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

Primary Purpose

Cryptococcal Meningitis, HIV Infections

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Fluconazole
Amphotericin B
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cryptococcal Meningitis focused on measuring CM, HIV, Meningitis

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Southern California CRS
  • Byramjee Jeejeebhoy Medical College (BJMC) CRS
  • Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
  • Moi University Clinical Research Center (MUCRC) CRS
  • San Miguel CRS
  • Wits Helen Joseph Hospital CRS (Wits HJH CRS)
  • Durban International Clinical Research Site CRS
  • Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
  • Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site
  • Parirenyatwa CRS

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Active Comparator

Experimental

Experimental

Active Comparator

Arm Label

Stage 1, Fluconazole 1200mg

Stage 1, Fluconazole 1600mg

Stage 1, Fluconazole 2000mg

Stage 1, Ampho B

Stage 2, Fluconazole 1600mg

Stage 2, Fluconazole 2000mg

Stage 2, Ampho B

Arm Description

Participants receive Fluconazole 1200mg induction dose in Stage 1

Participants receive Fluconazole 1600mg induction dose in Stage 1

Participants receive Fluconazole 2000mg induction dose in Stage 1

Participants receive Amphotericin B followed by Fluconazole in Stage 1

Participants receive Fluconazole 1600mg induction dose in Stage 2

Participants receive Fluconazole 2000mg induction dose in Stage 2

Participants receive Amphotericin B followed by Fluconazole in Stage 2

Outcomes

Primary Outcome Measures

Number of Participants Who Discontinued Study-provided High Dose Fluconazole or Ampho B
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.
Categorized Quantitative Culture Results
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.
Change in Log10 Quantitative CSF Culture Results
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.
Kaplan Meier (KM) Proportion of Participant Mortality
Kaplan Meier Proportion of participants who died over study with 90% Confidence Intervals.

Secondary Outcome Measures

Results of the Neurological Examination
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).
Results of Functional Status Evaluation
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'.
Length of Hospitalization
Duration of first hospitalization in days starting at entry in safety population.
Number of Hospital Admissions
Count of number of times a participant was admitted to the hospital.
Number of Participants With Progression of Symptoms
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
Number of Participants With CNS IRIS
Number of participants who were diagnosed with CNS immune reconstitution inflammatory syndrome (IRIS)
Number of Participants With Grade 3 and 4 Adverse Events
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

Full Information

First Posted
April 20, 2009
Last Updated
November 2, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00885703
Brief Title
High-Dose Fluconazole for the Treatment of Cryptococcal Meningitis in HIV-Infected Individuals
Official Title
A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
April 16, 2010 (Actual)
Primary Completion Date
January 12, 2017 (Actual)
Study Completion Date
January 12, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cryptococcal Meningitis, HIV Infections
Keywords
CM, HIV, Meningitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
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)
Allocation
Randomized
Enrollment
168 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Stage 1, Fluconazole 1200mg
Arm Type
Experimental
Arm Description
Participants receive Fluconazole 1200mg induction dose in Stage 1
Arm Title
Stage 1, Fluconazole 1600mg
Arm Type
Experimental
Arm Description
Participants receive Fluconazole 1600mg induction dose in Stage 1
Arm Title
Stage 1, Fluconazole 2000mg
Arm Type
Experimental
Arm Description
Participants receive Fluconazole 2000mg induction dose in Stage 1
Arm Title
Stage 1, Ampho B
Arm Type
Active Comparator
Arm Description
Participants receive Amphotericin B followed by Fluconazole in Stage 1
Arm Title
Stage 2, Fluconazole 1600mg
Arm Type
Experimental
Arm Description
Participants receive Fluconazole 1600mg induction dose in Stage 2
Arm Title
Stage 2, Fluconazole 2000mg
Arm Type
Experimental
Arm Description
Participants receive Fluconazole 2000mg induction dose in Stage 2
Arm Title
Stage 2, Ampho B
Arm Type
Active Comparator
Arm Description
Participants receive Amphotericin B followed by Fluconazole in Stage 2
Intervention Type
Drug
Intervention Name(s)
Fluconazole
Other Intervention Name(s)
Diflucan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Amphotericin B
Other Intervention Name(s)
Amphotericin B deoxycholate, Ampho B, Amphocin, Fungizone, AmBisome, Abelecet, Amphotec
Intervention Description
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
Primary Outcome Measure Information:
Title
Number of Participants Who Discontinued Study-provided High Dose Fluconazole or Ampho B
Description
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.
Time Frame
Measured from study entry through Week10
Title
Categorized Quantitative Culture Results
Description
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.
Time Frame
At entry, Week 2, and Week 10
Title
Change in Log10 Quantitative CSF Culture Results
Description
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.
Time Frame
Entry and Week 2
Title
Kaplan Meier (KM) Proportion of Participant Mortality
Description
Kaplan Meier Proportion of participants who died over study with 90% Confidence Intervals.
Time Frame
Measured from study entry through Week 24
Secondary Outcome Measure Information:
Title
Results of the Neurological Examination
Description
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).
Time Frame
Measured at study entry, Week 2, and Week 10
Title
Results of Functional Status Evaluation
Description
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'.
Time Frame
Measured 6 weeks before enrollment, at study entry, at Week 10, and at Week 24
Title
Length of Hospitalization
Description
Duration of first hospitalization in days starting at entry in safety population.
Time Frame
Measured from study entry through Week 10
Title
Number of Hospital Admissions
Description
Count of number of times a participant was admitted to the hospital.
Time Frame
Measured from study entry through Week 24
Title
Number of Participants With Progression of Symptoms
Description
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
Time Frame
Measured from study entry through Week 24
Title
Number of Participants With CNS IRIS
Description
Number of participants who were diagnosed with CNS immune reconstitution inflammatory syndrome (IRIS)
Time Frame
Measured from study entry through Week 24
Title
Number of Participants With Grade 3 and 4 Adverse Events
Description
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
Time Frame
Measured from study entry through Week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Umesh G. Lalloo, MD, FRCP
Organizational Affiliation
Nelson R. Mandela School of Medicine
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Robert A. Larsen, MD
Organizational Affiliation
USC School of Medicine
Official's Role
Study Chair
Facility Information:
Facility Name
University of Southern California CRS
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033-1079
Country
United States
Facility Name
Byramjee Jeejeebhoy Medical College (BJMC) CRS
City
Pune
State/Province
Maharashtra
ZIP/Postal Code
411001
Country
India
Facility Name
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
City
Kericho
State/Province
Rift Valley
ZIP/Postal Code
20200
Country
Kenya
Facility Name
Moi University Clinical Research Center (MUCRC) CRS
City
Eldoret
ZIP/Postal Code
30100
Country
Kenya
Facility Name
San Miguel CRS
City
Lima
ZIP/Postal Code
32
Country
Peru
Facility Name
Wits Helen Joseph Hospital CRS (Wits HJH CRS)
City
Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2092
Country
South Africa
Facility Name
Durban International Clinical Research Site CRS
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
4013
Country
South Africa
Facility Name
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
City
Chiang Mai
ZIP/Postal Code
50200
Country
Thailand
Facility Name
Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site
City
Kampala
Country
Uganda
Facility Name
Parirenyatwa CRS
City
Harare
Country
Zimbabwe

12. IPD Sharing Statement

Citations:
PubMed Identifier
19365271
Citation
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Description
Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

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

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