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

• Discontinuation of study-provided fluconazole or ampho B, including precipitating and surrounding adverse events [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: Yes ]
• Qualitative and quantitative CSF culture results at entry, Week 2, and when conducted thereafter [ Time Frame: At entry, Week 2, and through Week 24 ] [ Designated as safety issue: No ]
• Survival [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: Yes ]

• Discontinuation of fluconazole or ampho B, including precipitating and surrounding adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Qualitative and quantitative CSF culture results at entry, week 2, and when conducted thereafter [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Survival [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

• Results of the neurological examination [ Time Frame: Measured at study entry, Week 2, Week 10, and through Week 24 ] [ Designated as safety issue: No ]
• Length of hospitalization [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
• Recurrence/relapse of CM based on clinical presentation [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
• CNS immune reconstitution inflammatory syndrome (IRIS) [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]
• Additional safety parameters including: Grade 3 and 4 adverse events; dose modifications; duration of temporary treatment interruptions; permanent discontinuation of either agent [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: Yes ]
• Results of functional status evaluation [ Time Frame: Measured at baseline, at study entry, at Week 10, and through Week 24 ] [ Designated as safety issue: No ]
• Number and nature of hospital readmissions [ Time Frame: Measured through Week 24 ] [ Designated as safety issue: No ]

• Results of the neurological examination and functional status evaluation [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Length of hospitalization and number and nature of hospital readmissions [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Recurrence/relapse of CM based on clinical presentation [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• CNS immune reconstitution inflammatory syndrome (IRIS) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Pharmacology [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Additional safety parameters including: Grade 3 and 4 adverse events; dose modifications; duration of temporary treatment interruptions; permanent discontinuation of either agent [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Antifungal drug susceptibility of cryptococcal isolates [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Cryptococcal meningitis (CM) is an infection of the membranes covering the brain and spinal cord, caused by the fungus Cryptococcus neoformans. CM most often affects people with compromised immune systems, like those with advanced HIV infection. This study will explore the safety, tolerability, and therapeutic effect of a new treatment regimen with high-dose fluconazole for management of CM in HIV-infected patients.

CM is the most common central nervous system (CNS) complication of AIDS worldwide and accounts for up to a third of all deaths from AIDS in many developing countries. Current treatments for CM are lacking in both effectiveness and accessibility, particularly in limited-resources settings. Conventional therapies utilizing an amphotericin B deoxycholate (ampho B)-based regimen require maintaining intravenous access (IV) and monitoring and treating any associated complications. The price to acquire ampho B can also be prohibitive to successful treatment. Cumulatively, a treatment course with ampho B is neither cost effective nor administratively efficient, leaving patients either untreated or inadequately treated with low-dose regimens of fluconazole alone.

Fluconazole is widely available, inexpensive, can be given orally, has a demonstrated safety profile over a broad range of doses, and has proven activity against the fungus that causes CM, Cryptococcus neoformans. All of these factors make fluconazole a potential treatment option for a wide range of people. However, at its present recommended dosage, fluconazole is only expected to be successful in 34% to 42% of patients. This rate is lower than regimens combining fluconazole with other treatments including flucytosine or ampho B.

The purpose of this study is to evaluate whether high-dose fluconazole is safe and effective for the treatment of CM for up to 10 weeks. This study will also collect information about treating CM with ampho B (either alone or with another drug, either flucytosine or fluconazole).

For this study, up to 192 HIV-infected people with CM will participate for a duration of 24 weeks. This study will proceed in 2 stages. Each stage may consist of up to 4 steps. Stage 1 will measure the maximum tolerated dose (MTD) of fluconazole in participants. Stage 2 will be for the purpose of dose validation.

Participants will take part in only one stage of the study. If enrolled in Stage 1, participants will be randomly assigned to receive either fluconazole only or an ampho B-based regimen (a regimen that is either ampho B alone or ampho B in combination with 5-fluorocytosine or fluconazole, according to the local standard of care).There will be three possible fluconazole doses available for the start of the fluconazole-only treatment. The dosage will depend on when a participant enters the study. If enrolled in Stage 2, participants will be randomly assigned to Step 1 to receive treatment with either fluconazole only (at doses found to be safe in Stage 1) or an ampho B-based regimen.

After randomization in Step 1, participants in either Stage 1 or Stage 2 may enroll in up to three additional steps. In Step 2, participants who were randomly assigned to receive the ampho B-based regimen and who are intolerant to the regimen (experience a treatment limiting toxicity [TLT]) will receive fluconazole only. Participants who are receiving study-provided fluconazole in Step 1 or in Step 2 may enroll in Step 3 if they have a negative cerebrospinal fluid (CSF) culture. Participants in Step 3 will receive fluconazole until Week 10. At Week 10, all participants will enroll in Step 4 and receive a lower daily dose of fluconazole until the end of the study (Week 24). Participants in both stages beginning treatment with ampho B will receive daily ampho B intravenously for up to 2 weeks. Fluconazole will be given orally.

Before entering the study, potential participants will attend a screening visit where they will have their CM diagnosis confirmed with CSF collected via lumbar puncture. HIV testing will also be conducted, along with clinical assessments, and a health and medical history questionnaire. Participants will also have a blood collection, an electrocardiogram (ECG), and a pregnancy test (if applicable). Once accepted into the study, participants will again answer questions about their health and medication history; have a complete physical exam, blood collection, HIV testing, neurological exam, lumbar puncture, and ECG; and may have a pregnancy test (if applicable).

Participants will have study visits during Weeks 1 (at Days 1, 4, and 7), 2, 4, 6, 8, 10, and 24. Participants receiving treatment with ampho B may have a few more study visits than other participants. Total study duration will be 24 weeks. Plasma, urine, serum, and CSF samples will be collected from all participants and stored for possible future use.

• Cryptococcal Meningitis
• HIV Infections

• Drug: Fluconazole
  Dosages will be 1200 mg, 1600 mg, or 2000 mg for Stage 1, Arm A. MTD determined in Stage 1 will be given to participants in Stage 2, Arm C. All participants will receive lower doses (a minimum daily dose of 200 mg) throughout the study.
  Other Name: Diflucan
• Drug: Amphotericin B
  Ampho B given intravenously for approximately 2 weeks at a dosage of 0.7 to 1.0 mg/kg, dependent on participant's weight
  Other Names:

  • Ampho B
  • Amphocin
  • Fungizone
  • AmBisome
  • Abelecet
  • Amphotec

• Experimental: Stage 1, Arm A
  Participants receiving fluconazole only
  Intervention: Drug: Fluconazole
• Experimental: Stage 1, Arm B
  Participants receiving ampho B followed by fluconazole
  Interventions:

  • Drug: Fluconazole
  • Drug: Amphotericin B
• Experimental: Stage 2, Arm C
  Participants receiving fluconazole only at MTD determined in Stage 1
  Intervention: Drug: Fluconazole
• Experimental: Stage 2, Arm D
  Participants receiving ampho B followed by fluconazole
  Interventions:

  • Drug: Fluconazole
  • Drug: Amphotericin B

• Bicanic T, Meintjes G, Rebe K, Williams A, Loyse A, Wood R, Hayes M, Jaffar S, Harrison T. Immune Reconstitution Inflammatory Syndrome in HIV-Associated Cryptococcal Meningitis: A Prospective Study. J Acquir Immune Defic Syndr. 2009 Apr 9; [Epub ahead of print]
• Pappalardo MC, Szeszs MW, Martins MA, Baceti LB, Bonfietti LX, Purisco SU, Baez AA, Melhem MS. Susceptibility of clinical isolates of Cryptococcus neoformans to amphotericin B using time-kill methodology. Diagn Microbiol Infect Dis. 2009 Apr 1; [Epub ahead of print]
• Seddon J, Mangeya N, Miller RF, Corbett EL, Ferrand RA. Recurrence of cryptococcal meningitis in HIV-infected patients following immune reconstitution. Int J STD AIDS. 2009 Apr;20(4):274-5.

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