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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
  Purpose

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.


Condition Intervention Phase
Cryptococcal Meningitis Fungal Meningitis Drug: Sertraline Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Survival [ Time Frame: 18 weeks ]
    18-week survival. The comparison will be between sertraline 400mg group and placebo


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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.


Estimated Enrollment: 550
Actual Study Start Date: March 9, 2015
Estimated Study Completion Date: September 27, 2017
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day).
Drug: Sertraline
Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Other Names:
  • Zoloft
  • Lustral
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.
Drug: Sertraline
Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.
Other Names:
  • Zoloft
  • Lustral

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01802385

Locations
Uganda
Infectious Disease Institute
Kampala, Uganda
Mbarara University of Science and Technology
Mbarara, Uganda
Sponsors and Collaborators
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
Investigators
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
  More Information

Additional Information:
Publications:
Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01802385     History of Changes
Other Study ID Numbers: S4 0296-01
R01NS086312-01 ( U.S. NIH Grant/Contract )
Study First Received: February 27, 2013
Last Updated: June 15, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
cryptococcal meningitis
cryptococcus
meningitis
yeast
fungus

Additional relevant MeSH terms:
Meningitis
Meningitis, Cryptococcal
Meningitis, Fungal
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Fungal Infections
Mycoses
Cryptococcosis
Central Nervous System Infections
Sertraline
Antidepressive Agents
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 18, 2017