Cryptococcal Antigen Screening Plus Sertraline

Study Overview
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Brief Summary
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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
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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+).

Official Title
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Cryptococcal Antigen Screening Plus Sertraline

Conditions
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Cryptococcosis, Cryptococcal Infections, AIDS-Related Opportunistic Infections

Intervention / Treatment
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* Drug: Sertraline
* Drug: Placebo Oral Tablet
* Drug: Fluconazole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cryptococcal antigen, preemptive treatment, CRAG+, sertraline, fluconazole, randomized clinical trial, HIV