Operational Research for Cryptococcal Antigen Screening (ORCAS)

Operational Research for Cryptococcal Antigen Screening to Improve ART Survival

This will be a stepped wedge randomized trial design to evaluate the implementation of cryptococcal antigen (CRAG) screening and preemptive anti-fungal therapy of HIV-infected persons entering antiretroviral therapy (ART) outpatient treatment in Uganda. Those who are ART eligible with a CD4≤100 cells/mcL will have a serum/plasma CRAG performed by lateral flow assay. Those who are CRAG-positive and asymptomatic will be treated with high dose fluconazole. After 6 months survival with retention-in-care will be compared between those who are CRAG+ and CRAG negative

Study Overview

• Status: Completed
• Conditions: Cryptococcosis; Cryptococcal Meningitis; Cryptococcus Neoformans
• Intervention / Treatment: Drug: Fluconazole

• Study Type: Interventional
• Enrollment (Actual): 3049
• Phase: Phase 4

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Infectious Disease Institute, Makerere University
  • Kampala, Uganda
    • Kampala Capital Council Authority Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infection
• CD4≤100 cells/mcL
• Cryptococcal antigen (CRAG) positive
• age >14 years

Exclusion Criteria:

• Suspected Cryptococcal meningitis
• Prior known history of cryptococcal meningitis
• currently receiving HIV antiretroviral therapy
• Allergy to any azole antifungal medication
• Persons with known serious hepatic co-morbidities, transaminitis, or clinical jaundice who should not receive fluconazole in the opinion of the study investigator.
• Current known pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CrAg Screening and Fluconazole; Cryptococcal Antigen (CrAg) Screening with preemptive antifungal treatment per World Health Organization (WHO) guidelines. Randomized Stepped Wedge design of phased implementation.	Drug: Fluconazole; Fluconazole 800mg orally daily for 2 weeks, then 400mg daily for 8 weeks; Other Names: Diflucan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retention in care	before/after CRAG screening implementation (All persons); CRAG positive persons treated with high-dose fluconazole as compared to 6-month survival of CRAG negative persons who are eligible for antiretroviral therapy.	6-month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cryptococcal meningitis-free survival time	Cryptococcal meningitis-free survival time in those who are asymptomatic CRAG positive and treated with fluconazole compared to CRAG-negative persons with CD4<100 cells/mcL	6-month
Survival Time	Survival time among CRAG+ vs. CRAG negative persons with CD4<100 cells/mcL.	6-month
Uptake of CRAG screening and preemptive treatment		baseline
Time from CRAG+ test to receipt of fluconazole therapy		Days from CD4 testing
All-cause discontinuation of fluconazole	Number of participants with early discontinuation of fluconazole for any reason (e.g. non-compliance, adverse event)	6-month
Percentage of participants with symptomatic cryptococcal meningitis		baseline
Risk factors for symptomatic cryptococcal meningitis		baseline

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: Centers for Disease Control and Prevention; Makerere University; Infectious Diseases Institute, Uganda
• Investigators: Principal Investigator: David B Meya, MMed, Makerere University; Study Director: Radha Rajasingham, MD, Infectious Disease Institute

Publications and helpful links

General Publications

• Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care. J Acquir Immune Defic Syndr. 2012 Apr 15;59(5):e85-91. doi: 10.1097/QAI.0b013e31824c837e.
• Meya DB, Manabe YC, Castelnuovo B, Cook BA, Elbireer AM, Kambugu A, Kamya MR, Bohjanen PR, Boulware DR. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis. 2010 Aug 15;51(4):448-55. doi: 10.1086/655143.
• Meya DB, Kiragga AN, Nalintya E, Morawski BM, Rajasingham R, Park BJ, Mubiru A, Kaplan JE, Manabe YC, Boulware DR. Reflexive Laboratory-Based Cryptococcal Antigen Screening and Preemptive Fluconazole Therapy for Cryptococcal Antigenemia in HIV-Infected Individuals With CD4 <100 Cells/microL: A Stepped-Wedge, Cluster-Randomized Trial. J Acquir Immune Defic Syndr. 2019 Feb 1;80(2):182-189. doi: 10.1097/QAI.0000000000001894.

Helpful Links

• Infectious Disease Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2012
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: February 16, 2012
• First Posted (Estimate): February 17, 2012

Study Record Updates

• Last Update Posted (Actual): June 4, 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; implementation science; cryptococcal meningitis; aids; stepped wedge design; retention-in-care
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections and Mycoses; Mycoses; Meningitis, Fungal; Central Nervous System Fungal Infections; Meningitis; Meningitis, Cryptococcal; Cryptococcosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; 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; Fluconazole
• Other Study ID Numbers: HS1254; U01GH000517 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After publication, data to be shared upon request to the Infectious Disease Institute Research Department as per the institutional data sharing policy.
• IPD Sharing Time Frame: Upon request
• IPD Sharing Access Criteria: Upon request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No