High-Dose Fluconazole for the Treatment of CM in HIV-infected People - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00885703

Purpose

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.

Condition	Intervention	Phase
Cryptococcal Meningitis HIV Infections	Drug: Fluconazole Drug: Amphotericin B	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study
Official Title:	A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis

Resource links provided by NLM:

MedlinePlus related topics: AIDS Meningitis

Drug Information available for: Fluconazole Amphotericin B

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

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 ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:

192

Arms	Assigned Interventions
Stage 1, Arm A: Experimental Participants receiving fluconazole only	Drug: Fluconazole Dosages will be at 1200, 1600, or 2000 mg for Stage 1, Arm A and Stage 2, Arm C. All participants will receive lower doses at 400-800mg throughout the study.
Stage 1, Arm B: Experimental Participants receiving ampho B followed by fluconazole	Drug: Fluconazole Dosages will be at 1200, 1600, or 2000 mg for Stage 1, Arm A and Stage 2, Arm C. All participants will receive lower doses at 400-800mg throughout the study. 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
Stage 2, Arm C: Experimental Participants receiving fluconazole only at MTD determined in Stage 1	Drug: Fluconazole Dosages will be at 1200, 1600, or 2000 mg for Stage 1, Arm A and Stage 2, Arm C. All participants will receive lower doses at 400-800mg throughout the study.
Stage 2, Arm D: Experimental Participants receiving ampho B followed by fluconazole	Drug: Fluconazole Dosages will be at 1200, 1600, or 2000 mg for Stage 1, Arm A and Stage 2, Arm C. All participants will receive lower doses at 400-800mg throughout the study. 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

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.

Eligibility

Ages Eligible for Study:	16 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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 licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load
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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00885703

Locations

United States, California
USC CRS	Recruiting
Los Angeles, California, United States, 90033
Contact: Luis M. Mendez 323-343-8288 lmendez@usc.edu

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair:	Beatriz Bustamante, MD	INMENSA
Study Chair:	Umesh G. Lalloo, MD, FRCP	Nelson R. Mandela School of Medicine
Study Chair:	Robert A. Larsen, MD	USC School of Medicine
Study Chair:	J. Allen McCutchan, MD	University of California, San Diego

More Information

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.

Responsible Party:	DAIDS ( Rona Siskind )
Study ID Numbers:	ACTG A5225, HiFLAC
Study First Received:	April 20, 2009
Last Updated:	February 8, 2010
ClinicalTrials.gov Identifier:	NCT00885703 History of Changes
Health Authority:	United States: Food and Drug Administration

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

CM
HIV
Meningitis

Additional relevant MeSH terms:

Abelcet
Anti-Infective Agents
Antiprotozoal Agents
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Infection
Liposomal amphotericin B
Meningitis
Anti-Bacterial Agents
Mycoses
Antiparasitic Agents
Antifungal Agents
Therapeutic Uses
Antibiotics, Antifungal
Meningitis, Cryptococcal

Amebicides
Central Nervous System Fungal Infections
Retroviridae Infections
Fluconazole
Amphotericin B
RNA Virus Infections
Meningitis, Fungal
Immune System Diseases
Acquired Immunodeficiency Syndrome
Nervous System Diseases
Central Nervous System Diseases
Pharmacologic Actions
Immunologic Deficiency Syndromes
Virus Diseases
Central Nervous System Infections

ClinicalTrials.gov processed this record on February 08, 2010