Trial no.:	PACTR202407866544155	Date of Approval:	23/07/2024
Trial Status:	Retrospective registration - This trial was registered after enrolment of the first participant

TRIAL DESCRIPTION

Public title

THE DECIDE-TB TRIAL

Official scientific title

Validation of Treatment Decision Algorithms for childhood tuberculosis at district health care levels in Mozambique and Zambia - the Decide-TB cluster-randomized pragmatic trial

Brief summary describing the background and objectives of the trial

Childhood tuberculosis remains globally underdiagnosed and untreated, and tuberculosis-related mortality occurs mostly in undiagnosed children. Diagnosis of childhood tuberculosis is challenged by a low microbiological detection yield in children, explained among others by the paucibacillary nature of tuberculosis in children, the difficulty of collecting respiratory samples in young children, and the lack of specificity of clinical and radiological features, especially in children with HIV infection or severe malnutrition, requiring good clinical knowledge for clinicians for appropriate clinical diagnosis. This is particularly critical at low levels of healthcare in the context of the decentralisation of paediatric tuberculosis care to increase access to diagnosis and treatment. To this effect, in 2022, WHO conditionally recommended the use of treatment decision algorithms (TDAs) to improve the diagnosis of pulmonary tuberculosis in children. TDAs assign scores to clinical, radiographic, and/or microbiological features and recommend treatment initiation above a pre-defined total score. This enables rapid and standardised treatment decision-making for children with presumed tuberculosis. The Decide-TB project aims to generate evidence for the implementation of a comprehensive TDA-based approach for TB in children living in high-TB burden and resource-limited countries at the district hospital (DH) and primary health centre (PHC) levels and to facilitate the integration of this evidence within practices and policies.

Type of trial

RCT

Acronym (If the trial has an acronym then please provide)

DTB

Disease(s) or condition(s) being studied

Infections and Infestations,Paediatrics

Sub-Disease(s) or condition(s) being studied

Tuberculosis

Purpose of the trial

Validation of treatment algorithms

Anticipated trial start date

01/04/2024

Actual trial start date

01/06/2024

Anticipated date of last follow up

21/07/2026

Actual Last follow-up date

26/07/2027

Anticipated target sample size (number of participants)

30240

Actual target sample size (number of participants)

Recruitment status

Recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Parallel: different groups receive different interventions at same time during study	Randomised	Simple randomization using a randomization table created by a computer software program	Central randomisation by phone/fax	Open-label(Masking Not Used)

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Control Group	Standard of care	N/A	In this stepped wedge design, the duration the standard of care (SOC) phase in each distrcit is determined by the randomization sequence, which begins three months after the implementation starts. - In the first district, the SOC phase will last for 3 months before transitioning to the intervention. - In the second district, the SOC phase will last for 6 months. - In the third district, the SOC phase will last for 9 months. - In the fourth district, the SOC phase will last for 12 months.	Prior to the introduction of the intervention (i.e., the comprehensive TDA-based approach), DHs and PHCs in study districts will implement TB diagnosis for children as per the current SOC (control) in both countries . In Mozambique, the SOC is based on local algorithms which include: TB symptoms screening (including history of contact with TB), HIV testing, Xpert testing on induced sputum (and stool), and a tuberculin skin test (TST). Urine LAM is indicated for CLHIV. No CXR is performed. Mozambique will also pilot test WHO-suggested TDAs A&B in selected districts outside of Decide-TB. In Zambia, the SOC is based on the Union desk guide algorithm [22] which includes: TB symptom screening (including history of contact with TB), HIV testing and Xpert testing on respiratory or stool samples. Urine LAM is indicated for CLHIV and children with SAM, and children with sepsis, as well as other diseases associated with immune-suppression such as chronic kidney diseases and cancer. CXRs are performed depending on the facilities. Other tests and imaging are advised in presumed extrapulmonary TB cases. In both countries, presence of one or more symptom, suggestive CXR, or contact with a TB case warrants a TB diagnosis. A confirmed TB diagnosis is made based on a positive Xpert or LAM test. Mozambique will adopt shortly the WHO recommendation to shorten TB treatment in children. In Zambia, this recommendation is approved for phase implementation since September 2022.	2940	Active-Treatment of Control Group
Experimental Group	The comprehensive TDA based approach	N/A	In this step wedge randomization cluster design, the duration of intervention phase is dependent on the randomization sequence, which begins three months after the trial starts. The intervention of phase varies by district: - In the first district, the intervention phase will last for 21 months before transitioning to the intervention. - In the second district, the intervention phase will last for 18 months. - In the third district, the intervention phase will last for 15 months. - In the fourth district, the intervention phase will last for 12 months.	The intervention consists of implementing a comprehensive TDA-based approach for TB diagnosis and treatment decision-making, including shorter treatment for non-severe TB in children identified as TB presumptive cases through a CDSS. It will also include the management of high-risk groups. In practice, all sick children will be assessed using the WHO-suggested TDAs A with CXR (DH) and B without CXR (PHC). CLHIV and those hospitalised with SAM at DH will have further assessment and treatment decisions based on the PAANTHER and TB-Speed SAM TDAs, respectively. The final design of the comprehensive TDA-based approach was discussed in detail, adapted by key stakeholders in each country, and approved during two in-country workshops hosted by the country's NTPs and scientific partners (INS in Mozambique and UNZA in Zambia), with the support of Decide TB consortium members (IRD, University of Bordeaux, Stellenbosch University, Imperial College London, LMU). The diagnostic algorithms include TB contact history, symptom assessment, clinical examination, microbiological testing (Xpert MTB/RIF Ultra) on sputum, NPA, GA, and stool, CXR, urine LAM in SAM children, and CLHIV. Abdominal ultrasound will be performed at DH in high-risk group children (examination included in PAANTHER and TB-Speed SAM TDAs), and CXR will be available at DH and some PHCs per country or facility situation. The TDA-based approach provides a scoring system for clinical and radiographic features or positive microbiological tests and recommends TB treatment initiation above a pre-defined total score. Clinical and microbiological assessment data will be incorporated into a CDSS to help with the clinical decision to initiate TB treatment. The CDSS will incorporate specific features and test results for high-risk group children based on the PAANTHER TDA and the TB-Speed SAM TDA and will incorporate the results of the severity assessment to guide the choice of TB treatment duration once children are diagnosed.	27300

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
All sick children aged below 15 years entering the selected health facilities (DH and PHC) at either outpatient (OPD) or inpatient (IPD) departments, including children from high-risk groups, as well as children identified as contact of TB cases through community- or facility-based household contact tracing. Children with presumptive TB including children from high-risk groups with informed consent provided for data sharing for research within the NTP DHIS2 data collection tool.	There will be no exclusion criteria for the programmatic pilot: all children will be offered the intervention.	Adolescent: 13 Year-18 Year,Child: 6 Year-12 Year,Infant: 0 Month-23 Month,Infant: 1 Month-23 Month,New born: 0 Day-1 Month,Preschool Child: 2 Year-5 Year	0 Month(s)	15 Year(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

05/09/2023

University of Zambia Biomedical Research Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
University of Zambia, School of Medicine. Ridgeway Campus. Nationalist Road	Lusaka	10101	Zambia

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	Proportion of children started on treatment for TB among sick children attending care at participant health facilities for any health complaints	Through out the project
Secondary Outcome	Proportion of children treated for TB among those with presumptive TB, including children with microbiologically confirmed TB.	Through out the project
Secondary Outcome	Proportion of children from high-risk groups treated for TB (age <2 years , CLHIV, children with SAM) i) among all children from high-risk groups attending care, ii) among children from high-risk groups with presumptive TB.	Throughout the project
Secondary Outcome	Proportion of children with TB that are microbiologically confirmed (i.e. smear or Xpert or LAM positive), ratio of <5 to 5-14 years among children with TB, ratio of pulmonary TB to extrapulmonary TB (EPTB).	Throughout the Project
Secondary Outcome	Time from presumptive TB identification to final TB treatment decision and access to TB diagnostic assessment defined as the proportion of children with presumptive TB having completed assessment with the TDAs and CDSS, including in high-risk groups .	From the start of intervention to the end of the project
Secondary Outcome	Concordance of the TDA result and the final TB treatment decision using the proportion of children wrongly initiated or not initiated on TB treatment defined as: i) children not started on TB treatment despite positive score; ii) children initiated on TB treatment despite negative score. Reasons for both decisions will be collected4.	From the start of intervention to the end of the project
Secondary Outcome	Proportion of missed TB cases (false negative) and over-diagnosed TB cases (unlikely TB with a positive score, i.e. false positive).	From the start of intervention to the end of the project
Secondary Outcome	Concordance of the severity evaluation and decision for short TB treatment regimen using the proportion of i) children with 4-month TB treatment regimen used despite severe disease as assessed by the clinical/CXR evaluation; ii) children with 6-month TB treatment regimen despite non-severe disease as assessed by the clinical/CXR evaluation.	From the start of intervention to the end of the project
Secondary Outcome	Proportion of false positive and false negative TB severity assessments at low level of health care: i) children with non-severe disease according to clinical criteria despite severe disease as evaluated by expert CXR read; ii) children with clinically assessed severe disease despite non-severe disease as evaluated by expert CXR read.	From the start of intervention to the end of the project
Secondary Outcome	Proportion of children with presumptive TB and with non-severe TB disease initiated on shorter TB treatment.	From the start of intervention to the end of the project
Secondary Outcome	TB treatment outcomes as defined per WHO (treatment success, cured, treatment completion, loss to follow-up, death, treatment failure) overall and stratified by severity and regimen duration.	From the start of intervention to the end of the project
Secondary Outcome	Deaths averted assessed through modelling.	Throughout the Project
Secondary Outcome	Number of adult with TB, including microbiologically confirmed TB, and proportion of all TB diagnosed that is child TB.	Throughout the project
Secondary Outcome	Preferences of users (healthcare providers) in delivering childhood TB screening, diagnosis, and treatment decision-making comparing the comprehensive TDA-based approach vs. the SOC approach.	Throughout the project
Secondary Outcome	Local social value (i.e., alignment with values / preferences and perceived potential to impact on lived experience) of the comprehensive TDA-based approach, including associated digital tools, to users (healthcare providers) as part of their work duties in childhood TB care.	Throughout the project
Secondary Outcome	Local social value of the comprehensive TDA-based approach, including associated digital tools, to beneficiaries (children and their caregivers) receiving a diagnosis of TB.	Throughout the project
Secondary Outcome	Health systems and socioeconomic factors influencing preferences and local social value of the comprehensive TDA-based approach, including associated digital tools, for users and beneficiaries.	Throughout the project
Secondary Outcome	Feasibility of implementing and delivering the comprehensive TDA-based approach, including associated digital tools: health systems, logistical, managerial, challenges faced during implementation, and solutions found.	From the start of intervention to the end of the project
Secondary Outcome	Fidelity to intervention delivery and to implementation strategies: adherence to intervention procedures and implementation guide/manuals, adaptations, quality of implementation and intervention delivery.	From the start of intervention to the end of the project
Secondary Outcome	Contextual factors influencing intervention delivery and implementation (at individual, facility, health systems and community-level): barriers and facilitators.	From the start of intervention to the end of the project
Secondary Outcome	Sustained intervention delivery: 6 months post-intervention assessment of sustained use of the comprehensive TDA-based approach, including associated digital tools, at health facility, district, national and international level; barriers and facilitators to sustainability.	6 months post-intervention
Secondary Outcome	Cost analyses of the SOC and of the comprehensive TDA-based approach: ▪ Total TB care costs from the health system perspective. ▪ Unit cost per TB care activity (e.g. clinical assessment, CXR). ▪ Total TB care costs of overdiagnosis (false positive) - intervention only. ▪ Total costs incurred by parents/caregivers for receiving child TB care.	Throughout the project
Secondary Outcome	Cost-effectiveness of the comprehensive TDA-based approach compared to the SOC: ▪ Modelled health impact measure: ● Number of children treated for TB. ● Number of adults treated for TB. ● Number of deaths. ● Disability-Adjusted Life Years (DALYs): measure of healthy life lost, either through premature death or living with disability due to illness. ▪ Cost-effectiveness measure i.e. incremental cost per: ● Incremental number of children treated for TB. ● Death averted. ● DALY averted.	Throughout the project
Secondary Outcome	Budget impact of the comprehensive TDA-based approach scale up compared to the SOC over 5 years: ▪ Cost of scaling up the comprehensive TDA-based approach nationally. ▪ Cumulative number of children and adults treated for TB, lives saved, and DALYs averted during a 5-year scale-up.	Throughout the project
Secondary Outcome	Roles, practices and processes among implementers and decision-makers of the comprehensive TDA-based approach, including associated digital tools, at district-level.	Throughout the project
Secondary Outcome	Mechanism of translation of the research results and evidence on the comprehensive TDA-based approach, including associated digital tools, into public policies and practices: experience and perceptions of key stakeholders at regional, national and district-level.	At the end of the project

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
Roan Antelope General Hospital	Mpelembe Road, Section 1 Roan	Luanshya		Zambia
Mikomfwa Urban Health Centre	Luanshya Masiti Road	Luanshya		Zambia
Allessandras Urban Health Centre	Buntungwa Avenue. 90456	Luanshya		Zambia
Malaika Urban Health Centre	Along Masaiti Mpongwe Road	Luanshya		Zambia
Fisenge Urban Health Centre	Off Luanshya Road	Luanshya		Zambia
Kawama Urban Health Centre	Kawama Road	Luanshya		Zambia
Chaisa Urban Health Centre	Mpatamatu Road	Luanshya		Zambia
Thomson District Hospital	145, Lumumba Road	Luanshya		Zambia
Chawama Urban Health Centre	Chiwempala road	Chingola		Zambia
Kasompe Urban Health Centre	4th Lane	Chingola		Zambia
Muchinshi Rural Health Centre	Muchinshi along Solwezi road	Chingola		Zambia
Chiwempala Urban Health Centre	Mafuta Road	Chingola		Zambia
Nchanga 1 Urban Health Centre	off Mporokoso road, Nchanga North.	Chingola		Zambia
Kabundi East Urban Health Clinic	Sambilila Rd	Chingola		Zambia
Nchanga North Referal Hospital	Jumbe rd. Plot No, 927	Chingola		Zambia
Mtendere Mission Referal Hospital	Chirundu, Southern Province	Chirundu		Zambia
Hachipilika Rural Health Centre	Chirundu, Southern ProvinceRural Health Centre	Chirundu		Zambia
Chipepo Rural Health Centre	Chirundu, Southern Province	Chirundu		Zambia
Lusitu Rural Health Centre	Chirundu, Southern Province	Chirundu		Zambia
Kapululira Rural Health Centre	Chirundu, Southern Province	Chirundu		Zambia
Sikoongo Rural Health Centre	Chirundu, Southern Province	Chirundu		Zambia
Jamba Rural Health Centre	Chirundu, Southern Province	Chirundu		Zambia
Kalomo District Hospital	Boma road, Kalomo Southern Province	Kalomo		Zambia
Kalomo Urban Health Centre	Off Lusaka- Livingstone road , Kalomo Southern Province	Kalomo		Zambia
Namwianga Urban Health Centre	Kalomo Southern Province	Kalomo		Zambia
Mawaya Urban Health Centre	Off Lusaka- Livingstone road , Kalomo Southern Province	Kalomo		Zambia
Siachitema Rural Health Centre	Kalomo Southern Province	Kalomo		Zambia
Habulile Rural Health Centre	Kalomo, Southern Province	Kalomo		Zambia
Nkandanzovu Rural Health Centre	26.20162362/-16.57278453, Southern Province	Kalomo		Zambia

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
The European Commission as part of European and Developing Countries Clinical Trials Partnership EDCTP3 Horizon Europe 2020 program	Anna van Saksenlaan, 51 - 2593 HW The Hague, The Netherlands	Hague		Netherlands

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	University of Zambia School of Medicine	University Teaching Hospital Nationalist Rd P.O Box 50110, Ridgeway, Lusaka	Lusaka	10101	Zambia	University
Primary Sponsor	Instituto Nacional de Saude	Av. Eduardo Mondlane, No 1008 Ministerio da Saude PO Box 264, Maputo	Maputo		Mozambique	Research Institute

COLLABORATORS
Name	Street address	City	Postal code	Country
University of Bordeaux	Bordeaux Population Health, Inserm U1219, IRD EMR271 Universite de Bordeaux 146 Rue Leo Saignat, 33076 BORDEAUX Cedex	Bordeaux		France
University of Zambia School of Medicine	University Teaching Hospital Nationalist Rd P.O Box 50110, Ridgeway, Lusaka	Lusaka	10101	Zambia
Imperial College London	Department of Infectious Disease Imperial College London 235 Norfolk Place	London		United Kingdom
Institut de Recherche pour le Developpement	911, avenue Agropolis - BP64501 - 34394	Montpellier		France
Instituto Nacional de Saude	Av. Eduardo Mondlane, No 1008 Ministerio da Saude	Maputo		Mozambique
MInistry of Health National Tuberculosis and Leprosy Program	Ndeke House, Haile Selassie Avenue	Lusaka	10101	Zambia
Ministry of Health National Tuberculosis Program	Av. Eduardo Mondlane 1008.	Maputo		Mozambique
University of Stellenbosch	Francie van Zijl Drive Tygerberg 7505	Capetown		South Africa
The University of Sheffield	Firth Court. Western Bank Sheffield. S10 2TN	Sheffield South Yorkshire		United Kingdom
Eduardo Mondlane University	Praca 25 de Junho Caixa Postal 257	Maputo		Mozambique
Ludwig Maximilians Universitat	Geschwister-Scholl-Platz 1, 80539	Munich		Germany
Adera	Cite de la Photonique, Batiment GIENAH 11 avenue de Canteranne CS60040 33608	Pessac		France

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	Olivier Marcy	olivier.marcy@u-bordeaux.fr	+330557574723	Bordeaux Population Health, Inserm U1219, IRD EMR271 Universite de Bordeaux 146 Rue Leo Saignat, 33076 BORDEAUX Cedex
City	Postal code	Country	Position/Affiliation
Bordeaux		France	Research Director
Role	Name	Email	Phone	Street address
Principal Investigator	Chishala Chanda	cchabala@gmail.com	+26021250753	University of Zambia, School of Medicine. Department of Paediatrics and Child Health. Ridgeway Campus. Nationalist Road
City	Postal code	Country	Position/Affiliation
Lusaka	10101	Zambia	Paediatrician and Lecturer
Role	Name	Email	Phone	Street address
Principal Investigator	Joanna Orne Gliemann	joanna.orne-gliemann@u-bordeaux.fr	+330557574723	Bordeaux Population Health, Inserm U1219, IRD EMR271 Universite de Bordeaux, 146 Rue Leo Saignat, 33076 BORDEAUX Cedex.
City	Postal code	Country	Position/Affiliation
Bordeaux		France	Social Science Researcher
Role	Name	Email	Phone	Street address
Principal Investigator	James Seddon	james.seddon@imperial.ac.uk	+4402075943179	Department of Infectious Disease Imperial College London 235 Norfolk Place
City	Postal code	Country	Position/Affiliation
London		United Kingdom	Paediatrician
Role	Name	Email	Phone	Street address
Public Enquiries	Natasha Namuziya	natashanamuziya@gmail.com	+26021250753	University of Zambia School of Medicine. University Teaching Hospitals.Nationalist Rd
City	Postal code	Country	Position/Affiliation
Lusaka	10101	Zambia	Paediatrician and Honorary Lecturer
Role	Name	Email	Phone	Street address
Public Enquiries	Clementine Roucher	clementine.roucher@u-bordeaux.fr	+330557574723	Bordeaux Population Health, Inserm U1219, IRD EMR271 Universite de Bordeaux, 146 Rue Leo Saignat, 33076 BORDEAUX Cedex
City	Postal code	Country	Position/Affiliation
Bordeaux		France	Clinical Project Manager
Role	Name	Email	Phone	Street address
Public Enquiries	Katia Cossa	katia.cossa@ins.gov.mz	+25821311038	Instituto Nacional de Saude Av. Eduardo Mondlane, No 1008 Ministerio da Saude
City	Postal code	Country	Position/Affiliation
Maputo		Mozambique	Project Manager
Role	Name	Email	Phone	Street address
Scientific Enquiries	Olivier Marcy	olivier.marcy@u-bordeaux.fr	+330557574723	Bordeaux Population Health, Inserm U1219, IRD EMR271 Universite de Bordeaux 146 Rue Leo Saignat, 33076 BORDEAUX Cedex
City	Postal code	Country	Position/Affiliation
Bordeaux		France	Research Director
Role	Name	Email	Phone	Street address
Scientific Enquiries	Chishala Chabala	cchabala@gmail.com	+26021250753	University of Zambia, School of Medicine. Department of Paediatrics and Child Health. Ridgeway Campus. Nationalist Road
City	Postal code	Country	Position/Affiliation
Lusaka	10101	Zambia	Paediatrician and Lecturer
Role	Name	Email	Phone	Street address
Scientific Enquiries	Joanna Orne Gliemann	joanna.orne-gliemann@u-bordeaux.fr	+330557574723	Bordeaux Population Health, Inserm U1219, IRD EMR271 Universite de Bordeaux 146 Rue Leo Saignat, 33076 BORDEAUX Cedex
City	Postal code	Country	Position/Affiliation
Bordeaux		France	Social Science Researcher
Role	Name	Email	Phone	Street address
Scientific Enquiries	James Seddon	james.seddon@imperial.ac.uk	4402075943179	Department of Infectious Disease Imperial College London 235 Norfolk Place
City	Postal code	Country	Position/Affiliation
London		United Kingdom	Paediatrician

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	Individual participant data will be available after de-identifcation	Informed Consent Form,Statistical Analysis Plan,Study Protocol	Access to data will be given after the publication of the main study results based on global data	Data can be requested by Decide-TB consortium members and partners, as well as external research groups. Data can be utilised for secondary studies of the Decide-TB project, country-specific analyses, contributions to individual data meta-analyses, and analyses unrelated to the Decide-TB project's study topic. The request for data access must be submitted to the publication committee together with a concept paper detailing the analysis or study's aims, how the data will be utilised, the list of data or material requested, and how the original authors will be credited. Once the application is granted, data will be shared in accordance to a data and/or material sharing agreement that secures the terms of use.
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
https://decide-tb.com	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

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