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Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Infectious Disease Institute, Kampala, Uganda
National Institute of Neurological Disorders and Stroke (NINDS)
Mbarara University of Science and Technology
Medical Research Council
Wellcome Trust
Makerere University
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01802385
First received: February 27, 2013
Last updated: June 15, 2017
Last verified: June 2017
February 27, 2013
June 15, 2017
March 9, 2015
September 2017   (Final data collection date for primary outcome measure)
Survival [ Time Frame: 18 weeks ]
18-week survival. The comparison will be between sertraline 400mg group and placebo
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.
Complete list of historical versions of study NCT01802385 on ClinicalTrials.gov Archive Site
  • 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.
  • 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.
  • Cost analysis [ Time Frame: 18 weeks ]
    Cost-benefit of adjunctive sertraline therapy
  • Switching to Open Label Sertraline [ Time Frame: 14 weeks ]
    Incidence of switching from blinded to open-labeled study drug due to severe depression occurring between 4 to 14 weeks.
Not Provided
 
Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis
Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

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.

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.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
  • Cryptococcal Meningitis
  • Fungal Meningitis
Drug: Sertraline
Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Other Names:
  • Zoloft
  • Lustral
  • Placebo Comparator: Placebo
    Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day).
    Intervention: Drug: Sertraline
  • 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.
    Intervention: Drug: Sertraline

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
550
September 27, 2017
September 2017   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Uganda
Tanzania
 
NCT01802385
S4 0296-01
R01NS086312-01 ( US NIH Grant/Contract Award Number )
Yes
Not Provided
Yes
Not Provided
University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
  • Infectious Disease Institute, Kampala, Uganda
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Mbarara University of Science and Technology
  • Medical Research Council
  • Wellcome Trust
  • Makerere University
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
University of Minnesota - Clinical and Translational Science Institute
June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP