Cryptococcal Antigen Screening Plus Sertraline

NCT03002012 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: U01AI12500333238
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Cryptococcosis; Cryptococcal Infections; AIDS-Related Opportunistic Infections

Keywords

cryptococcal antigen; preemptive treatment; CRAG+; sertraline; fluconazole; randomized clinical trial; HIV

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• 6-month Survival

  6 months

• Cumulative Incidence of Symptomatic Cryptococcal Meningoencephalitis

  6 months

• Number of Clinical Adverse Events (Grade 3-5)

  6 months

• Number of Laboratory Grade 3-5 Adverse Events

  6 months

• All-Cause Premature Study Drug/Placebo Discontinuation

  6 months

Other Outcomes (1)

• Adherence to Study Drug

  12 weeks

Study Arms (2)

Sertraline

EXPERIMENTAL

Fluconazole Standard of Care + Sertraline

Drug: Sertraline; Drug: Fluconazole

Control

PLACEBO COMPARATOR

Fluconazole Standard of Care + Placebo Oral Tablet

Drug: Placebo Oral Tablet; Drug: Fluconazole

Interventions

Sertraline DRUG

sertraline 400mg/day

Also known as: Zoloft, Lustral, Sertraline hydrochloride

Sertraline

Placebo Oral Tablet DRUG

matched placebo tablet

Also known as: Placebo

Control

Fluconazole DRUG

Standard of Care Fluconazole per World Health Organization and Ugandan Guidelines (800mg/day x 2 weeks, 400mg/day x10 weeks, 200mg through 6 months).

Also known as: Fluconazole 200mg tab

Control; Sertraline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Minnesota: lead
• Infectious Diseases Institute, Uganda: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Mbarara University of Science and Technology: collaborator

Study Sites (1)

Infectious Disease Institute, Makerere University

Kampala, 22418, Uganda

Location

Related Publications (1)

• 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.

  PMID: 32415846 RESULT

Related Links

• PreventCrypto.org has information and training materials for cryptococcal antigen screening and treatment

MeSH Terms

Conditions

Cryptococcosis; AIDS-Related Opportunistic Infections

Interventions

Sertraline; Fluconazole

Condition Hierarchy (Ancestors)

Mycoses; Bacterial Infections and Mycoses; Infections; HIV Infections; Blood-Borne Infections; Communicable Diseases; Opportunistic Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

1-Naphthylamine; Amines; Organic Chemicals; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Trial was terminated early by the NIAID DSMB for excess harm.

Results Point of Contact

• Title: David Boulware
• Organization: University of Minnesota

boulw001@umn.edu

612-624-1966

Study Officials

• Elizabeth K Nalintya, MBChB MPH

  Infectious Disease Institute

  STUDY DIRECTOR

• Radha Rajasingham, MD

  University of Minnesota

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2016
• First Posted: December 23, 2016
• Study Start: November 15, 2017
• Primary Completion: March 13, 2018
• Study Completion: March 13, 2018
• Last Updated: June 9, 2020
• Results First Posted: December 26, 2019

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Available for at least 5 years
• Access Criteria: Upon request to the Principal Investigator

Locations

UG (1)