Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Cryptococcal Meningitis, Fungal Meningitis

Intervention / Treatment
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* Drug: Sertraline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Placebo<br>Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) + placebo | |
| Experimental: Sertraline 400mg<br>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. | Drug: Sertraline<br>* Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.<br>* Other names: Lustral;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | 18-week survival. The comparison will be between sertraline 400mg group and placebo | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Occurence of Adverse Events) | Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions | 18 weeks | 
| Count of Participants With Cerebrospinal Fluid Sterility | Number of participants with sterile cerebrospinal fluid at 2 weeks | 14 days | 
| Center for Epidemiologic Studies in Depression (CES-D) Scale | 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. | 14 weeks | 
| Quantitative Neurocognitive Performance Score (QNPZ-8) | 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. | 14 weeks | 
| Fungal Clearance as Determined by Early Fungicidal Activity of CDF | 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. | 14 days | 
| Number of Participants Experiencing IRIS OR Relapse | Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse | 18 weeks | 
| Event Free Survival | Event free survival of composite events of: death,central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse. | 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cryptococcal meningitis, cryptococcus, meningitis, yeast, fungus