Clinical trial NCT00001030: The Safety and Effectiveness of Clarithromycin and Rifabutin Used Alone or in Combination to Prevent Mycobacterium Avium Complex (MAC) or Disseminated MAC Disease in HIV-Infected Patients
Official title: A Prospective, Randomized, Comparative Study of the Safety and Efficacy of Clarithromycin Versus Rifabutin Versus the Combination of Clarithromycin Plus Rifabutin for the Prevention of Mycobacterium Avium Complex (MAC) Bacteremia or Disseminated MAC Disease in HIV-Infected Patients With CD4 Lymphocyte Counts <= 100 Cells/mm3
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Mycobacterium Avium-intracellulare Infection
HIV Infections
Keywords: Rifabutin
Mycobacterium avium-intracellulare Infection
Acquired Immunodeficiency Syndrome
Clarithromycin
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 1100
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To compare the efficacy and safety of clarithromycin alone versus rifabutin alone versus the two drugs in combination for the prevention or delay of Mycobacterium avium Complex (MAC) bacteremia or disseminated MAC disease. To compare other parameters such as survival, toxicity, and quality of life among the three treatment arms. To obtain information on the incidence and clinical grade of targeted gynecologic conditions.

Persons with advanced stages of HIV are considered to be at particular risk for developing disseminated MAC disease. The development of an effective regimen for the prevention of disseminated MAC disease may be of substantial benefit in altering the morbidity and possibly the mortality associated with this disease and its treatment.

Detailed description: Persons with advanced stages of HIV are considered to be at particular risk for developing disseminated MAC disease. The development of an effective regimen for the prevention of disseminated MAC disease may be of substantial benefit in altering the morbidity and possibly the mortality associated with this disease and its treatment.

Patients are randomized to receive clarithromycin alone, rifabutin alone, or the two drugs in combination daily. Patients are evaluated every 4 weeks for the first 8 weeks and every 8 weeks thereafter for the duration of the study. Patients are followed for 24 months. Per amendment, a pharmacokinetic substudy will be conducted.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Recommended:

* PCP prophylaxis.

Allowed:

* GM-CSF or G-CSF.
* Erythropoietin.
* Therapies (including antiretrovirals) available through expanded access or treatment IND programs.
* Other non-experimental therapies available by prescription.
* Antihistamines other than those specifically excluded.

Patients must have:

* Evidence or diagnosis of HIV infection or a history of an AIDS-defining condition by CDC criteria.
* CD4 count \<= 100 cells/mm3 within 90 days prior to study entry.
* Two baseline blood sample cultures negative for MAC within 30 days of study entry.
* No suspected disseminated MAC disease, in the opinion of the clinician.

NOTE:

* Patients with elevated GGT and/or triglycerides are allowed.

NOTE:

* Patients may co-enroll on ACTG 081/981/181, ACTG 175, ACTG 204, ACTG 193, ACTG 241, or other acceptable protocols.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Known or suspected tuberculous infection or other non-tuberculous mycobacterial infection requiring chemotherapy or chemoprophylaxis (with the exception of isoniazid prophylaxis alone).

NOTE:

* Patients may enroll who successfully completed tuberculosis (TB) treatment and have been off anti-TB drugs for more than 6 months with no symptoms of mycobacterial infection.
* Active TB.
* Known hypersensitivity to study drugs.
* Malabsorption as defined by persistent diarrhea with more than 8 stools per day for \> 6 weeks.

Concurrent Medication:

Excluded:

* Frequent (more than once per month), repeated, or continuous treatment courses of quinolones, erythromycin, spiramycin, azithromycin, clarithromycin, or clindamycin.
* Concomitant terfenadine or astemizole.

Prior Medication:

Excluded:

* Prophylaxis with azithromycin, clarithromycin, or rifabutin for more than 4 months.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Oakland
country: United States
facility: Children's Hosp. & Research Ctr. Oakland, Ped. Clinical Research Ctr. & Research Lab.
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Washington
country: United States
facility: Howard University Hosp., Div. of Infectious Diseases, ACTU
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Chicago Children's CRS
state: Illinois
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp. CORE Ctr.
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp. of Indiana
state: Indiana
city: Iowa City
country: United States
facility: Univ. of Iowa Healthcare, Div. of Infectious Diseases
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - East Campus A0102 CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Med. Ctr., Div. of Infectious Diseases
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Omaha
country: United States
facility: Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
state: Nebraska
city: Bronx
country: United States
facility: Bronx-Lebanon Hosp. IMPAACT CRS
state: New York
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Ctr.
state: New York
city: New York
country: United States
facility: Beth Israel Med. Ctr. (Mt. Sinai)
state: New York
city: New York
country: United States
facility: Cornell University A2201
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas HealthCare System, Carolinas Med. Ctr.
state: North Carolina
city: Greensboro
country: United States
facility: Regional Center for Infectious Disease, Wendover Medical Center CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Children's Hosp. of Philadelphia IMPAACT CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: Mbeya
country: Tanzania
facility: Mbeya Med. Research Program, Mbeya Referral Hosp. CRS
Study officials:
name: Benson CA
role: STUDY_CHAIR
name: Cohn DL
role: STUDY_CHAIR
References:
citation: Currier JS, Williams P, Feinberg J, Becker S, Owens S, Benson CA. ACTG 815: a prospective study of bacterial infections in advanced HIV disease. Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:131 (abstract no 364)
citation: Mascolini M. FDA advisory committee deadlocks on delavirdine. Food and Drug Administration. AIDS Treat News. 1996 Dec 6;(No 260):3-5.
citation: Watts DH, Spino C, Benson C, Yu B, Katzenstein D, Hammer S, Stratton P, Korvick J. A comparison of gynecologic findings in HIV-positive women with CD4 lymphocyte counts 200 to 500/cc and less than 100/cc. Int Conf AIDS. 1996 Jul 7-12;11(2):275 (abstract no ThB4137)
citation: Fichtenbaum CJ, Zackin R, Feinberg J, Benson C, Griffiths JK; AIDS Clinical Trials Group New Works Concept Sheet Team 064. Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection. AIDS. 2000 Dec 22;14(18):2889-93. doi: 10.1097/00002030-200012220-00010.
citation: Cohn DL. Prevention strategies for Mycobacterium avium-intracellulare complex (MAC) infection. A review of recent studies in patients with AIDS. Drugs. 1997;54 Suppl 2:8-15; discussion 28-9. doi: 10.2165/00003495-199700542-00004.
citation: Watts DH, Spino C, Zaborski L, Katzenstein D, Hammer S, Benson C. Comparison of gynecologic history and laboratory results in HIV-positive women with CD4+ lymphocyte counts between 200 and 500 cells/microl and below 100 cells/microl. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Apr 15;20(5):455-62. doi: 10.1097/00042560-199904150-00007.
citation: Fichtenbaum CJ, Powderly WG. Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis. 1998 Mar;26(3):556-65. doi: 10.1086/514571.
citation: Benson CA, Williams PL, Cohn DL, Becker S, Hojczyk P, Nevin T, Korvick JA, Heifets L, Child CC, Lederman MM, Reichman RC, Powderly WG, Notario GF, Wynne BA, Hafner R. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: A randomized, double-blind, placebo-controlled trial. The AIDS Clinical Trials Group 196/Terry Beirn Community Programs for Clinical Research on AIDS 009 Protocol Team. J Infect Dis. 2000 Apr;181(4):1289-97. doi: 10.1086/315380. Epub 2000 Apr 13.
citation: Currier JS, Williams P, Feinberg J, Becker S, Owens S, Fichtenbaum C, Benson C; Adult Clinical Trial Group. Impact of prophylaxis for Mycobacterium avium complex on bacterial infections in patients with advanced human immunodeficiency virus disease. Clin Infect Dis. 2001 Jun 1;32(11):1615-22. doi: 10.1086/320515. Epub 2001 Apr 30.