp, Indianapolis,  Indiana,  46202,  United States
Maryland
      Johns Hopkins Hosp, Baltimore,  Maryland,  21287,  United States
Massachusetts
      Beth Israel Deaconess Med Ctr, Boston,  Massachusetts,  02215,  United States
      Boston Med Ctr, Boston,  Massachusetts,  02118,  United States
Minnesota
      Univ of Minnesota, Minneapolis,  Minnesota,  55455,  United States
      St Paul Ramsey Med Ctr, St. Paul,  Minnesota,  55101,  United States
      Hennepin County Med Clinic, Minneapolis,  Minnesota,  55415,  United States
Missouri
      St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis,  Missouri,  63112,  United States
New York
      Univ of Rochester Medical Center, Rochester,  New York,  14642,  United States
      Bellevue Hosp / New York Univ Med Ctr, New York,  New York,  10016,  United States
      Jack Weiler Hosp / Bronx Municipal Hosp, Bronx,  New York,  10465,  United States
      Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx,  New York,  10461,  United States
      SUNY / Erie County Med Ctr at Buffalo, Buffalo,  New York,  14215,  United States
      Beth Israel Med Ctr, New York,  New York,  10003,  United States
      Columbia Presbyterian Med Ctr, New York,  New York,  100323784,  United States
      Montefiore Adolescent AIDS Prog / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States
North Carolina
      Univ of North Carolina, Chapel Hill,  North Carolina,  275997215,  United States
Ohio
      Univ of Cincinnati, Cincinnati,  Ohio,  452670405,  United States
      Ohio State Univ Hosp Clinic, Columbus,  Ohio,  432101228,  United States
      Univ of Kentucky Lexington, Cincinnati,  Ohio,  45267,  United States
Pennsylvania
      Univ of Pennsylvania at Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
South Carolina
      Julio Arroyo, West Columbia,  South Carolina,  29169,  United States
Tennessee
      Vanderbilt Univ Med Ctr, Nashville,  Tennessee,  37203,  United States
Washington
      Univ of Washington, Seattle,  Washington,  981224304,  United States

Study chairs or principal investigators

Benson CA,  Study Chair
Chaisson RE,  Study Chair
Currier JS,  Study Chair

Study ID Numbers:  ACTG 223
Record last reviewed:  June 1999
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00001058
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08