Clinical Trial: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Brief Summary:

This is a phase III trial to determine whether adjunctive sertraline will lead to improved survival 18-week survival.

There was an initial phase I/II unmasked dose finding pharmacokinetic study of CSF concentrations in 172 persons conducted from August 2013 to August 2014.


Detailed Summary:

This is a phase III randomized trial to evaluate whether sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, will lead to improved survival . 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 III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at 400mg/day. We will use a permutated block randomization in a 1:1 allocation (n=275 per arm). Total anticipated enrollment: 550 subjects.


Sponsor: University of Minnesota - Clinical and Translational Science Institute

Current Primary Outcome: Survival [ Time Frame: 18 weeks ]

18-week survival. The comparison will be between sertraline 400mg group and placebo


Original Primary Outcome: Early Fungicidal Activity [ Time Frame: 14 days ]

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.


Current Secondary Outcome:

  • Safety [ Time Frame: 18 weeks ]
    Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
  • Intolerance [ Time Frame: 18 weeks ]
    Time to dose-reduction for intolerance
  • Microbiologic [ Time Frame: 14 days ]
    2 week CSF culture sterility
  • Neurocognitive Performance [ Time Frame: 14 weeks ]
    Quantitative neurocognitive performance score (QNPZ-8) and Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks.
  • Early Fungicidal Activity [ Time Frame: 14 days ]
    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) of clearance of the Cryptococcus colony forming units (cfu) per mL of CSF per day, compared to standard therapy alone.
  • IRIS and Relapse Incidence [ Time Frame: 18 weeks ]
    Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse
  • Event free survival [ Time Frame: 18 weeks ]
    Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse.


Original Secondary Outcome:

  • Safety [ Time Frame: 12 weeks ]
    Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
  • Intolerance [ Time Frame: 12 weeks ]
    Time to dose-reduction for intolerance
  • Survival [ Time Frame: 10 weeks ]
    10-week survival time
  • Microbiologic [ Time Frame: 14 days ]
    2 week CSF culture sterility
  • Neurocognitive Performance [ Time Frame: 12 weeks ]
    Quantitative neurocognitive performance score (QNPZ-8) and Center for Epidemiologic Studies in Depression (CES-D) scale at 4 and 12 weeks.


Information By: University of Minnesota - Clinical and Translational Science Institute

Dates:
Date Received: February 27, 2013
Date Started: March 9, 2015
Date Completion: June 30, 2018
Last Updated: April 17, 2017
Last Verified: April 2017