Cryptococcal Antigen Screening Plus Sertraline (C-ASSERT)

Cryptococcal meningitis or "Crypto" is a life threatening fungal infection around the brain that requires hospitalization for treatment for 14 days and then continued therapy. Crypto causes 15-20% of HIV/AIDS-related deaths worldwide. However, this infection can be detected before one develops symptoms and becomes ill. People can be screened for infection by a blood test to detect "cryptococcal antigen," (called CrAg), which is part of the fungus, in blood. The World Health Organization and over 22 countries worldwide recommend CrAg screening of all persons with advanced AIDS entering or re-entering into HIV care.

However, it is not known how best to treat people with cryptococcal antigen in their blood, who don't otherwise yet have symptoms of infection around their brain. If no treatment is given, almost all people will develop infection of the brain and/or die. International guidelines suggest using both HIV medicines and an anti-fungal medicine, called fluconazole, to treat this early infection. However, despite this treatment approximately 1 in 4 people may get sick and/or die.

Researchers have recently discovered another medicine that may work against the Cryptococcus fungus. This medicine is called Sertraline, and it is actually a medicine that has been used for more than 25 years to treat depression (sadness). Sertraline is one of the most commonly used medicines worldwide.

The purpose of this research clinical trial is to determine if standard fluconazole antifungal therapy plus a high dose of Sertraline, will be better than standard fluconazole therapy alone for treating early disseminated cryptococcal infection in persons who are asymptomatic and do not yet have infection of the brain (i.e. meningitis).

This study seeks to test if Sertraline will improve survival through 6-months. Prior studies have shown that >90% of those who survive 6-months will survive >5 years.

Study Overview

• Status: Terminated
• Conditions: Cryptococcosis; AIDS-Related Opportunistic Infections; Cryptococcal Infections
• Intervention / Treatment: Drug: Sertraline; Drug: Fluconazole; Drug: Placebo Oral Tablet

Detailed Description

This is a double-blind, randomized placebo-controlled clinical trial testing sertraline as an antifungal medicine in combination with fluconazole for treatment of HIV-infected persons with AIDS and asymptomatic cryptococcal antigenemia (CrAg+).

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 3

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda, 22418
    • Infectious Disease Institute, Makerere University

Participation Criteria

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:

• HIV-infected
• Cryptococcal antigen (CrAg) positive in blood
• Age >=18 years
• Written informed consent
• Women of childbearing potential who are participating in sexual activity that could lead to pregnancy must agree to use one reliable method of contraception while receiving fluconazole >=400mg/day

Exclusion Criteria:

• Prior history of cryptococcal meningitis
• Suspected meningitis or mania
• Suspected/known cirrhosis, jaundice, or alanine aminotransferase (ALT) >5x upper limit of normal
• Receiving an antidepressant medicine
• Receiving antifungal therapy, >1 week
• Pregnant or Breastfeeding
• Contraindication to sertraline or fluconazole
• Current rifampin use or other prohibited medication
• Electrocardiogram corrected QT interval (QTc) >450ms

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sertraline; Fluconazole Standard of Care + Sertraline	Drug: Sertraline; sertraline 400mg/day; Other Names: Zoloft; Lustral; Sertraline hydrochloride; Drug: Fluconazole; Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).; Other Names: Fluconazole 200mg tab
Placebo Comparator: Control; Fluconazole Standard of Care + Placebo Oral Tablet	Drug: Fluconazole; Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).; Other Names: Fluconazole 200mg tab; Drug: Placebo Oral Tablet; matched placebo tablet; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 Month Meningitis-free Survival	Cryptococcal meningitis free survival with retention-in-care through 6 months; Those who die of any cause are failures; Those developing symptomatic cryptococcal meningitis are failures; Those lost to follow up and unable to be tracked are considered failures	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-month Survival	Survival through 6 months	6 months
Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis	Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months	6 months
Number of Clinical Adverse Events (Grade 3-5)	Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months	6 months
Number of Laboratory Grade 3-5 Adverse Events	Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale	6 months
All-Cause Premature Study Drug/Placebo Discontinuation	Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months	6 months
Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time	Prevalence of depression by Patient Health Questionnaire (PHQ-9) over 6 months as measured at baseline, 4 weeks, 8 weeks, and 12 weeks. The PHQ-9 is a 9-item instrument for screening, diagnosing, monitoring, and measuring the severity of depression. Items are rated on a scale from 0 (not at all) to 3 (nearly every day). Total score is a sum of 9 item scores (Range 0-27). Greater scores indicate greater depressive symptoms. PHQ-9 scores of: 0-4 Minimal/No depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderate severe depression; 20-27 Severe depression. This endpoint reports the median (interquartile range) of the PHQ-9 scores over time.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence to Study Drug	Participants' percent adherence to study drug regiment by pharmacy medication counts, representing the percent of the total prescribed medication taken by participants.	12 weeks

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Mbarara University of Science and Technology; Infectious Diseases Institute, Uganda
• Investigators: Study Director: Elizabeth K Nalintya, MBChB MPH, Infectious Disease Institute; Study Director: Radha Rajasingham, MD, University of Minnesota

Publications and helpful links

General Publications

• Boulware DR, Nalintya E, Rajasingham R, Kirumira P, Naluyima R, Turya F, Namanda S, Rutakingirwa MK, Skipper CP, Nikweri Y, Hullsiek KH, Bangdiwala AS, Meya DB. Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial. Med Mycol. 2020 Nov 10;58(8):1037-1043. doi: 10.1093/mmy/myaa033.

Helpful Links

• PreventCrypto.org has information and training materials for cryptococcal antigen screening and treatment
• Preventing Deaths from Cryptococcal Meningitis
• Global Action Fund for Fungal Infections (GAFFI)

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2017
• Primary Completion (Actual): March 13, 2018
• Study Completion (Actual): March 13, 2018

Study Registration Dates

• First Submitted: December 14, 2016
• First Submitted That Met QC Criteria: December 20, 2016
• First Posted (Estimate): December 23, 2016

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: HIV; sertraline; randomized clinical trial; fluconazole; cryptococcal antigen; preemptive treatment; CRAG+
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Bacterial Infections and Mycoses; Parasitic Diseases; Mycoses; HIV Infections; Infections; Communicable Diseases; Opportunistic Infections; AIDS-Related Opportunistic Infections; Cryptococcosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Sertraline; Fluconazole
• Other Study ID Numbers: U01AI125003 (U.S. NIH Grant/Contract); 33238 (Other Identifier: DAIDS-ES ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: A formal written data sharing plan exists. Protocol and trial documents can be shared. De-identified data can be shared after trial completion.
• IPD Sharing Time Frame: Available for at least 5 years
• IPD Sharing Access Criteria: Upon request to the Principal Investigator
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No