Amphotericin Alone or in Combination With Fluconazole for AIDS-Associated Meningitis
Condition: Cryptococcal Meningitis
MeSH terms: Meningitis, Cryptococcal; Meningitis
Intervention: Amphotericin B; Fluconazole
Intervention description: Amphotericin B 0.7 mg/kg IV for the first 14 days of treatment. This period may be extended up to an additional 7 days.; Fluconazole 400 or 800 mg daily. Among subjects whose baseline weight is less than 40 kg, randomized fluconazole doses will be 200 mg/kg daily or 400 mg/kg daily.
Intervention MeSH terms: Fluconazole; Amphotericin B; Liposomal amphotericin B
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 143.0
Sex: All
Minimum age: 13 Years
Healthy volunteers: No
Keywords: Bacterial infections, HIV infection, cryptococcal meningitis

Summary:

      This study will examine the effectiveness and safety of a combination treatment for
      cryptococcal meningitis, a fungal infection common in persons with acquired immune deficiency
      syndrome (AIDS) in the developing world. The standard initial treatment includes two
      medications: amphotericin B for 2 weeks followed by 8 weeks of fluconazole. This study will
      look at whether study participants recover more quickly and have fewer side effects if they
      are given both drugs at the same time for 2 weeks followed by 8 weeks of fluconazole as
      compared to the standard treatment. Participants will be followed for approximately 6 months
      from the time they are enrolled into the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  First episode of cryptococcal meningitis as evidenced by a positive cerebrospinal
             fluid (CSF) stain or cryptococcal antigen, CSF culture pending

          -  Documentation of proven diagnosis of HIV-1 infection by acceptable labs at any time in
             the past: this testing includes Enzyme-linked immunosorbent assay (ELISA) or approved
             rapid testing method with confirmation by Western blot, a second positive ELISA, a
             positive HIV antigen, or HIV RNA detection.

        OR

        -Presumptive diagnosis of HIV-1 by approved rapid testing method at screening. This testing
        must be confirmed by a second ELISA (or Western blot), a positive HIV antigen, or HIV RNA
        detection within 10 days of study entry.

        OR

          -  Presumptive HIV+. If serologic testing is not available, a history of an AIDS-defining
             illness (Category C, CDC, 1993) or any of the following conditions: extrapulmonary
             Pneumocystis carinii 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.

          -  Subjects who are 13 years of age or greater.

          -  Baseline electrocardiogram (ECG) with QTc interval less than or equal to 500
             milliseconds as determined by use of Fredericia's Correction formula.

          -  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:

          -  Pregnancy. Urine or serum testing must be performed at study entry or within the 7
             days prior to study entry.

          -  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 percent per
             year] when used consistently and correctly.) Emergency contraceptive treatment and
             coitus interruptus are not considered effective forms of contraception.

          -  Breastfeeding.

          -  A concurrent central nervous system (CNS) process that in the opinion of the
             investigator would interfere with assessment of response, such as lymphoma,
             toxoplasmosis, or tuberculosis.

          -  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.

          -  Estimated creatinine clearance of less than 50 mL/min. NOTE: Testing must be performed
             at study entry or within the 7 days prior to study entry.

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5x the
             upper limit of normal or bilirubin greater than 2.5 x the upper limit of normal.
             Results from tests performed within the 7 days prior to study entry may be used.

          -  Known intolerance of or allergy to fluconazole or amphotericin B.

          -  Subjects unlikely to survive for 2 weeks.

          -  Coma.

          -  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. Subjects taking fluconazole at less than or equal to 200 mg/day for
             prophylaxis are not excluded.

          -  Inability to take oral medications.

          -  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 barbiturates.

          -  Subjects who are receiving nevirapine at baseline.

          -  Strong clinical suspicion of untreated active tuberculosis. (Patients on anti-TB
             therapy not including rifampin or rifamycin may be eligible.)

          -  Previous participation in this study or ongoing participation in another trial with an
             investigational drug.

          -  Prior case of cryptococcosis with diagnosed central nervous system involvement.