Clinical trial NCT01802385: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis
Official title: Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cryptococcal Meningitis
Fungal Meningitis
Keywords: cryptococcal meningitis
cryptococcus
meningitis
yeast
fungus
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Infectious Disease Institute, Kampala, Uganda
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Mbarara University of Science and Technology
name: Medical Research Council
name: Wellcome Trust
name: Makerere University
First posted: 2013-03-01
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Survival
timeFrame: 18 weeks
Secondary outcomes:
measure: Safety (Occurence of Adverse Events)
timeFrame: 18 weeks
measure: Count of Participants With Cerebrospinal Fluid Sterility
timeFrame: 14 days
measure: Center for Epidemiologic Studies in Depression (CES-D) Scale
timeFrame: 14 weeks
measure: Quantitative Neurocognitive Performance Score (QNPZ-8)
timeFrame: 14 weeks
measure: Fungal Clearance as Determined by Early Fungicidal Activity of CDF
timeFrame: 14 days
measure: Number of Participants Experiencing IRIS OR Relapse
timeFrame: 18 weeks
measure: Event Free Survival
timeFrame: 18 weeks
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Disease Institute
city: Mbarara
country: Uganda
facility: Mbarara University of Science and Technology
Study officials:
affiliation: Infectious Disease Institute
name: David B Meya, MBCHB MMed
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Joshua Rhein, MD
role: STUDY_DIRECTOR
affiliation: University of Minnesota
name: David R Boulware, MD MPH
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.