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

June 2, 2020 updated by: University of Minnesota

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

460

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Uganda
      • Kampala, Uganda
        • Infectious Disease Institute
      • Mbarara, Uganda
        • Mbarara University of Science and Technology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival
Time Frame: 18 weeks
18-week survival. The comparison will be between sertraline 400mg group and placebo
18 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety (Occurence of Adverse Events)
Time Frame: 18 weeks
Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions
18 weeks
Count of Participants With Cerebrospinal Fluid Sterility
Time Frame: 14 days
Number of participants with sterile cerebrospinal fluid at 2 weeks
14 days
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.
14 weeks
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.
14 weeks
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.
14 days
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
18 weeks
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.
18 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Minnesota

Collaborators

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

Investigators

  • 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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 9, 2015

Primary Completion (ACTUAL)

September 1, 2017

Study Completion (ACTUAL)

September 27, 2017

Study Registration Dates

First Submitted

February 27, 2013

First Submitted That Met QC Criteria

February 28, 2013

First Posted (ESTIMATE)

March 1, 2013

Study Record Updates

Last Update Posted (ACTUAL)

June 9, 2020

Last Update Submitted That Met QC Criteria

June 2, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • S4 0296-01
  • R01NS086312-01 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Time Frame

Open

IPD Sharing Access Criteria

Contact of the Principal Investigator

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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