Computer Aided Screening for Tuberculosis in Low Resource Environments (CASTLE)

People living with HIV (PLHIV) who require admission to hospital in WHO Africa region have poor outcomes. TB is very common in this group, but can be difficult to diagnose.

The CASTLE trial aims to determine whether systematic screening for tuberculosis using digital chest X-ray with computer-aided diagnosis (DCXR-CAD) plus urine lipoarabinomannan testing with Fujifilm SILVAMP TB LAM (FujiLAM) plus usual care can improve admission outcomes for hospitalised PLHIV, compared to usual care alone.

Our study is a single centre, unblinded, cluster-randomised (by day of admission) trial of DCXR-CAD plus FujiLAM plus usual care vs. usual care alone for screening for TB in unselected adult PLHIV admitted to a district general hospital in Malawi.

The primary outcome is the proportion of people starting TB treatment by the time of death or hospital discharge. The secondary outcomes are all-cause mortality at 56 days from enrolment, proportion of people starting TB treatment within 24 hours from enrolment, and proportion of people with undiagnosed TB. In the CASTLE study we collect a single sputum sample for M. tb culture from participants and undiagnosed TB specifically refers to a person who did not start TB treatment by the time of death or discharge from hospital and has a M. tb cultured from their sputum sample.

Alongside the two trial arms, a third smaller diagnostic cohort arm (1 in 9 of admission days / trial clusters) will explore the range of underlying infectious pathology. The diagnostic cohort does not contribute to trial outcomes.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Tuberculosis Infection
• Intervention / Treatment: Diagnostic test: CAD4TB; Diagnostic test: FujiLAM

Detailed Description

CASTLE is funded by Wellcome, grant reference 203905/Z/16/Z

• Study Type: Interventional
• Enrollment (Actual): 498
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Malawi
  • Zomba, Malawi
    • Zomba Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Requires acute admission to a hospital medical ward at Zomba Central Hospital for any reason
• Is living with HIV (existing or new diagnosis, irrespective of ART status)
• Willing and able to give informed consent

Exclusion Criteria:

• Aged <18 years
• Has been admitted to a medical ward for longer than 18 hours
• Taking TB treatment before admission or has received treatment for TB within the preceding 6 months.
• Has already been in the study during an earlier hospital admission.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Usual Care; Participants in the usual care arm will receive no specific trial intervention. Usual care includes tests routinely available at Zomba Central Hospital, including (but not limited to) conventional (plain film) chest X-ray, urine Alere LAM and sputum Xpert Mtb/Rif on treating clinician request.
Experimental: DCXR-CAD and FujiLAM and usual care; Participants randomized to the intervention arm will receive TB screening using DCXR-CAD and urine FujiLAM. The CAD score and FujLAM results will be appended into their medical notes for treating clinicians to see. If patients have a CAD score above a pre-determined threshold the study team will attempt to collect sputum for Xpert Mtb/Rif. Chest X-ray images will be available for clinicians to view. This is in addition to usual care (detailed above).	Diagnostic test: CAD4TB; CAD4TB is a Computer Aided Diagnosis (CAD) image processing algorithm that can aid interpretation of Chest X-ray images to accurately detect tuberculosis.; Diagnostic test: FujiLAM; Fujifilm SILVAMP TB LAM is a high sensitivity test for mycobacterial lipoarabinomannan (LAM) in urine samples.
Other: Diagnostic cohort; Patients in the observational enhanced diagnostic arm will receive an enhanced package of diagnostics. This is a smaller arm (1 in 9 of all clusters) and is observational only - participants in this arm do not contribute to trial outcomes.	Diagnostic test: CAD4TB; CAD4TB is a Computer Aided Diagnosis (CAD) image processing algorithm that can aid interpretation of Chest X-ray images to accurately detect tuberculosis.; Diagnostic test: FujiLAM; Fujifilm SILVAMP TB LAM is a high sensitivity test for mycobacterial lipoarabinomannan (LAM) in urine samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TB treatment initiation	Proportion of participants started on TB treatment	From time of enrolment into trial to time of discharge from hospital or death (whichever is earlier)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Time (in days) to death from any case.	Censored at 56 days from enrolment
Undiagnosed TB	Positive sputum culture for mycobacterium tuberculosis at reference lab and participant is not on TB treatment at time of hospital discharge or death.	From time of enrolment into trial to time of discharge from hospital or death (whichever is earlier)
Same day TB treatment	Proportion of people starting TB treatment within 24 hours of enrollment	24 hours from enrolment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality (measured as a proportion)	Proportion of people dying by 56 days from enrolment.	56 days from enrolment
Inpatient mortality	Proportion of people dying prior to hospital discharge	Censored at 56 days for those who are still alive and admitted to hospital at 56 days from enrolment.
Confirmed TB	The proportion of TB diagnoses that are microbiologically confirmed vs. clinically diagnosed without microbiological confirmation.	From time of enrolment into trial to time of discharge from hospital or death (whichever is earlier)
Intervention fidelity	Proportion of people randomised to DCXR-CAD plus FujiLAM who have a valid CxR and CAD score recorded, and a FujiLAM result.	24 hours from enrolment
Diagnostic accuracy of DCXR-CAD	Sensitivity, specificity, positive and negative predictor value compared to a composite microbiological gold standard.	From time of enrolment into trial to time of discharge from hospital or death (whichever is earlier)
Prevalence of infectious disease (enhanced diagnostic cohort)	To describe the proportion of patients meeting a clinical or clinical / microbiological description for the following: Sepsis; Invasive bacterial disease; Cryptococcal disease; Pneumocystis jirovecci pneumonia; Bacterial pneumonia; Immune reconstitution inflammatory syndrome (IRIS); HIV treatment failure	From time of enrolment into trial to time of discharge from hospital or death (whichever is earlier)

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Liverpool School of Tropical Medicine; Kamuzu University of Health Sciences; Malawi-Liverpool-Wellcome Trust Clinical Research Programme
• Investigators: Principal Investigator: Rachael M Burke, London School of Hygiene and Tropical Medicine

Publications and helpful links

General Publications

• Burke RM, Nyirenda S, Twabi HH, Nliwasa M, Joekes E, Walker N, Nyirenda R, Gupta-Wright A, Fielding K, MacPherson P, Corbett EL. Design and protocol for a cluster randomised trial of enhanced diagnostics for tuberculosis screening among people living with HIV in hospital in Malawi (CASTLE study). PLoS One. 2022 Jan 10;17(1):e0261877. doi: 10.1371/journal.pone.0261877. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2020
• Primary Completion (Actual): March 31, 2022
• Study Completion (Actual): May 26, 2022

Study Registration Dates

• First Submitted: September 1, 2020
• First Submitted That Met QC Criteria: September 7, 2020
• First Posted (Actual): September 10, 2020

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 23, 2023
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Infections; Communicable Diseases; Tuberculosis; Latent Tuberculosis
• Other Study ID Numbers: 17799

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD will be shared on LSHTM Data Compass.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No