Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM)
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|ClinicalTrials.gov Identifier: NCT01802385|
Recruitment Status : Completed
First Posted : March 1, 2013
Results First Posted : January 13, 2020
Last Update Posted : June 9, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Cryptococcal Meningitis Fungal Meningitis||Drug: Sertraline||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||460 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis|
|Actual Study Start Date :||March 9, 2015|
|Actual Primary Completion Date :||September 2017|
|Actual Study Completion Date :||September 27, 2017|
No Intervention: Placebo
Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) + placebo
Experimental: Sertraline 400mg
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.
Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
- Survival [ Time Frame: 18 weeks ]18-week survival. The comparison will be between sertraline 400mg group and placebo
- Safety (Occurence of Adverse Events) [ Time Frame: 18 weeks ]Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions
- Count of Participants With Cerebrospinal Fluid Sterility [ Time Frame: 14 days ]Number of participants with sterile cerebrospinal fluid at 2 weeks
- Center for Epidemiologic Studies in Depression (CES-D) Scale [ Time Frame: 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) [ Time Frame: 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 [ 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.
- Number of Participants Experiencing IRIS OR Relapse [ 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01802385
|Infectious Disease Institute|
|Mbarara University of Science and Technology|
|Principal Investigator:||David B Meya, MBCHB MMed||Infectious Disease Institute|
|Study Director:||Joshua Rhein, MD||University of Minnesota|
|Study Chair:||David R Boulware, MD MPH||University of Minnesota|