To assess the safety and effectiveness of SCH 39304 as primary treatment of acute cryptococcal meningitis in HIV-infected patients. Safety and effectiveness of maintenance therapy following successful treatment of acute disease are also evaluated. Cryptococcal meningitis is a significant cause of illness and death in HIV-infected patients. Intravenous amphotericin B is effective for acute disease but relapse occurs in the majority of patients. Maintenance therapy is recommended but must be balanced against the multiple toxicities of the drugs used and the problems associated with the weekly administration of intravenous therapy. Treatments that are equally or more effective and less toxic than traditional methods are needed, especially oral therapy. SCH 39304 is an orally active antifungal drug that in animal studies is active against a wide range of systemic fungal infections including infections due to Cryptococcus. Features of SCH 39304 suggest that it might be of value in the treatment of cryptococcal meningitis.

Condition	Treatment or Intervention	Phase
Meningitis, Cryptococcal HIV Infections	Drug: SCH 39304	Phase I

Further Study Details: 

Expected Total Enrollment:  50

Cryptococcal meningitis is a significant cause of illness and death in HIV-infected patients. Intravenous amphotericin B is effective for acute disease but relapse occurs in the majority of patients. Maintenance therapy is recommended but must be balanced against the multiple toxicities of the drugs used and the problems associated with the weekly administration of intravenous therapy. Treatments that are equally or more effective and less toxic than traditional methods are needed, especially oral therapy. SCH 39304 is an orally active antifungal drug that in animal studies is active against a wide range of systemic fungal infections including infections due to Cryptococcus. Features of SCH 39304 suggest that it might be of value in the treatment of cryptococcal meningitis.

HIV-infected patients with a diagnosis of acute cryptococcal meningitis, previously untreated or relapsed following a successfully treated acute episode, are enrolled in the study. SCH 39304 is administered orally once daily for 3 days followed by a lower dose once daily for 12 weeks. Patients who respond to primary therapy are randomized to receive SCH 39304 maintenance therapy at a higher dose once weekly or at the lower dose once daily for up to 12 months under this protocol.

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

Criteria

Inclusion Criteria

Concurrent Medication: Allowed:

• Currently approved antiviral therapy.
• Maintenance therapy for cytomegalovirus retinitis or toxoplasmosis.
• Rifampin.
• Isoniazid.
• Dilantin or barbiturates if investigator agrees to rigorously monitor anticonvulsant drug levels.
• Coumarin-type anticoagulants if investigator agrees to rigorously monitor prothrombin time.
• Prophylactic treatment for Pneumocystis carinii pneumonia (PCP).

Concurrent Treatment: Allowed:

• Local radiotherapy for mucocutaneous Kaposi's sarcoma.

Prior Medication: Allowed:

• Amphotericin B, up to 1 mg/kg, during the previous 7 days.

Patients must be HIV positive by 2 methodologies and have either primary cryptococcal meningitis with no prior anti-cryptococcal therapy or relapsed disease after prior therapy.

• Prior therapy for cryptococcal meningitis is limited to approved drugs.
• Written informed consent either from patient or patient's parent or legal guardian is required.

Exclusion Criteria

Co-existing Condition: Patients with the following conditions or symptoms are excluded:

• History of hypersensitivity to imidazole or azole compounds.
• Central nervous system disease.
• Acute opportunistic infection.
• Underlying conditions that in the opinion of the investigator could preclude assessment of response.

Concurrent Medication: Excluded:

• Systemic antifungal drugs other than study drug.
• Any investigational drug other than treatment IND drugs.
• Oral hypoglycemic agents.
• Oral contraceptives.
• Cytotoxic chemotherapy.

Patients with the following are excluded:

• Unable to take oral medications.
• Concurrent central nervous system disease which in opinion of investigator would interfere with assessment of response.
• Concurrent acute opportunistic infection requiring therapy (patients who develop an acute opportunistic infection after initiation of study medication may remain on study medication).

Prior Medication: Excluded within 7 days of study entry:

• Amphotericin B, > 1 mg/kg.

Alabama
      Birmingham Veterans Administration Med Ctr, Birmingham,  Alabama,  35233,  United States
California
      Univ of California / San Diego Treatment Ctr, San Diego,  California,  921036325,  United States
      San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States
      Dr Robert Larsen, Los Angeles,  California,  90033,  United States
District of Columbia
      George Washington Univ Med Ctr, Washington,  District of Columbia,  20037,  United States
Georgia
      Med College of Georgia, Augusta,  Georgia,  30912,  United States
      Emory Univ School of Medicine, Atlanta,  Georgia,  30303,  United States
Illinois
      Rush Presbyterian - Saint Luke's Med Ctr, Chicago,  Illinois,  60612,  United States
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States
Louisiana
      Tulane Univ School of Medicine, New Orleans,  Louisiana,  70112,  United States
Massachusetts
      Univ Hosp, Boston,  Massachusetts,  02118,  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
      Mount Sinai Med Ctr, New York,  New York,  10029,  United States
      Bronx Veterans Administration / Mount Sinai Hosp, Bronx,  New York,  10468,  United States
      Beth Israel Med Ctr, New York,  New York,  10003,  United States
      Erie County Med Ctr, Buffalo,  New York,  14215,  United States
North Carolina
      Univ of North Carolina, Chapel Hill,  North Carolina,  275997215,  United States
      Duke Univ Med Ctr, Durham,  North Carolina,  27710,  United States
Ohio
      Holmes Hosp / Univ of Cincinnati Med Ctr, Cincinnati,  Ohio,  452670405,  United States
      Ohio State Univ Med Ctr, Columbus,  Ohio,  43210,  United States
      Univ Hosp of Cleveland / Case Western Reserve Univ, Cleveland,  Ohio,  44106,  United States
Pennsylvania
      Buckley Braffman Stern Med Associates, Philadelphia,  Pennsylvania,  19107,  United States
South Carolina
      Julio Arroyo, West Columbia,  South Carolina,  29169,  United States
Texas
      Audie L Murphy Veterans Administration Hosp, San Antonio,  Texas,  78284,  United States
      Houston Veterans Administration Med Ctr, Houston,  Texas,  77030,  United States
      Univ TX Health Science Ctr, Houston,  Texas,  77030,  United States
Virginia
      Richmond AIDS Consortium, Richmond,  Virginia,  23219,  United States

Study chairs or principal investigators

WG Powderly,  Study Chair

Study ID Numbers:  ACTG 125; C89-258
Record last reviewed:  December 1994
Last Updated:  October 13, 2004
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000677
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08