Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Overview

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 Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: September 2017

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.

Interventions

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

Arms, Groups and Cohorts

  • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Minnesota
  • Collaborator
    • Infectious Disease Institute, Kampala, Uganda
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • David B Meya, MBCHB MMed, Principal Investigator, Infectious Disease Institute
    • Joshua Rhein, MD, Study Director, University of Minnesota
    • David R Boulware, MD MPH, Study Chair, University of Minnesota

References

Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, Musubire A, Akampurira A, Smith KD, Alhadab A, Williams DA, Abassi M, Bahr NC, Velamakanni SS, Fisher J, Nielsen K, Meya DB, Boulware DR; ASTRO-CM Study Team. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis. 2016 Jul;16(7):809-818. doi: 10.1016/S1473-3099(16)00074-8. Epub 2016 Mar 10.

Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother. 2012 Jul;56(7):3758-66. doi: 10.1128/AAC.00212-12. Epub 2012 Apr 16.

Smith KD, Achan B, Hullsiek KH, McDonald TR, Okagaki LH, Alhadab AA, Akampurira A, Rhein JR, Meya DB, Boulware DR, Nielsen K; ASTRO-CM/COAT Team. Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother. 2015 Dec;59(12):7197-204. doi: 10.1128/AAC.01299-15. Epub 2015 Aug 31.

Citations Reporting on Results

Rhein J, Huppler Hullsiek K, Tugume L, Nuwagira E, Mpoza E, Evans EE, Kiggundu R, Pastick KA, Ssebambulidde K, Akampurira A, Williams DA, Bangdiwala AS, Abassi M, Musubire AK, Nicol MR, Muzoora C, Meya DB, Boulware DR; ASTRO-CM team. Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. Lancet Infect Dis. 2019 Aug;19(8):843-851. doi: 10.1016/S1473-3099(19)30127-6.

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