High-Dose Fluconazole for the Treatment of CM in HIV-Infected People

Condition(s) targeted: Cryptococcal Meningitis; HIV Infections

Intervention: Fluconazole (Drug); Amphotericin B (Drug)

Phase: Phase 1/Phase 2

Status: Not yet recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Beatriz Bustamante, MD, Study Chair, Affiliation: INMENSA
Umesh G. Lalloo, MD, FRCP, Study Chair, Affiliation: Nelson R. Mandela School of Medicine
Robert A. Larsen, MD, Study Chair, Affiliation: USC School of Medicine
J. Allen McCutchan, MD, Study Chair, Affiliation: University of California, San Diego

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.

Official title: A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis

Study design: Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

Discontinuation of fluconazole or ampho B, including precipitating and surrounding adverse events

Qualitative and quantitative CSF culture results at entry, week 2, and when conducted thereafter

Survival

Secondary outcome:

Results of the neurological examination and functional status evaluation

Length of hospitalization and number and nature of hospital readmissions

Recurrence/relapse of CM based on clinical presentation

CNS immune reconstitution inflammatory syndrome (IRIS)

Pharmacology

Additional safety parameters including: Grade 3 and 4 adverse events; dose modifications; duration of temporary treatment interruptions; permanent discontinuation of either agent

Antifungal drug susceptibility of cryptococcal isolates

Detailed description: Cryptococcal meningitis (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 which causes CM, Cryptococcus neoforman. 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. This study will evaluate fluconazole administered alone and at doses of 1200, 1600, and/or 2000 mg/day will be well tolerated in and safe for patients for the treatment of CM.

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

Participants will take part in only one stage of the study. If enrolled for Stage 1, participants will be randomly assigned to receive either fluconazole only or ampho B followed by fluconazole treatment. 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.

Participants in Stage 2 will also be randomly assigned to either receive treatment with fluconazole only or ampho-B followed by fluconazole.

Participants in Stage 2 receiving fluconazole only will start with a dose of either 1200 mg daily, 1600 mg daily, or 2000 milligrams daily, depending on the MTD determined in Stage 1. After 10 weeks on study, dosage will be reduced to 400 mg daily (Step 3) and subsequently to 200 mg daily (Step 4), until the end of the study.

Participants in both Stages beginning treatment with ampho B will receive their medication daily for about 2 weeks. Administration of ampho B will take approximately 1 hour. Flucytosine may also be given in combination with ampho B. After about 2 weeks of receiving ampho B, participant will be given fluconazole until the end of the study, with a dose reduction after 10 weeks.

Before entering the study, potential participants will attend a screening visit where they will have their CM diagnosis confirmed with spinal fluid collected via lumbar puncture. HIV testing will also be conducted, along with a physical examination, health and medical history questionnaire. Participants will also have blood drawn, 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 physical exam, blood drawn, HIV testing, neurological exam, lumbar puncture, and may have a pregnancy test (if applicable). Participants will have study visits during Weeks 1, 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 6 months.

Minimum age: 16 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria - Step 1

- Cryptococcal meningitis 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

- 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 locally licensed ELISA or rapid HIV test kit

- 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 3 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, participants must

use a form of contraceptive listed below while on study treatment and for 6 weeks after has been discontinued

- 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 of 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

- For patients with a co-morbid complication of HIV, anticipated difficulty, in the

opinion of the site investigator, in judging response to study treatment as a result of the co-morbid complication or the drugs used to treat it

- 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 opinion of site investigator,

including symptoms of ischemia, coronary artery disease, congestive heart failure, or arrhythmia

- ECG (electrocardiogram) 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, 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,

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

Inclusion Criteria - Step 4

- On study treatment at week 10 (day 63-77)

Exclusion Criteria - Step 4

- None

Related publications:

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.

Last updated: April 20, 2009