Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis
- Registration Number
- NCT01802385
- Lead Sponsor
- University of Minnesota
- 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. See NCT03002012.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 460
- Cryptococcal meningitis diagnosed by CSF cryptococcal antigen (CRAG)
- HIV-1 infection
- Ability and willingness of the participant or legal guardian/representative to provide informed consent
- Willing to receive protocol-specified lumbar punctures
- Age < 18 years
- Receipt of >=3 doses of amphotericin therapy
- Cannot or unlikely to attend regular clinic visits
- History of known liver cirrhosis
- Presence of jaundice
- Pregnancy
- Current breastfeeding
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Sertraline 400mg Sertraline Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy at 400mg/day for 2 weeks, then 200mg for 12 weeks, and then tapered over 3 weeks.
- Primary Outcome Measures
Name Time Method Survival 18 weeks 18-week survival. The comparison will be between sertraline 400mg group and placebo
- Secondary Outcome Measures
Name Time Method Safety (Occurence of Adverse Events) 18 weeks Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions
Count of Participants With Cerebrospinal Fluid Sterility 14 days Number of participants with sterile cerebrospinal fluid at 2 weeks
Center for Epidemiologic Studies in Depression (CES-D) Scale 14 weeks Center for Epidemiologic Studies in Depression (CES-D) scale at 14 weeks. CES-D scores are based on a 20 item survey with total scores ranging from 0 to 60. Higher scores suggest a greater presence of depressive symptoms. A CES-D score of 16 or higher is interpreted to indicate a risk for depression.
Quantitative Neurocognitive Performance Score (QNPZ-8) 14 weeks Quantitative neurocognitive performance Z-score (QNPZ-8) at 14 weeks. The QNPZ-8 is a mean score of testing of 8 neurocognitive domains. Eqach domain is scaled based on a Z-score where the mean = 0 for the HIV-negative Ugandan population, accounting for age and educational status. Each +1 unit is one standard deviation better than the population norm. Each -1 unit is one standard deviation worse than the population norm.
Fungal Clearance as Determined by Early Fungicidal Activity of CDF 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.
Number of Participants Experiencing IRIS OR Relapse 18 weeks Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse
Event Free Survival 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.
Trial Locations
- Locations (2)
Infectious Disease Institute
🇺🇬Kampala, Uganda
Mbarara University of Science and Technology
🇺🇬Mbarara, Uganda