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Completed

NCT Number: NCT01802385

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. See NCT03002012.

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Key information

Conditions

Cryptococcal Meningitis Bacterial Infections and Mycoses Central Nervous System Diseases Central Nervous System Fungal Infections Central Nervous System Infections Cryptococcosis Fungal Meningitis Infections Meningitis Meningitis, Cryptococcal Meningitis, Fungal Mycoses Nervous System Diseases Neuroinflammatory Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Infectious Disease Institute, Kampala, Uganda

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Sertraline

Drug

Sertraline 400mg/day for 2 weeks, then 200mg/day for 12 weeks, then tapered over 3 weeks.

Other names: Zoloft, Lustral

Primary outcomes

  1. Survival

    Time frame: 18 weeks

    18-week survival. The comparison will be between sertraline 400mg group and placebo

Secondary outcomes

  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.

Sponsors and collaborators

Lead sponsor

University of Minnesota

Other

Collaborators

  • Infectious Disease Institute, Kampala, Uganda
  • Makerere University
  • Mbarara University of Science and Technology
  • Medical Research Council
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Wellcome Trust

Registry information

Acronym: ASTRO-CM

Important dates

Study start
2015
Primary completion
2017
Study completion
2017
First posted
Mar 1, 2013
Registry last updated
Jun 9, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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