The primary purpose of this study is to assess the safety and tolerability of the 3 study drug regimens and to determine whether the safety and efficacy of combination therapy supports development of a phase III trial of combination therapy.

Condition	Intervention	Phase
Cryptococcal Meningitis	Drug: Amphotericin B  Drug: Fluconazole	Phase II

Further Study Details: 

Expected Total Enrollment:  150

This is a prospective, randomized, open-label, multicenter phase II clinical trial of combination therapy for the treatment of acute cryptococcal meningitis in HIV-positive subjects. Subjects will be randomly assigned to 1 of 3 arms including 1 standard therapy and 2 investigational arms. Standard treatment arm - amphotericin B 0.7mg/kg (IV) for 14 days followed by 8 weeks (56 days) of fluconazole at 400mg/day PO Low-dose fluconazole arm - amphotericin B 0.7mg/kg (IV) and fluconazole 400mg/day PO for 14 days followed by 8 weeks (56 days) of fluconazole at 400mg/day PO High-dose fluconazole arm - amphotericin B 0.7mg/kg (IV) and fluconazole 800mg/day PO for 14 days followed by 8 weeks (56 days) of fluconazole at 800mg/day PO. Among subjects whose baseline weight is <40kg, randomized fluconazole doses will be 200 mg/day and 400 mg/day for the low-dose and high-dose arms, respectively. Study drug treatment will be administered for 10 weeks (70 days). Fluconazole will only be administered orally. For subjects with difficulty swallowing, fluconazole may be administered as crushed tablets via nasogastric tube.

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

Criteria

Inclusion Criteria:

1. First episode of cryptococcal meningitis as evidenced by a positive CSF stain or cryptococcal antigen, CSF culture pending

2. a) Documentation of proven diagnosis of HIV-1 infection by acceptable labs at any time in the past: this testing includes ELISA or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection.

   OR b) Presumptive diagnosis of HIV-1 by approved rapid testing method at screening. This testing must be confirmed by a second ELISA (or WB), a positive HIV antigen, or HIV RNA detection within 10 days of study entry.

   OR c) If serologic testing is not available, a history of an AIDS-defining illness (Category C, CDC, 1993, See Appendix D) or any of the following conditions: extrapulmonary Pneumocystis carnii disease; multi-dermatomal herpes zoster (>10 lesions in a non-contiguous site); American trypanosomiasis (Chagas disease) of the CNS; Penicillium marneffei disease; visceral leishmaniasis; non-Hodgkin''''s lymphoma of any cell-type; Hodgkin''''s lymphoma; bartonellosis; microsporidiosis (>1 month''''s duration); nocardiosis; invasive aspergillosis; or Rhodococcus equi disease. Confirmation of HIV infection by lab testing, i.e., ELISA or approved rapid testing method with confirmation by Western blot, a second positive ELISA, a positive HIV antigen, or HIV RNA detection must be performed within 10 days of study entry.

3. Subjects who are >13 years of age.
4. Baseline ECG with QT interval less than 500 milliseconds.
5. Ability of subject or legally authorized representative to give informed consent. For subjects who are unable to provide informed consent, sites will follow their own individual Institutional Review Board (IRB) policy regarding the informed consent process.

Exclusion Criteria:

1. Pregnancy. Urine or serum testing must be performed within the 7 days prior to study entry.
2. Women of childbearing potential unwilling to use a medically approved and highly effective form of birth control while on study drug and for 2 weeks after last dose. Acceptable forms of birth control include an intrauterine device (IUD), oral contraceptives, condoms, abstinence, injectable contraceptive, or any other highly effective means of birth control. (A highly effective method of birth control is defined as those which result in a low failure rate [i.e. less than 1% per year*] when used consistently and correctly.) Emergency contraceptive treatment and coitus interruptus are not considered effective forms of contraception.
3. Breastfeeding.
4. A concurrent CNS process that in the opinion of the investigator would interfere with assessment of response, such as lymphoma, toxoplasmosis, or tuberculosis.
5. Other conditions that in the opinion of the investigator would jeopardize the safety of a subject participating in the study or would render the subject unable to comply with the study plan, such as homelessness or IV drug use.
6. Estimated creatinine clearance of <50 mL/min. NOTE: Testing must be performed within the 7 days prior to study entry.
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5x the upper limit of normal or bilirubin >2.5 x the upper limit of normal. Testing must be performed within the 7 days prior to study entry.
8. Known intolerance of or allergy to fluconazole or amphotericin B.
9. Subjects unlikely to survive for 2 weeks.
10. Coma.
11. More than 3 days of any systemic antifungal therapy for this fungal infection, or the need for concurrent systemic antifungal therapy, including flucytosine or interferon-g.
12. Inability to take oral medications.
13. Subjects who have received the following drugs within 7 days of study enrollment: rifampin, rifamycin, rifabutin, phenytoin, carbamazepine, cyclosporin A, tacrolimus, sirolimus, or long-acting barbituates.
14. Subjects who are receiving nevirapine at baseline.
15. Strong clinical suspicion of untreated active tuberculosis. (Patients on anti-TB therapy not including rifampin or rifamycin may be eligible.)
16. Previous participation in this study or ongoing participation in another trial with an investigational drug.

Please refer to this study by ClinicalTrials.gov identifier  NCT00145249

Maureen Mehigan      (301) 402-9420 

Alabama
      University of Alabama at Birmingham, Birmingham,  Alabama,  35233,  United States; Recruiting
California
      University of Southern California, Los Angeles,  California,  90033,  United States; Recruiting
      Harbor - UCLA Medical Center REI, Torrance,  California,  90509,  United States; Recruiting
Colorado
      University of Colorado Health Science Center, Denver,  Colorado,  80262,  United States; Recruiting
Florida
      University Of Florida, Gainesville,  Florida,  32610,  United States; Recruiting
      University of Miami School of Medicine/ Jackson Memorial Hospital, Miami,  Florida,  33136-1096,  United States; Recruiting
Louisiana
      Tulane University Health Center, New Orleans,  Louisiana,  70112,  United States; Recruiting
Michigan
      Wayne State University, Detroit,  Michigan,  48201,  United States; Recruiting
Texas
      University of Texas Houston Medical School, Houston,  Texas,  77030,  United States; Recruiting
      VA Medical Center, Houston,  Texas,  77030,  United States; Recruiting
Thailand
      Ramathibodi Hospital, Mahidol University, Bangkok,  10400,  Thailand; Recruiting
      Chiang Mai University,, Chaing Mai,  50200,  Thailand; Recruiting
      Siriraj Hospital, Mahidol University, Bangkok,  10700,  Thailand; Recruiting
      Bamrasnaradura Institution, Nonthaburi,  11000,  Thailand; Recruiting
      Khon Kaen University, Khon Kaen,  40002,  Thailand; Recruiting

Study ID Numbers:  03-154; BAMSG 3-01
Last Updated:  September 2, 2005
Record first received:  September 2, 2005
ClinicalTrials.gov Identifier:  NCT00145249
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-09-06