Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

• Early Fungicidal Activity [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  To determine whether adjunctive sertraline will lead to a faster rate of fungal clearance from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA), compared to standard therapy alone.
  
  

• Safety [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
  
  
• Intolerance [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Time to dose-reduction for intolerance
  
  
• Survival [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
  10-week survival time
  
  
• Microbiologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  2 week CSF culture sterility
  
  
• Neurocognitive Performance [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Quantitative neurocognitive performance score (QNPZ-8) and Center for Epidemiologic Studies in Depression (CES-D) scale at 4 and 12 weeks.
  
  

This is a phase I/II randomized trial to evaluate the early fungicidal activity (EFA) of sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, with the hypothesis that adjunctive sertraline will lead to faster fungal clearance. Cryptococcal meningitis diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects that meet eligibility requirements will be able to enter study. A non-randomized phase I dose-escalation study will first be conducted to help optimize dosing for a larger randomized phase II study.

Phase I Design: In addition to standard induction therapy for cryptococcal meningitis, subjects will receive increasing doses of sertraline in a dose-escalation study design. The first subjects enrolled into the study will receive 100 mg/day of sertraline. This dose will be sequentially increased by 100 mg/day in groups of n=5 up to a maximum of 400mg daily. Total anticipated enrollment: 20 subjects.

Phase II Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at two different doses to be determined in Phase I of the trial. We will use a permutated block randomization in a 1:1:1 allocation (n=40 per arm). Total anticipated enrollment: 120 subjects.