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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00885703
First received: April 20, 2009
Last updated: July 2, 2014
Last verified: July 2014

April 20, 2009
July 2, 2014
February 2010
November 2015   (final data collection date for primary outcome measure)
  • 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 ]
Complete list of historical versions of study NCT00885703 on ClinicalTrials.gov Archive Site
  • 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 ]
Not Provided
Not Provided
 
High-Dose Fluconazole for the Treatment of Cryptococcal Meningitis in HIV-Infected Individuals
A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis

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 168 HIV-infected people with CM will participate for a duration of 24 weeks. This study will proceed in 2 stages and each stage may consist of up to 4 steps. Participants may take part in only one stage of the study. Stage 1 will measure the maximum tolerated dose (MTD) of fluconazole in participants. Stage 2 will be for the purpose of dose validation.

Stage 1 of the study was completed in January 2014. The two higher doses of fluconazole that were tested in Stage 1 (1600 mg/day and 2000 mg/day) will be tested further in Stage 2 of the study.

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) will be tested further in Stage 2 of the study.

Participants enrolled in Stage 2 will be randomly assigned to Step 1 to receive treatment with either fluconazole only (at one of the 2 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 (at the same or a lower dose than in Step 1 or Step 2) until Week 10. At Week 10, all participants will enroll in Step 4 and receive a lower daily dose of fluconazole (i.e., less than received in Steps 1, 2, or 3) 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, and may have extra visits for individualized reasons. 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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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 (1600 mg or 2000 mg) will be given to participants in Stage 2, Arm C. Participants in both stages of the study will receive lower doses of fluconazole (a minimum daily dose of 200 mg) in Steps 2, 3, and 4 than in Step 1.
    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 a participant's weight
    Other Names:
    • Amphotericin B deoxycholate
    • 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-based regimen 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-based regimen followed by fluconazole
    Interventions:
    • Drug: Fluconazole
    • Drug: Amphotericin B

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
168
Not Provided
November 2015   (final data collection date for primary outcome measure)

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 participants who are currently taking nevirapine, the inability to discontinue nevirapine and replace it with a drug that does not have fluconazole drug interactions (e.g., efavirenz) 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 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 manual of operations (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 (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
Both
16 Years and older
No
United States,   India,   Kenya,   Peru,   South Africa,   Thailand,   Uganda,   Zimbabwe
 
NCT00885703
A5225 (HiFLAC), 10149, ACTG A5225, HiFLAC, A5225/HiFLAC, A5225
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Not Provided
Study Chair: Umesh G. Lalloo, MD, FRCP Nelson R. Mandela School of Medicine
Study Chair: Robert A. Larsen, MD USC School of Medicine
National Institute of Allergy and Infectious Diseases (NIAID)
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP