Cryptococcal Antigen Screening Plus Sertraline

Phase 3

Terminated

Conditions: Cryptococcosis
Cryptococcal Infections
AIDS-Related Opportunistic Infections

Interventions: Drug: Placebo Oral Tablet
Drug: Sertraline
Drug: Fluconazole

Registration Number: NCT03002012

Lead Sponsor: University of Minnesota

Brief Summary: 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.

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+).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 22

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Fluconazole	Fluconazole Standard of Care + Placebo Oral Tablet
Control	Placebo Oral Tablet	Fluconazole Standard of Care + Placebo Oral Tablet
Sertraline	Sertraline	Fluconazole Standard of Care + Sertraline
Sertraline	Fluconazole	Fluconazole Standard of Care + Sertraline

Primary Outcome Measures

Name	Time	Method
6 Month Meningitis-free Survival	6 months	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

Secondary Outcome Measures

Name	Time	Method
6-month Survival	6 months	Survival through 6 months
Number of Laboratory Grade 3-5 Adverse Events	6 months	Number of Laboratory Grade 3-5 Adverse Events through 6 months as per the Division of AIDS (DAIDS) grading scale
Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis	6 months	Cumulative incidence of symptomatic cryptococcal meningoencephalitis through 6 months
Number of Clinical Adverse Events (Grade 3-5)	6 months	Number of Clinical Adverse Events by Division of AIDS (DAIDS) Scale for Grade 3-5 events through 6 months
All-Cause Premature Study Drug/Placebo Discontinuation	6 months	Number of participants whose study drug/placebo use was halted prematurely due to any cause through 6 months
Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time	12 weeks	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.