The Safety and Effectiveness of Rifabutin, Combined With Clarithromycin or Azithromycin, in HIV-Infected Patients

Evaluation of the Safety, Tolerance and Pharmacokinetics of Rifabutin/Clarithromycin Combination and Rifabutin/Azithromycin Combination in HIV-Infected Patients

PER 03/10/94 AMENDMENT: PART B. To determine whether there is an effect on plasma drug levels of azithromycin and rifabutin as measured by changes in the plasma concentration-time curve (AUC) when these drugs are taken concomitantly.

ORIGINAL PRIMARY: To gain preliminary information about the safety and tolerance of clarithromycin and azithromycin in combination with rifabutin (three potential agents against Mycobacterium avium-intracellulare) in HIV-infected patients with CD4 counts < 200 cells/mm3.

ORIGINAL SECONDARY: To determine whether there is an effect on the pharmacokinetics of the macrolide antibiotics or rifabutin when these drugs are taken concomitantly. To monitor the effect of rifabutin therapy on dapsone serum levels in patients taking dapsone for PCP prophylaxis. To monitor the effect of macrolide/rifabutin combination therapies on AZT or ddI serum levels.

Two new macrolide antibiotics, clarithromycin and azithromycin, and rifabutin (a rifamycin derivative) have all demonstrated in vitro and in vivo activity against Mycobacterium avium-intracellulare, a common systemic bacterial infection complicating AIDS. Further information is needed, however, regarding the clinical and pharmacokinetic interaction of these drugs used in combination.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Mycobacterium Avium-intracellulare Infection
• Intervention / Treatment: Drug: Rifabutin; Drug: Clarithromycin; Drug: Azithromycin

Detailed Description

Two new macrolide antibiotics, clarithromycin and azithromycin, and rifabutin (a rifamycin derivative) have all demonstrated in vitro and in vivo activity against Mycobacterium avium-intracellulare, a common systemic bacterial infection complicating AIDS. Further information is needed, however, regarding the clinical and pharmacokinetic interaction of these drugs used in combination.

AMENDED 03/10/94 (Part B): Approximately 38 HIV-infected or uninfected subjects are randomized to receive azithromycin or rifabutin (Groups 3 and 4) daily for 14 days, followed by a combination regimen of both drugs for 4 additional weeks. Patients are followed weekly. Pharmacokinetic sampling will be performed on days 14, 15, and 42-45.

ORIGINAL: Sixty-eight patients are randomly assigned to one of four groups (17 patients per group). They receive either clarithromycin or azithromycin in combination with rifabutin on one of two different dosing schedules. Patients receive medication for 6 weeks and undergo follow-up weekly during drug administration and at week 8.

• Study Type: Interventional
• Enrollment: 91
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Univ of Arizona / Health Science Ctr
  • California
    • Palo Alto, California, United States, 94304
      • Palo Alto Veterans Affairs Health Care System
    • San Francisco, California, United States, 94114
      • Davies Med Ctr
  • Colorado
    • Denver, Colorado, United States, 802044507
      • Denver Public Health Dept
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown Univ Med Ctr
  • Louisiana
    • New Orleans, Louisiana, United States, 701122699
      • Tulane Univ Med School
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Univ of Maryland at Baltimore / Veterans Adm
  • Missouri
    • St Louis, Missouri, United States, 63108
      • Washington Univ School Of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Univ of North Carolina School of Medicine
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
      • Univ of Rhode Island / Roger Williams Med Ctr
  • Virginia
    • Richmond, Virginia, United States, 232980533
      • Med College of Virginia / School of Pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

• Primary or secondary PCP prophylaxis with TMP/SMX, dapsone, or aerosolized pentamidine.
• Any approved therapy for antiretroviral treatment, or antiretroviral therapy available through FDA-sanctioned treatment IND or treatment protocol.

Patients must have:

AMENDED (PART B):

• Either HIV infection OR no HIV infection.
• CD4 count unspecified.

ORIGINAL:

• Documented HIV infection.
• CD4 count < 200 cells/mm3 within 90 days prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

• Known Mycobacterium avium-intracellulare (MAI) bacteremia or presence of a clinical syndrome compatible with MAI (i.e., fevers, weight loss, elevated LDH and alkaline phosphatase).
• Fever = or > 38.5 deg C (100.4 deg F) within 7 days prior to study entry.

Concurrent Medication:

Excluded:

• Acute or chronic use of phenobarbital, carbamazepine, rifampin, dilantin, fluconazole, itraconazole, ketoconazole, ciprofloxacin, beta-blockers, or clarithromycin.
• Oral contraceptives.
• Acute therapy for an AIDS-related opportunistic infection or malignancy, or other acute medical illness, or infection.
• Maintenance therapy for CMV, cryptococcal meningitis, or toxoplasmosis.
• Cytotoxic chemotherapy.

Patients with the following prior conditions are excluded:

• History of intolerance or hypersensitivity to study drugs, other macrolide antibiotics, or rifampin.
• Three or more loose bowel movements per day within 3 months prior to study entry.
• Unintentional weight loss >= 5 percent of body weight within 3 months prior to study entry.

Prior Medication:

Excluded:

• Rifabutin within 30 days prior to study entry.
• Clarithromycin or azithromycin within 14 days prior to study entry.
• Acute therapy for an AIDS-related opportunistic infection or malignancy, or other acute medical illness, or infection within 28 days prior to study entry.

Prior Treatment:

Excluded:

• Blood transfusions within 1 month prior to study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: R Hafner

Publications and helpful links

General Publications

• Hafner R, Bethel J, Standiford HC, Follansbee S, Cohn DL, Polk RE, Mole L, Raasch R, Kumar P, Mushatt D, Drusano G; DATRI 001B Study Group. Tolerance and pharmacokinetic interactions of rifabutin and azithromycin. Antimicrob Agents Chemother. 2001 May;45(5):1572-7. doi: 10.1128/AAC.45.5.1572-1577.2001.

Study record dates

Study Major Dates

• Study Completion (ACTUAL): July 1, 1998

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (ESTIMATE): August 31, 2001

Study Record Updates

• Last Update Posted (ESTIMATE): October 31, 2012
• Last Update Submitted That Met QC Criteria: October 29, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: Mycobacterium avium-intracellulare Infection; Drug Interactions; Azithromycin; Clarithromycin; Rifabutin
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections, Nontuberculous; Infections; Communicable Diseases; Mycobacterium Infections; Mycobacterium avium-intracellulare Infection; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Rifabutin; Clarithromycin; Azithromycin
• Other Study ID Numbers: DATRI 001; 11732 (REGISTRY: DAIDS ES Registry Number)