Clinical trial NCT00000677: SCH 39304 as Therapy for Acute Cryptococcal Meningitis in HIV-Infected Patients Followed by Maintenance Therapy
Official title: SCH 39304 as Therapy for Acute Cryptococcal Meningitis in HIV-Infected Patients Followed by Maintenance Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Meningitis, Cryptococcal
HIV Infections
Keywords: Sch 39304
AIDS-Related Opportunistic Infections
Meningitis
Cryptococcosis
Drug Evaluation
Antifungal Agents
Acquired Immunodeficiency Syndrome
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Schering-Plough
First posted: 2001-08-31
Enrollment: 50
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham Veterans Administration Med Ctr
state: Alabama
city: Los Angeles
country: United States
facility: Dr Robert Larsen
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: San Francisco AIDS Clinic / San Francisco Gen Hosp
state: California
city: Washington
country: United States
facility: George Washington Univ Med Ctr
state: District of Columbia
city: Atlanta
country: United States
facility: Emory Univ School of Medicine
state: Georgia
city: Augusta
country: United States
facility: Med College of Georgia
state: Georgia
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: New Orleans
country: United States
facility: Tulane Univ School of Medicine
state: Louisiana
city: Boston
country: United States
facility: Univ Hosp
state: Massachusetts
city: St Louis
country: United States
facility: St Louis Regional Hosp / St Louis Regional Med Ctr
state: Missouri
city: Bronx
country: United States
facility: Bronx Veterans Administration / Mount Sinai Hosp
state: New York
city: Buffalo
country: United States
facility: Erie County Med Ctr
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Cincinnati
country: United States
facility: Holmes Hosp / Univ of Cincinnati Med Ctr
state: Ohio
city: Cleveland
country: United States
facility: Univ Hosp of Cleveland / Case Western Reserve Univ
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Med Ctr
state: Ohio
city: Philadelphia
country: United States
facility: Buckley Braffman Stern Med Associates
state: Pennsylvania
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Houston
country: United States
facility: Houston Veterans Administration Med Ctr
state: Texas
city: Houston
country: United States
facility: Univ TX Health Science Ctr
state: Texas
city: San Antonio
country: United States
facility: Audie L Murphy Veterans Administration Hosp
state: Texas
city: Richmond
country: United States
facility: Richmond AIDS Consortium
state: Virginia
Study officials:
name: WG Powderly
role: STUDY_CHAIR
References:
citation: Lee BL, Padula AM, Tauber MG, Chambers HF, Sande MA. Oral SCH 39304 as primary, salvage, and maintenance therapy for cryptococcal meningitis in AIDS. J Acquir Immune Defic Syndr (1988). 1992;5(6):600-4.