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| Name | Class |
|---|---|
| Liverpool School of Tropical Medicine | OTHER |
| Kamuzu University of Health Sciences | OTHER |
| Malawi-Liverpool-Wellcome Trust Clinical Research Programme | OTHER |
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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.
CASTLE is funded by Wellcome, grant reference 203905/Z/16/Z
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Usual Care | No Intervention | 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. | |
| DCXR-CAD and FujiLAM and usual care | Experimental | 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 cohort | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CAD4TB | Diagnostic Test | CAD4TB is a Computer Aided Diagnosis (CAD) image processing algorithm that can aid interpretation of Chest X-ray images to accurately detect tuberculosis. |
| 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) |
| 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. |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rachael M Burke | London School of Hygiene and Tropical Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Zomba Central Hospital | Zomba | Malawi |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35007306 | Background | 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. | |
| 38748183 |
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IPD will be shared on LSHTM Data Compass.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | May 25, 2021 | Dec 13, 2022 | SAP_000.pdf |
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| ID | Term |
|---|---|
| D055985 | Latent Tuberculosis |
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
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| FujiLAM | Diagnostic Test | Fujifilm SILVAMP TB LAM is a high sensitivity test for mycobacterial lipoarabinomannan (LAM) in urine samples. |
|
| 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 |
| 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) |
| Derived |
| Burke RM, Nyirenda SK, Mtenga T, Twabi HH, Joekes E, Walker NF, Nyirenda R, Gupta-Wright A, Nliwasa M, Fielding K, MacPherson P, Corbett EL. Enhanced Tuberculosis Diagnosis With Computer-aided Chest X-ray and Urine Lipoarabinomannan in Adults With HIV Admitted to Hospital (CASTLE Study): A Cluster Randomized Trial. Clin Infect Dis. 2025 Jun 4;80(5):1143-1151. doi: 10.1093/cid/ciae273. |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D000085343 | Latent Infection |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |