High-Dose Fluconazole for the Treatment of Cryptococcal Meningitis in HIV-Infected Individuals

Inclusion Criteria - Step 1

• CM documented either by a positive CSF cryptococcal culture, a positive CSF India ink preparation, or a positive CSF cryptococcal antigen latex agglutination test within 7 days prior to entry. More information on this criterion can be found in the protocol.
• CSF collection for quantitative cryptococcal culture within 72 hours prior to study entry or planned to be performed at study entry
• HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by or within 10 days after study entry by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, by HIV-1 antigen, or by plasma HIV-1 RNA viral load. More information on this criterion can be found in the protocol.
• Ability to take oral medications
• For patients with a co-morbid complication of HIV, including opportunistic infections, receipt of stable treatment for the co-morbid complication and clinically stable, as judged by the site investigator
• For female participants of reproductive potential a negative serum or urine pregnancy test result must be obtained within 2 days prior to study entry
• All participants must agree not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).
• If participating in sexual activity that could lead to pregnancy, female study participants must agree to the simultaneous use of two forms of contraception (listed in protocol) during sexual activity, and male study participants must agree to use a condom during such sexual activity. This requirement continues while the study participant is on study treatment and for 6 weeks after fluconazole has been discontinued. More information on this criterion can be found in the protocol.
• Study participants who are not of reproductive potential (defined as women who have been post-menopausal for at least 24 consecutive months, women who have undergone surgical sterilization [e.g., hysterectomy or bilateral oophorectomy or salpingectomy], or men who have documented azoospermia) are eligible without the requirement to use contraceptives. More information on this criterion can be found in the protocol.
• Willingness and ability to adhere to dose schedules and mandatory procedures
• Measured or calculated creatinine clearance of 50 mL/min or more within 3 days prior to study entry
• Required laboratory values within 3 days prior to study entry. More information on this criterion can be found in the study protocol
• Ability and willingness of the participant or legal guardian/representative to give informed consent
• Availability at the site for at least 2 weeks of its standard-of-care ampho B-based regimen

Exclusion Criteria - Step 1

• Expected survival of 2 weeks or less, in the opinion of the site investigator and, if available, the primary care provider
• For patients with a comorbid complication of HIV, anticipated difficulty, in the opinion of the site investigator, in judging response to study treatment as a result of the comorbid complication or the drugs used to treat it
• Breastfeeding
• A prior episode of CM, either as indicated by patient or as noted in patient medical records
• Use of certain drugs within specified time periods. More information on this criterion can be found in the study protocol.
• Suspected or active tuberculosis (TB), even if untreated, for participants screening at the time that a 1200-mg daily fluconazole induction cohort is enrolling
• Known allergy, sensitivity to, or intolerance of fluconazole or other imidazole or triazole compounds or to ampho B or other components of the standard of care ampho B based regimen
• History of clinically significant cardiac disease, in the opinion of the site investigator, including symptoms of ischemia, coronary artery disease, congestive heart failure, or arrhythmia
• ECG with QTc interval greater than 450 msec within 7 days prior to study entry.
• History of CNS disorder (excluding mood disorders) or concurrent CNS disorder(s) that, in the opinion of the investigator, would interfere with assessment of efficacy (e.g., ability to perform CSF sampling) such as lymphoma, neurocysticercosis, or toxoplasmosis
• Receipt of investigational drug therapy within 30 days prior to study entry without prior approval
• Receipt of specified treatments for the current episode of CM. More information on this criterion can be found in the study protocol.
• Active drug or alcohol use, dependence, or other conditions that in the opinion of the site investigator would jeopardize the safety of a participant in the study or would render the person unable to comply with the study plan
• Breast-feeding

Inclusion Criterion - Step 2

• Randomization to an ampho B-based regimen in Step 1
• Receipt of at least one dose of ampho B-based regimen in Step 1
• Premature discontinuation of ampho B in response to the occurrence of any treatment-limiting toxicity, as described in Section 5 of the A5225/HiFLAC MOPS

Exclusion Criterion - Step 2

• Receipt of fluconazole monotherapy in Step 1
• Receipt of 8.4 mg/kg or more of ampho B
• At or beyond Day 17 in Step 1.

Inclusion Criteria - Step 3

• For participants in Step 1 who are currently receiving study-provided fluconazole and have no plans to discontinue study treatment, a negative CSF culture after 2 weeks incubation from a sample obtained at or before Week 6 (Day 35-49)
• For participants in Step 1 who are currently receiving an ampho B-based regimen or alternative treatment, completion of approximately 2 weeks of treatment
• For participants in Step 2 who are currently receiving study-provided fluconazole and have no plans to discontinue study treatment, negative CSF culture after 2 weeks incubation from a sample obtained at or before Week 6 (Day 35-49).

Exclusion Criteria - Step 3

• On study treatment beyond Week 10 (Day 77) in Step 1 or Step 2
• Currently off study treatment

Inclusion Criteria - Step 4

• On study treatment at Week 10 (Day 63-77) with no plans to discontinue study treatment

Exclusion Criteria - Step 4

• Currently off study treatment