Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Cryptococcal Meningitis Clinical Trial

— ASTRO-CM  

Official title:

Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01802385
• Other study ID #: S4 0296-01
• Secondary ID: R01NS086312-01
• Status: Completed
• Phase: Phase 3
• Start date: March 9, 2015
• Est. completion date: September 27, 2017

Study information

• Verified date: June 2020
• Source: University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 460
• Est. completion date: September 27, 2017
• Est. primary completion date: September 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cryptococcal Meningitis
• Fungal Meningitis
• Meningitis
• Meningitis, Cryptococcal
• Meningitis, Fungal

Intervention

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

Locations

Country	Name	City	State
Uganda	Infectious Disease Institute	Kampala
Uganda	Mbarara University of Science and Technology	Mbarara

Sponsors (7)

Lead Sponsor	Collaborator
University of Minnesota	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

Country where clinical trial is conducted

Uganda, 

References & Publications (4)

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 — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival	18-week survival. The comparison will be between sertraline 400mg group and placebo	18 weeks
Secondary	Safety (Occurence of Adverse Events)	Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions	18 weeks
Secondary	Count of Participants With Cerebrospinal Fluid Sterility	Number of participants with sterile cerebrospinal fluid at 2 weeks	14 days
Secondary	Center for Epidemiologic Studies in Depression (CES-D) Scale	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
Secondary	Quantitative Neurocognitive Performance Score (QNPZ-8)	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
Secondary	Fungal Clearance as Determined by Early Fungicidal Activity of CDF	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
Secondary	Number of Participants Experiencing IRIS OR Relapse	Cumulative incidence of central nervous system (CNS) cryptococcal-related paradoxical immune reconstitution inflammatory syndrome (IRIS) or culture-positive relapse	18 weeks
Secondary	Event Free Survival	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

External Links

•   Accordia Global Health Foundation
•   Infectious Disease Institute