Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM)
This is a phase III trial to determine whether adjunctive sertraline will lead to improved survival 18-week survival.
There is an initial phase I/II unmasked dose finding pharmacokinetic study of CSF concentrations in at least 20 persons.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis|
- Survival [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]18-week survival. There will be two comparisons: between the sertraline 400mg group and placebo, and between the sertraline 200mg group and placebo.
- Safety [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
- Intolerance [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]Time to dose-reduction for intolerance
- Microbiologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]2 week CSF culture sterility
- Neurocognitive Performance [ Time Frame: 14 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 14 weeks.
- 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) 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 ] [ Designated as safety issue: Yes ]Cumulative incidence of CNS cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse
- Cost analysis [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]Cost-benefit of adjunctive sertraline therapy
- Switching to Open Label Sertraline [ Time Frame: 14 weeks ] [ Designated as safety issue: Yes ]Incidence of switching from blinded to open-labeled study drug due to severe depression occurring between 4 to 14 weeks.
|Study Start Date:||August 2013|
|Estimated Study Completion Date:||July 2017|
|Estimated Primary Completion Date:||July 2017 (Final data collection date for primary outcome measure)|
Placebo Comparator: Placebo
Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day).
Experimental: Sertraline 200mg
Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) plus adjunctive sertraline therapy at 200mg/day for 14 weeks, then tapered over 3 weeks.
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.
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 I/II 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 III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at 200mg or 400mg/day. We will use a permutated block randomization in a 1:1:1 allocation (n=160 per arm). Total anticipated enrollment: 480 subjects.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01802385
|Contact: David B Meya, MBChB MMedemail@example.com|
|Contact: David R Boulware, MD MPHfirstname.lastname@example.org|
|Infectious Disease Institute||Recruiting|
|Contact: Darlisha Williams, MPH email@example.com|
|Principal Investigator: David B Meya, MBChB MMed|
|Mbarara University of Science and Technology||Not yet recruiting|
|Contact: Conrad Muzoora, MMed firstname.lastname@example.org|
|Contact: Kabanda Taseera, MMed MSc email@example.com|
|Principal Investigator: Conrad Muzoora, MMed|
|Principal Investigator: Kabanda Taseera, MMed MSc|
|Principal Investigator:||David B Meya, MBCHB MMed||Infectious Disease Institute|
|Study Director:||Joshua Rhein, MD||University of Minnesota - Clinical and Translational Science Institute|
|Study Chair:||David R Boulware, MD MPH||University of Minnesota - Clinical and Translational Science Institute|