ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00885703
Recruitment Status : Completed
First Posted : April 22, 2009
Results First Posted : March 12, 2018
Last Update Posted : March 12, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
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 explored the safety, tolerability, and therapeutic effect of a new treatment regimen with high-dose fluconazole for management of CM in HIV-infected patients.

Condition or disease Intervention/treatment Phase
Cryptococcal Meningitis HIV Infections Drug: Fluconazole Drug: Amphotericin B Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 168 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase 1 was the dose escalation phase which used a sequential model. Phase 2 was the dose validation phase which used a parallel model. Analyses combine arms from Phase 1 and Phase 2, as appropriate, for validation.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis
Actual Study Start Date : April 16, 2010
Actual Primary Completion Date : January 12, 2017
Actual Study Completion Date : January 12, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Meningitis
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Stage 1, Fluconazole 1200mg
Participants receive Fluconazole 1200mg induction dose in Stage 1
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Experimental: Stage 1, Fluconazole 1600mg
Participants receive Fluconazole 1600mg induction dose in Stage 1
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Experimental: Stage 1, Fluconazole 2000mg
Participants receive Fluconazole 2000mg induction dose in Stage 1
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Active Comparator: Stage 1, Ampho B
Participants receive Amphotericin B followed by Fluconazole in Stage 1
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Drug: Amphotericin B
Step 1: [For participants randomized to Ampho 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 2, Fluconazole 1600mg
Participants receive Fluconazole 1600mg induction dose in Stage 2
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Experimental: Stage 2, Fluconazole 2000mg
Participants receive Fluconazole 2000mg induction dose in Stage 2
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Active Comparator: Stage 2, Ampho B
Participants receive Amphotericin B followed by Fluconazole in Stage 2
Drug: Fluconazole

Step 1: [For participants randomized to Fluconazole] Induction dose of daily treatment of fluconazole given orally (adjusted according to weight).

Step 2: [For participants randomized to Ampho B only] If participant is intolerant to Ampho B, participant transitions to fluconazole dosage of 400-800mg daily given orally.

Step 3: If participant has a negative culture before week 10, participant transitions to consolidation therapy at dosage of 400mg daily given orally.

Step 4: At week 10, participant transitions to maintenance therapy at dosage of 200mg daily given orally.

Other Name: Diflucan
Drug: Amphotericin B
Step 1: [For participants randomized to Ampho 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



Primary Outcome Measures :
  1. Number of Participants Who Discontinued Study-provided High Dose Fluconazole or Ampho B [ Time Frame: Measured from study entry through Week10 ]

    Discontinuation of study-provided high dose fluconazole at or by week 10 Discontinuation of study-provided ampho B at or by week 2

    Discontinuation includes discontinuing for any reason, including progression of symptoms, death, etc.


  2. Categorized Quantitative Culture Results [ Time Frame: At entry, Week 2, and Week 10 ]
    Count of participants who were CM negative (had no cryptococcal growth), CM negative after switching treatment (switched from Fluconazole to Ampho B or vice versa and later became CM negative), CM positive, Died, Lost to follow-up. Note: CM positive means continued to have cryptococcal growth.

  3. Change in Log10 Quantitative CSF Culture Results [ Time Frame: Entry and Week 2 ]

    Change in quantitative CSF (cerebrospinal fluid) cultures.

    Note: No further CSF specimens are drawn following a negative culture. Thus, only week 2 CSF cultures are considered in this analysis.


  4. Kaplan Meier (KM) Proportion of Participant Mortality [ Time Frame: Measured from study entry through Week 24 ]
    Kaplan Meier Proportion of participants who died over study with 90% Confidence Intervals.


Secondary Outcome Measures :
  1. Results of the Neurological Examination [ Time Frame: Measured at study entry, Week 2, and Week 10 ]
    Results from Glasgow Coma Score, which provides assessment of impairment of conscious level in response to defined stimuli. Min score of 0 and max score of 15 (no mental impairment).

  2. Results of Functional Status Evaluation [ Time Frame: Measured 6 weeks before enrollment, at study entry, at Week 10, and at Week 24 ]

    Functional assessment of work status and ability. Consists of 2 measures: 1) Does participants have full time work status 2) Does participant have functional ability to work.

    The measure from 6 week before enrollment will be referred to as 'baseline'.


  3. Length of Hospitalization [ Time Frame: Measured from study entry through Week 10 ]
    Duration of first hospitalization in days starting at entry in safety population.

  4. Number of Hospital Admissions [ Time Frame: Measured from study entry through Week 24 ]
    Count of number of times a participant was admitted to the hospital.

  5. Number of Participants With Progression of Symptoms [ Time Frame: Measured from study entry through Week 24 ]

    Progression of symptoms is defined as:

    • Died (including early deaths)
    • Discontinued Fluconazole and started ampho B
    • Had a positive cryptococcal culture at week 10
    • Microbiological Failure (i.e., relapse of CM)
    • Complication of CM (e.g., obstructive hydrocephalus or vascular complications such as venous or arterial thrombosis)
    • CM IRIS causing increased inflammation after ART exposure
    • New CNS Ol (e.g., toxoplasmosis, PML, CNS lymphoma)
    • Possibly related to CM but mechanism indeterminate
    • Other defined complication unrelated to CM

  6. Number of Participants With CNS IRIS [ Time Frame: Measured from study entry through Week 24 ]
    Number of participants who were diagnosed with CNS immune reconstitution inflammatory syndrome (IRIS)

  7. Number of Participants With Grade 3 and 4 Adverse Events [ Time Frame: Measured from study entry through Week 24 ]

    Occurrence of grade 3 (severe) and 4 (life-threatening) sign and symptoms events (as defined by FSTRF Appendix 29)

    Occurrence of grade 3 (severe) and 4 (life-threatening) laboratory events (as defined by FSTRF Appendix 76)

    See DAIDS AE Grading table V1.0




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00885703


Locations
United States, California
University of Southern California CRS
Los Angeles, California, United States, 90033-1079
India
Byramjee Jeejeebhoy Medical College (BJMC) CRS
Pune, Maharashtra, India, 411001
Kenya
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
Kericho, Rift Valley, Kenya, 20200
Moi University Clinical Research Center (MUCRC) CRS
Eldoret, Kenya, 30100
Peru
San Miguel CRS
Lima, Peru, 32
South Africa
Wits Helen Joseph Hospital CRS (Wits HJH CRS)
Johannesburg, Gauteng, South Africa, 2092
Durban International Clinical Research Site CRS
Durban, KwaZulu-Natal, South Africa, 4013
Thailand
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Chiang Mai, Thailand, 50200
Uganda
Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site
Kampala, Uganda
Zimbabwe
Parirenyatwa CRS
Harare, Zimbabwe
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Umesh G. Lalloo, MD, FRCP Nelson R. Mandela School of Medicine
Study Chair: Robert A. Larsen, MD USC School of Medicine

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00885703     History of Changes
Other Study ID Numbers: A5225 (HiFLAC)
10149 ( Registry Identifier: DAIDS-ES )
ACTG A5225
HiFLAC
A5225/HiFLAC
A5225
First Posted: April 22, 2009    Key Record Dates
Results First Posted: March 12, 2018
Last Update Posted: March 12, 2018
Last Verified: February 2018

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

Additional relevant MeSH terms:
HIV Infections
Meningitis
Meningitis, Cryptococcal
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Central Nervous System Diseases
Nervous System Diseases
Meningitis, Fungal
Central Nervous System Fungal Infections
Mycoses
Cryptococcosis
Central Nervous System Infections
Fluconazole
Amphotericin B
Liposomal amphotericin B
Amphotericin B, deoxycholate drug combination
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists