NCT01802385

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
460

participants targeted

Target at P50-P75 for phase_3

Timeline
Completed

Started Mar 2015

Typical duration for phase_3

Geographic Reach
1 country

2 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

February 27, 2013

Completed
2 days until next milestone

First Posted

Study publicly available on registry

March 1, 2013

Completed
2 years until next milestone

Study Start

First participant enrolled

March 9, 2015

Completed
2.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

September 1, 2017

Completed
26 days until next milestone

Study Completion

Last participant's last visit for all outcomes

September 27, 2017

Completed
2.3 years until next milestone

Results Posted

Study results publicly available

January 13, 2020

Completed
Last Updated

June 9, 2020

Status Verified

June 1, 2020

Enrollment Period

2.5 years

First QC Date

February 27, 2013

Results QC Date

May 31, 2019

Last Update Submit

June 2, 2020

Conditions

Cryptococcal MeningitisFungal Meningitis

Keywords

cryptococcal meningitiscryptococcusmeningitisyeastfungus

Outcome Measures

Primary Outcomes (1)

  • Survival

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

    18 weeks

Secondary Outcomes (7)

  • Safety (Occurence of Adverse Events)

    18 weeks

  • Count of Participants With Cerebrospinal Fluid Sterility

    14 days

  • Center for Epidemiologic Studies in Depression (CES-D) Scale

    14 weeks

  • Quantitative Neurocognitive Performance Score (QNPZ-8)

    14 weeks

  • Fungal Clearance as Determined by Early Fungicidal Activity of CDF

    14 days

  • +2 more secondary outcomes

Study Arms (2)

Placebo

NO INTERVENTION

Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day) + placebo

Sertraline 400mg

EXPERIMENTAL

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

Interventions

SertralineDRUG

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

Also known as: Zoloft, Lustral
Sertraline 400mg

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Infectious Disease Institute

Kampala, Uganda

Location

Mbarara University of Science and Technology

Mbarara, Uganda

Location

Related Publications (13)

  • 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.

    PMID: 26971081BACKGROUND

  • 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.

    PMID: 22508310BACKGROUND

  • 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.

    PMID: 26324276BACKGROUND

  • 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.

    PMID: 31345462RESULT

  • Sadiq A, Kwizera R, Kiiza TK, Ayebare P, Ahimbisibwe C, Ndyetukira JF, Boulware DR, Meya DB. Experiences, challenges, gaps, and strategies for counselling persons presenting with advanced HIV-associated meningitis in Uganda. AIDS Res Ther. 2025 Feb 19;22(1):21. doi: 10.1186/s12981-025-00705-z.

    PMID: 39972326DERIVED

  • Okurut S, Boulware DR, Okafor E, Rhein J, Kajumbula H, Bagaya BS, Bwanga F, Olobo JO, Manabe YC, Meya DB, Janoff EN. Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis. Front Immunol. 2023 Dec 13;14:1275443. doi: 10.3389/fimmu.2023.1275443. eCollection 2023.

    PMID: 38152404DERIVED

  • Bahr NC, Skipper CP, Huppler-Hullsiek K, Ssebambulidde K, Morawski BM, Engen NW, Nuwagira E, Quinn CM, Ramachandran PS, Evans EE, Lofgren SM, Abassi M, Muzoora C, Wilson MR, Meya DB, Rhein J, Boulware DR. Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies. Clin Infect Dis. 2023 Mar 21;76(6):1080-1087. doi: 10.1093/cid/ciac853.

    PMID: 36303432DERIVED

  • Lofgren SM, Nicol MR, Kandole TK, Castillo-Mancilla J, Anderson PL, Mpoza E, Tugume L, Bangdiwala AS, Ssebambulidde K, Hullsiek KH, Rhein J, Meya DB, Boulware DR. Short Communication: A Descriptive Analysis of Dried Blood Spot Adherence Testing Among Ugandans with HIV Presenting with Cryptococcal Meningitis. AIDS Res Hum Retroviruses. 2021 Jul;37(7):529-533. doi: 10.1089/AID.2020.0202. Epub 2021 Apr 12.

    PMID: 33677986DERIVED

  • Kwizera R, Sadiq A, Ndyetukira JF, Nalintya E, Williams D, Rhein J, Boulware DR, Meya DB; COAT and ASTRO trial teams. Impact of community engagement and social support on the outcomes of HIV-related meningitis clinical trials in a resource-limited setting. Res Involv Engagem. 2020 Aug 20;6:49. doi: 10.1186/s40900-020-00228-z. eCollection 2020.

    PMID: 32843994DERIVED

  • Ahimbisibwe C, Kwizera R, Ndyetukira JF, Kugonza F, Sadiq A, Hullsiek KH, Williams DA, Rhein J, Boulware DR, Meya DB. Management of amphotericin-induced phlebitis among HIV patients with cryptococcal meningitis in a resource-limited setting: a prospective cohort study. BMC Infect Dis. 2019 Jun 26;19(1):558. doi: 10.1186/s12879-019-4209-7.

    PMID: 31242860DERIVED

  • Atherton RR, Ellis J, Cresswell FV, Rhein J, Boulware DR. Ophthalmic signs in Ugandan adults with HIV-associated cryptococcal meningitis: A nested analysis of the ASTRO-CM cohort. Wellcome Open Res. 2018 Oct 12;3:80. doi: 10.12688/wellcomeopenres.14666.2. eCollection 2018.

    PMID: 30345376DERIVED

  • Tugume L, Rhein J, Hullsiek KH, Mpoza E, Kiggundu R, Ssebambulidde K, Schutz C, Taseera K, Williams DA, Abassi M, Muzoora C, Musubire AK, Meintjes G, Meya DB, Boulware DR; COAT and ASTRO-CM teams. HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts. J Infect Dis. 2019 Feb 23;219(6):877-883. doi: 10.1093/infdis/jiy602.

    PMID: 30325463DERIVED

  • Ssebambulidde K, Bangdiwala AS, Kwizera R, Kandole TK, Tugume L, Kiggundu R, Mpoza E, Nuwagira E, Williams DA, Lofgren SM, Abassi M, Musubire AK, Cresswell FV, Rhein J, Muzoora C, Hullsiek KH, Boulware DR, Meya DB; Adjunctive Sertraline for Treatment of HIV-associated Cryptococcal Meningitis Team. Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis. Clin Infect Dis. 2019 May 30;68(12):2094-2098. doi: 10.1093/cid/ciy817.

    PMID: 30256903DERIVED

Related Links

MeSH Terms

Conditions

Meningitis, CryptococcalMeningitis, FungalMeningitis

Interventions

Sertraline

Condition Hierarchy (Ancestors)

Central Nervous System Fungal InfectionsMycosesBacterial Infections and MycosesInfectionsCryptococcosisCentral Nervous System InfectionsCentral Nervous System DiseasesNervous System DiseasesNeuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

1-NaphthylamineAminesOrganic ChemicalsNaphthalenesPolycyclic Aromatic HydrocarbonsHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsPolycyclic Compounds

Results Point of Contact

Title
Joshua Rhein
Organization
University of Minnesota
joshua.rhein@gmail.com
612-624-1966

Study Officials

  • David B Meya, MBCHB MMed

    Infectious Disease Institute

    PRINCIPAL INVESTIGATOR

  • Joshua Rhein, MD

    University of Minnesota

    STUDY DIRECTOR

  • David R Boulware, MD MPH

    University of Minnesota

    STUDY CHAIR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

February 27, 2013

First Posted

March 1, 2013

Study Start

March 9, 2015

Primary Completion

September 1, 2017

Study Completion

September 27, 2017

Last Updated

June 9, 2020

Results First Posted

January 13, 2020

Record last verified: 2020-06

Data Sharing

IPD Sharing
Will share
Shared Documents
STUDY PROTOCOL, SAP, ICF, CSR
Time Frame
Open
Access Criteria
Contact of the Principal Investigator

Locations

UG(2)