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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by University of Minnesota - Clinical and Translational Science Institute
Sponsor:
Collaborators:
Infectious Disease Research Institute
Mbarara University of Science and Technology
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01802385
First received: February 27, 2013
Last updated: September 2, 2014
Last verified: September 2014
  Purpose

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.


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

Study Type: Interventional
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

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 ] [ 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.


Secondary Outcome Measures:
  • 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 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 ] [ 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.


Estimated Enrollment: 630
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)
Arms Assigned Interventions
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.
Drug: Sertraline
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
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 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=210 per arm). Total anticipated enrollment: 630 subjects.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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

Contacts
Contact: David B Meya, MBChB MMed david.meya@gmail.com
Contact: David R Boulware, MD MPH boulw001@umn.edu

Locations
Uganda
Infectious Disease Institute Recruiting
Kampala, Uganda
Contact: Darlisha Williams, MPH       coat.trial@gmail.com   
Principal Investigator: David B Meya, MBChB MMed         
Mbarara University of Science and Technology Not yet recruiting
Mbarara, Uganda
Contact: Conrad Muzoora, MMed       conradmuzoora@gmail.com   
Contact: Kabanda Taseera, MMed MSc       kabtash@yahoo.com   
Principal Investigator: Conrad Muzoora, MMed         
Principal Investigator: Kabanda Taseera, MMed MSc         
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Infectious Disease Research Institute
Mbarara University of Science and Technology
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
Study First Received: February 27, 2013
Last Updated: September 2, 2014
Health Authority: Uganda: National Council for Science and Technology
Uganda: National Drug Authority
United States: Institutional Review Board
United States: Data and Safety Monitoring Board
United States: Food and Drug Administration

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 Infections
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Fungal Infections
Mycoses
Cryptococcosis
Sertraline
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 22, 2014