Clinical trial NCT03002012: Cryptococcal Antigen Screening Plus Sertraline
Official title: Cryptococcal Antigen Screening Plus Sertraline
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cryptococcosis
Cryptococcal Infections
AIDS-Related Opportunistic Infections
Keywords: cryptococcal antigen
preemptive treatment
CRAG+
sertraline
fluconazole
randomized clinical trial
HIV
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Infectious Diseases Institute, Uganda
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Mbarara University of Science and Technology
First posted: 2016-12-23
Enrollment: 22
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: 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+).

Eligibility criteria: 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

Primary outcomes:
measure: 6 Month Meningitis-free Survival
timeFrame: 6 months
Secondary outcomes:
measure: 6-month Survival
timeFrame: 6 months
measure: Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis
timeFrame: 6 months
measure: Number of Clinical Adverse Events (Grade 3-5)
timeFrame: 6 months
measure: Number of Laboratory Grade 3-5 Adverse Events
timeFrame: 6 months
measure: All-Cause Premature Study Drug/Placebo Discontinuation
timeFrame: 6 months
measure: Prevalence of Depression by Patient Health Questionnaire (PHQ-9) Over Time
timeFrame: 12 weeks
Other outcomes:
measure: Adherence to Study Drug
timeFrame: 12 weeks
Locations:
city: Kampala
country: Uganda
facility: Infectious Disease Institute, Makerere University
Study officials:
affiliation: Infectious Disease Institute
name: Elizabeth K Nalintya, MBChB MPH
role: STUDY_DIRECTOR
affiliation: University of Minnesota
name: Radha Rajasingham, MD
role: STUDY_DIRECTOR
References:
citation: 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.