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A5225/HiFLAC: A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis

Description

A5225/HiFLAC is a phase I/II dose escalation study of the safety and therapeutic effect of high-dose fluconazole alone for the treatment of cryptococcal meningitis (CM) in HIV-infected participants. A cohort treated with amphotericin B deoxycholate alone or in combination with 5-fluorocytosine serve as an internal standard treatment group for the study. The study will proceed in two stages. In Stage 1, Dose Escalation, up to three induction doses of fluconazole will be tested in sequentially enrolled cohorts (24 participants randomized to fluconazole and up to 8 participants randomized to an ampho B-based regimen comprise a cohort). Stage 2, Dose Validation, will not open until the maximum tolerated dose (MTD) of fluconazole has been identified in Stage 1. In Stage 2, induction doses of fluconazole that are found to be safe in Stage 1 will be tested in simultaneously enrolled cohorts. Thus, up to 96 subjects could participate in Stage 2 if all three fluconazole dose levels are deemed safe in stage 1. In each stage, participants will be randomized at entry. There are three doses of fluconazole being studied, 1200 mg, 1600 mg and 2000 mg daily until CSF cultures become negative. The amphotericin B dose is >=0.7 mg/kg.d for 14 days followed by fluconazole at 400 mg daily.Cerebrospinal fluid (CSF) is collected at screening or entry and every 2 weeks through week 10 until a negative culture is obtained. If a negative culture is obtained prior to week 10 the participant will receive fluconazole 400 mg daily until week 10. After week 10 all participants receive fluconazole at 200 mg daily to prevent relapse. Study participation for the participant ends at study week 24.Primary Endpoints:1. Safety - Discontinuation of fluconazole or ampho B, including precipitating and surrounding adverse events.2. Study Drug Activity - Qualitative and quantitative CSF culture results at entry, week 2, and when conducted thereafter. 3. Survival.The analysis plan has been developed to detect a >20% frequency of serious drug related toxic events from fluconazole. The microbial efficacy will be valuated based upon the change in colony counts from the CSF cultures taken at two week intervals until sterile.

Phase

N/A

Inclusion and Exclusion 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 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

Sites

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