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

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

For this study, 168 HIV-infected people with CM participated for a duration of 24 weeks. This
study proceeded with 2 stages and each stage consisted of up to 4 steps. Participants could
take part in only one stage of the study. Stage 1 measured the maximum tolerated dose (MTD)
of fluconazole in participants. Stage 2 consisted of dose validation and safety monitoring.

In Stage 1, participants were 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).Three doses of
fluconazole were tested, and the MTD was found to be 2000 mg/day. The two higher doses of
fluconazole tested in Stage 1 (1600 mg/day and 2000 mg/day doses) were tested further in
Stage 2 of the study.

Participants enrolled in Stage 2 were randomly assigned to receive treatment with either
fluconazole only (at one of the 2 doses (1600 mg/day or 2000 mg/day) found to be safe in
Stage 1) or an ampho B-based regimen.

After randomization in Step 1, participants in both Stage 1 and Stage 2 could be enrolled in
up to three additional steps. In Step 2, participants who were randomly assigned to receive
the ampho B-based regimen and who were intolerant to the regimen (experienced a treatment
limiting toxicity [TLT]) received fluconazole (400-800mg daily). Participants who received
study-provided fluconazole in Step 1 or in Step 2 could be enrolled in Step 3 if they had a
negative cerebrospinal fluid (CSF) culture. Participants in Step 3 received fluconazole
(400mg daily) until Week 10. At Week 10, all participants were enrolled in Step 4 and
received a daily dose of fluconazole of 200mg until the end of the study (Week 24).
Participants in both stages beginning treatment with ampho B received daily ampho B
intravenously for up to 2 weeks.

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

Study visits occurred during Weeks 1 (at Days 1, 4, and 7), 2, 4, 6, 8, 10, and 24, and extra
visits could occur for individualized reasons. Total study duration was 24 weeks. Plasma,
urine, serum, and CSF samples were collected from all participants and stored for possible
future use.

Note on efficacy population versus safety population: After entering the study, participants
had their CM diagnosis confirmed by testing of the CSF collected via lumbar puncture.
Confirmation could take up to 2 weeks after study entry. Due to the mortality rate of CM,
participants received treatment before CM diagnosis confirmation. Post-entry 12 participants
either reported non-confirmatory baseline results making them ineligible. An additional 2
participants were found to be ineligible for the study but died prior to being found
ineligible (one had non-confirmatory baseline results, one was on a disallowed medication)
All participants (n=168) are included in the safety population. Participants who were
ineligible after study entry were excluded from the efficacy population (n=16). The efficacy
population had 154 participants. Outcomes will specify if the efficacy population is used
instead of the safety population.

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. NOTE: Administration of fluconazole tablets via
nasogastric tube is permitted.

- For patients with a co-morbid complication of HIV, including opportunistic infections,
reasonable certainty that the site investigator will be able to perform CSF sampling
and manage expected study drug toxicities. More information on this criterion can be
found in the protocol.

- For female participants of reproductive potential (defined as girls who have reached
menarche or women who have not been post-menopausal for at least 24 consecutive months
[i.e., who have had menses within the preceding 24 months, or have not undergone
surgical sterilization, for example, a hysterectomy, or bilateral oophorectomy or
salpingotomy]) 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. More information on this criterion can be found in the protocol.

- The following laboratory values within 3 days prior to study entry: aspartate
aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase less
than or equal to 5 times the upper limit of normal (ULN); total bilirubin less than or
equal to 2.5 times ULN; absolute neutrophil count (ANC) equal to or greater than
750/mm^3; platelet count equal to or greater than 50,000/mm^3; hemoglobin equal to or
greater than 7.0 g/dL

- 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.

- For candidates who are currently taking nevirapine, the inability to discontinue
nevirapine and replace it with a drug that does not have fluconazole drug interactions
at or by study entry in the event they are randomized to a high-dose fluconazole
treatment arm. More information on this criterion can be found in the study protocol.

- 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. More
information on this criterion can be found in the study protocol.

- 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 of the A5225/HiFLAC core team

- 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

Inclusion Criteria - 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 manual of
operations (MOPS)

Exclusion Criteria - 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 (except as noted below), a negative CSF
culture after 2 weeks incubation from a sample obtained at or before Week 6 (Days
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. More
information on this criterion can be found in the study protocol.

- 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 (Days 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 (Days 63-77) with no plans to discontinue study treatment

Exclusion Criteria - Step 4

- Currently off study treatment