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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01802385
Recruitment Status : Completed
First Posted : March 1, 2013
Results First Posted : January 13, 2020
Last Update Posted : June 9, 2020
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

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Cryptococcal Meningitis Fungal Meningitis Drug: Sertraline Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 460 participants
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
Actual Study Start Date : March 9, 2015
Actual Primary Completion Date : September 2017
Actual Study Completion Date : September 27, 2017


Arm Intervention/treatment
No Intervention: Placebo
Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) + placebo
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




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


Secondary Outcome Measures :
  1. Safety (Occurence of Adverse Events) [ Time Frame: 18 weeks ]
    Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions

  2. Count of Participants With Cerebrospinal Fluid Sterility [ Time Frame: 14 days ]
    Number of participants with sterile cerebrospinal fluid at 2 weeks

  3. Center for Epidemiologic Studies in Depression (CES-D) Scale [ Time Frame: 14 weeks ]
    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.

  4. Quantitative Neurocognitive Performance Score (QNPZ-8) [ Time Frame: 14 weeks ]
    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.

  5. Fungal Clearance as Determined by Early Fungicidal Activity of CDF [ 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.

  6. Number of Participants Experiencing IRIS OR Relapse [ Time Frame: 18 weeks ]
    Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse

  7. 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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01802385


Locations
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Uganda
Infectious Disease Institute
Kampala, Uganda
Mbarara University of Science and Technology
Mbarara, Uganda
Sponsors and Collaborators
University of Minnesota
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
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Principal Investigator: David B Meya, MBCHB MMed Infectious Disease Institute
Study Director: Joshua Rhein, MD University of Minnesota
Study Chair: David R Boulware, MD MPH University of Minnesota
  Study Documents (Full-Text)

Documents provided by University of Minnesota:
Additional Information:
Publications of Results:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT01802385    
Other Study ID Numbers: S4 0296-01
R01NS086312-01 ( U.S. NIH Grant/Contract )
First Posted: March 1, 2013    Key Record Dates
Results First Posted: January 13, 2020
Last Update Posted: June 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Open
Access Criteria: Contact of the Principal Investigator
Keywords provided by University of Minnesota:
cryptococcal meningitis
cryptococcus
meningitis
yeast
fungus
Additional relevant MeSH terms:
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Meningococcal Infections
Meningitis, Cryptococcal
Meningitis, Fungal
Meningitis
Central Nervous System Diseases
Nervous System Diseases
Neisseriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
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