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A Study of Itraconazole in the Treatment and Prevention of Histoplasmosis, a Fungal Infection, in Patients With AIDS

This study has been completed.
Sponsor:
Collaborator:
Janssen Pharmaceuticals
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000975
First received: November 2, 1999
Last updated: March 28, 2012
Last verified: March 2012
  Purpose

To evaluate the feasibility of itraconazole as (1) primary therapy in histoplasmosis and (2) maintenance therapy after completion of primary therapy. To evaluate the effect of therapy of CNS histoplasmosis. To determine if resistance to drug occurs in patients who fail therapy.

Histoplasmosis is a serious opportunistic infection in patients with AIDS. Although the clinical response to amphotericin B treatment in the AIDS patients is generally good, administration difficulties and toxicity detract from its usefulness. Oral treatment with ketoconazole overcomes these limitations of amphotericin B, but does not appear to be effective for primary treatment in patients with AIDS. Itraconazole is a triazole compound in which preclinical studies have demonstrated activity against Histoplasmosis capsulatum. Preclinical studies have also shown that itraconazole appears effective in the treatment of histoplasmosis. The frequency of adverse reactions to itraconazole has been low in several studies. Central nervous system (CNS) involvement occurs in up to 20 percent of patients with histoplasmosis, and appears to have a poor response to amphotericin B treatment. Itraconazole has been used successfully in a small number of patients with cryptococcal meningitis, supporting a study of its use in CNS histoplasmosis.


Condition Intervention Phase
HIV Infections
Histoplasmosis
Drug: Itraconazole
Phase 2

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Pilot Study To Determine the Feasibility of Itraconazole for Primary Treatment and Suppression of Relapse of Disseminated Histoplasmosis in Patients With the Acquired Immunodeficiency Syndrome

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 30
Study Completion Date: September 1994
Detailed Description:

Histoplasmosis is a serious opportunistic infection in patients with AIDS. Although the clinical response to amphotericin B treatment in the AIDS patients is generally good, administration difficulties and toxicity detract from its usefulness. Oral treatment with ketoconazole overcomes these limitations of amphotericin B, but does not appear to be effective for primary treatment in patients with AIDS. Itraconazole is a triazole compound in which preclinical studies have demonstrated activity against Histoplasmosis capsulatum. Preclinical studies have also shown that itraconazole appears effective in the treatment of histoplasmosis. The frequency of adverse reactions to itraconazole has been low in several studies. Central nervous system (CNS) involvement occurs in up to 20 percent of patients with histoplasmosis, and appears to have a poor response to amphotericin B treatment. Itraconazole has been used successfully in a small number of patients with cryptococcal meningitis, supporting a study of its use in CNS histoplasmosis.

At least 30 patients with AIDS and an initial episode of disseminated histoplasmosis are selected for this study. Up to 5 patients will have a diagnosis of CNS histoplasmosis. Therapy with all other systemic antifungal agents must be halted before study entry. Patients receive itraconazole for 3 days followed by daily oral doses for a total of 12 weeks. Patients who are doing well clinically, without evidence of clinical failure or dose-limiting toxicity, are permitted to continue maintenance therapy to prevent relapse at a reduced dose for an additional 12 months. Patients who are being treated for CNS histoplasmosis will continue to receive itraconazole.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

  • Vincristine, vinblastine, bleomycin, or interferon for Kaposi's sarcoma.
  • Erythropoietin.
  • Didanosine by exemption for 10 patients.
  • Barbiturates.
  • Coumarin-type anticoagulants.
  • Oral contraceptives.
  • Digoxin.
  • Methadone.
  • Narcotics.
  • Acyclovir.
  • Acetaminophen.
  • Sulfonamides.
  • Trimethoprim / sulfamethoxazole.
  • Pentamidine for Pneumocystis carinii pneumonia (PCP) or PCP prophylaxis.
  • Topical antifungals.
  • Pyrimethamine.
  • Ganciclovir.
  • AZT.
  • Stress doses of steroids in patients with adrenal insufficiency.

Concurrent Treatment:

Allowed:

  • Dose reduction or interruption of myelosuppressive therapy and transfusion to maintain hemoglobin of 7 or more g/dl.
  • Radiation therapy.

Patient must:

  • Show laboratory evidence of HIV infection and disseminated histoplasmosis.
  • Be oriented to person, place, and time.
  • Be able to give written informed consent (appropriate consent must be obtained from a parent or legal guardian for patients under 18 years of age).

Allowed:

  • Abnormal liver function tests in Grade 3 toxicity range if liver biopsy shows evidence that histoplasmosis caused these abnormalities.
  • Mucocutaneous candidiasis.

Prior Medication:

Allowed:

  • Amphotericin B or ketoconazole for pulmonary histoplasmosis at least 3 months prior to study entry.
  • Azidothymidine (AZT).
  • Vincristine, vinblastine, bleomycin, or interferon for mucocutaneous Kaposi's sarcoma.
  • Prophylaxis for Pneumocystis carinii pneumonia (PCP).

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

  • Severely ill, or at risk of dying from histoplasmosis within the first week of treatment, as indicated by systolic blood pressure less than 90 mm Hg , or PO2 less than 60.
  • Active CNS lesions, malignancies, or infections other than MAI.
  • Severe malabsorption syndrome (persistent diarrhea more than 4 weeks duration with at least 4 loose stools per day accompanied by a 10 percent or greater weight loss).
  • Requiring cytotoxic therapy for malignancies.
  • Any systemic fungal infection other than histoplasmosis.
  • Systemic Mycobacterium avium intracellulare.
  • Receiving treatment for other acute opportunistic infections whose signs and symptoms have not yet resolved or stabilized.
  • History of allergy to or intolerance of imidazoles or azoles.

Concurrent Medication:

Excluded:

  • All other systemic antifungal agents.
  • Investigational drugs not specifically allowed.
  • Oral hypoglycemics.
  • Rifamycins.
  • Phenytoin.
  • Carbamazepine.
  • Steroids in excess of physiologic replacement doses not specifically allowed.
  • Cytotoxic chemotherapy.
  • Discouraged:
  • Antacids.
  • Sucralfate.
  • H2 blockers.

Patients with the following are excluded:

  • Severely ill, or at risk of dying from histoplasmosis within the first week of treatment.
  • Active CNS infections, malignancies or lesions not documented to be caused by histoplasmosis, which would interfere with assessment of response.
  • Unable to take oral medications reliably.
  • Severe malabsorption syndrome.
  • Requiring cytotoxic therapy for malignancies.
  • Any systemic fungal infection other than histoplasmosis.
  • Systemic Mycobacterium avium intracellulare.
  • Receiving treatment for other acute opportunistic infections whose signs and symptoms have not yet resolved or stabilized.

Prior Medication:

Excluded for greater than 1 week within the last 3 months:

  • Fluconazole.
  • Itraconazole.
  • SCH 39304.
  • Amphotericin B greater than 1.5 mg/kg, or any other antifungal for this episode of disseminated histoplasmosis.

Patients who the investigator feels would be undependable with regard to adherence to the protocol.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000975

Locations
United States, California
USC CRS
Los Angeles, California, United States, 90033
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana Univ. School of Medicine, Infectious Disease Research Clinic
Indianapolis, Indiana, United States, 46202
United States, Louisiana
Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
New Orleans, Louisiana, United States, 70112
United States, Minnesota
University of Minnesota, ACTU
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington U CRS
St. Louis, Missouri, United States
United States, New York
Cornell University A2201
New York, New York, United States, 10021
Univ. of Rochester ACTG CRS
Rochester, New York, United States, 14642
United States, North Carolina
Duke Univ. Med. Ctr. Adult CRS
Durham, North Carolina, United States, 27710
United States, Ohio
Univ. of Cincinnati CRS
Cincinnati, Ohio, United States, 45267
The Ohio State Univ. AIDS CRS
Columbus, Ohio, United States
United States, Pennsylvania
Pitt CRS
Pittsburgh, Pennsylvania, United States
Sponsors and Collaborators
Janssen Pharmaceuticals
Investigators
Study Chair: LJ Wheat
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000975     History of Changes
Other Study ID Numbers: ACTG 120, 11095
Study First Received: November 2, 1999
Last Updated: March 28, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
AIDS-Related Opportunistic Infections
Histoplasmosis
Drug Evaluation
Antifungal Agents
Acquired Immunodeficiency Syndrome

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
Communicable Diseases
HIV Infections
Histoplasmosis
Immunologic Deficiency Syndromes
Infection
Immune System Diseases
Lentivirus Infections
Mycoses
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Hydroxyitraconazole
Itraconazole
14-alpha Demethylase Inhibitors
Anti-Infective Agents
Antifungal Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014