Ignite Creation Date:
2024-05-06 @ 3:06 PM
Last Modification Date:
2024-10-26 @ 1:43 PM
Study NCT ID:
NCT04528823
Status:
COMPLETED
Last Update Posted:
2023-07-17
First Post:
2020-07-13
Brief Title:
GXT - GeneXpert or Chest-X-ray or Tuberculin Skin Testing for Household Contact Assessment
Sponsor:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Organization:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Study Overview
Official Title:
GXT - GeneXpert or Chest-X-ray or Tuberculin Skin Testing for Household Contact Assessment a Cluster Randomized Trial
Status:
COMPLETED
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The objective of the study is to compare outcomes from three different strategies for the management of household HH contacts of individuals with newly diagnosed microbiologically confirmed active pulmonary TB The study is a cluster randomized trial with three arms of equal size The first eligible member of the HH who provides signed informed consent to participate will be randomized to one of the three strategies The three different study arms are as follows
1 Standard care control arm Participants will receive symptom screening and tuberculin skin testing TST If symptom screen positive andor TST positive they undergo chest x-rays CXR If CXR abnormal they undergo microbiological investigation If CXR normal or if microbiological investigation negative TST positive receive latent TB infection LTBI treatment If microbiological investigation is positive they will be offered treatment for active TB For children under 5 years of age in Brazil sputum induction will be performed for bacteriological investigation
2 GeneXpert GX Participants follow an algorithm similar to the standard care however participants with positive symptom screen andor positive TST will receive GX ie GX replaces CXR in standard care algorithm GX positive are considered to have active TB TST positive and GX negative receive LTBI treatment If an individual is not able to provide sputum they will undergo a CXR
3 CXR for allNoTST Participants will receive symptom screening and CXR No TST will be performed If CXR abnormal or symptom positive they undergo microbiological investigation If the CXR is normal andor microbiological investigations negative - they receive LTBI treatment as per national guidelines If microbiological investigation is positive they will be offered treatment for active TB
The study population includes HIV uninfected persons aged 5-50 years who are HH contacts of individuals with newly diagnosed microbiologically confirmed active pulmonary TB The planned number of household contacts to recruit is about 1434 in total or about 455 for each of the three arms The study will take place in Benin and Brazil
The primary study outcome is of those eligible for LTBI therapy the proportion starting therapy within 3 months of the index TB patient starting active TB treatment Secondary outcomes measured in each study arm include societal costs prevalence of microbiologically confirmed and clinically diagnosed active TB prevalence of TB infection Incidence of adverse events proportion who complete LTBI therapy sensitivity and specificity of Chest Xray reading in each study side and prevalence of active TB diagnosed using CXR in participants who cannot produce a sputum sample Details of the statistical analysis plan for each primary and secondary outcome are provided below Applicable for Brazil only To evaluate the applicability and performance of material for bacteriological investigation obtained from induced sputum in children under 5 years of age
Study participants will be recruited over 18 months Participants will be followed until LTBI treatment is completed
1 Standard care control arm Participants will receive symptom screening and tuberculin skin testing TST If symptom screen positive andor TST positive they undergo chest x-rays CXR If CXR abnormal they undergo microbiological investigation If CXR normal or if microbiological investigation negative TST positive receive latent TB infection LTBI treatment If microbiological investigation is positive they will be offered treatment for active TB For children under 5 years of age in Brazil sputum induction will be performed for bacteriological investigation
2 GeneXpert GX Participants follow an algorithm similar to the standard care however participants with positive symptom screen andor positive TST will receive GX ie GX replaces CXR in standard care algorithm GX positive are considered to have active TB TST positive and GX negative receive LTBI treatment If an individual is not able to provide sputum they will undergo a CXR
3 CXR for allNoTST Participants will receive symptom screening and CXR No TST will be performed If CXR abnormal or symptom positive they undergo microbiological investigation If the CXR is normal andor microbiological investigations negative - they receive LTBI treatment as per national guidelines If microbiological investigation is positive they will be offered treatment for active TB
The study population includes HIV uninfected persons aged 5-50 years who are HH contacts of individuals with newly diagnosed microbiologically confirmed active pulmonary TB The planned number of household contacts to recruit is about 1434 in total or about 455 for each of the three arms The study will take place in Benin and Brazil
The primary study outcome is of those eligible for LTBI therapy the proportion starting therapy within 3 months of the index TB patient starting active TB treatment Secondary outcomes measured in each study arm include societal costs prevalence of microbiologically confirmed and clinically diagnosed active TB prevalence of TB infection Incidence of adverse events proportion who complete LTBI therapy sensitivity and specificity of Chest Xray reading in each study side and prevalence of active TB diagnosed using CXR in participants who cannot produce a sputum sample Details of the statistical analysis plan for each primary and secondary outcome are provided below Applicable for Brazil only To evaluate the applicability and performance of material for bacteriological investigation obtained from induced sputum in children under 5 years of age
Study participants will be recruited over 18 months Participants will be followed until LTBI treatment is completed
Detailed Description:
Background
At a recent United Nations high level conference on TB a target was set that more than 30 million individuals should be treated for LTBI over the next 5 years This ambitious goal will require massive scaling up of LTBI diagnosis and treatment - which will be challenging if not impossible with current approaches to diagnosis and treatment of latent TB Two aspects of management of LTBI - need for CXR and need for TST - are controversial as both can create important barriers to LTBI initiation thereby reducing the individual as well as public health benefits of treatment For TST difficulties in training and quality assurance of administration and reading and a global shortage of tuberculin material have reduced uptake CXR was recommended by WHO in its 2018 guidelines for LTBI management as part of investigations to rule our active TB however CXR services are not accessible in many settings and even if accessible the cost for a CXR often falls on patients and is often prohibitively expensive An alternate strategy is to use GeneXpert equipment with the Xpert MTBRif test hereafter labelled GX to replace CXR to exclude prevalent active TB
Study Objectives
To compare outcomes from three different strategies for the management of HIV uninfected persons aged 5-50 years who are HH contacts of newly diagnosed microbiologically confirmed active pulmonary TB 0-5 years only in Brazil
Design
This will be a cluster randomized trial with three arms of equal size clusters will be defined as all the household contacts of patients with newly diagnosed active pulmonary TB The first eligible member of the HH who provides signed informed consent to participate will be randomized to one of the three strategies All subsequently enrolled members of the same HH will be assigned to the same study arm
Study participants will be randomized to one of three different study arms
1 Standard care control arm Participants will receive symptom screening and tuberculin skin testing TST If symptom screen positive andor TST positive they undergo chest x-rays CXR If CXR abnormal they undergo microbiological investigation If CXR normal or if microbiological investigation negative TST positive receive latent TB infection LTBI treatment If microbiological investigation is positive they will be offered treatment for active TB For children under 5 years of age in Brazil sputum induction will be performed for bacteriological investigation
2 GeneXpert GX Participants follow an algorithm similar to the standard care however participants with positive symptom screen andor positive TST will receive GX ie GX replaces CXR in standard care algorithm GX positive are considered to have active TB TST positive and GX negative receive LTBI treatment If an individual is not able to provide sputum they will undergo a CXR
3 CXR for allNoTST Participants will receive symptom screening and CXR No TST will be performed If CXR abnormal or symptom positive they undergo microbiological investigation If the CXR is normal andor microbiological investigations negative - they receive LTBI treatment as per national guidelines If microbiological investigation is positive they will be offered treatment for active TB
Population and Setting
HIV uninfected persons aged 5-50 years who are household contacts newly diagnosed microbiologically confirmed active pulmonary TB can participate in the study The planned number of household contacts to recruit is about 1434 in total or about 455 for each of the three arms The study will take place in five cities in two countries Benin Cotonou and Porto Novo and Brazil Rio de Janeiro Manaus and Porto Alegre In each city clinics will be selected that are representative of the diagnostic facilities and capacities available in most clinics in the country For Brazil only they will include under 5 HIV uninfected
Study duration
Study participants will be recruited over a period of 18 months Participants will be followed until LTBI treatment is completed 4-6 months depending on what treatment is given
Outcomes
Primary Outcome
Of those eligible measured or estimated for LTBI therapy the proportion starting therapy within 3 months of the index TB patient starting active TB treatment
Secondary outcomes
1 Societal costs health system and patient costs of the full cascade of care - from initial identification to LTBI therapy completion
2 Prevalence of microbiologically confirmed and clinically diagnosed active TB - detected as part of the initial contact investigation who initiate LTBI treatment within 3 months of the index TB patient starting active TB treatment
3 Prevalence of positive TST 5 mm or 10 mm - overall and by age group
4 Incidence of grade 1-4 adverse events related to LTBI therapy
5 Proportion who complete LTBI therapy - defined as having taken at least 80 of doses in 120 of allowed time
6 Sensitivity and specificity of CXR reading by usual providers in each study site reference standard will be readings by external reviewers
7 Prevalence of active TB diagnosed using CXR in participants who cannot produce a sputum sample
8 Applicable for Brazil only To evaluate the applicability and performance of material for bacteriological investigation obtained from induced sputum in children under 5 years of age
Statistical analyses
Primary analysis The primary outcome is the proportion starting LTBI therapy of those eligible measured or estimated for latent TB therapy Eligible will be defined as aged 5-50 years HIV uninfected and TST 5mm For the no TST arm the expected prevalence for HIV uninfected HH contacts aged 5 years and older will be estimated from age-specific prevalence of positive TST among HH contacts tested in the other two arms This expected prevalence will be used to estimate the proportion eligible for LTBI therapy in the no TST arm Treatment initiation will be defined as being given a prescription for LTBI therapy or dispensed the first month of pills needed for LTBI therapy Since this is a dichotomous outcome the primary analysis will be a logistic regression using an identity link and estimated via generalized estimating equations GEE to account for clustering by household An exchangeable correlation structure and empirical standard errors will be used The proportion starting LTBI therapy within 3 months of the index TB patient starting active TB treatment will be compared in each experimental arm against the standard arm
Secondary analyses
1 Societal costs health system and patient costs of the full cascade of care - from initial identification to LTBI therapy completion will be considered Using all relevant cost components and an ingredients approach differences in health system costs will be assessed for each of the strategies Patient time will be valuated based on an assumption of income equivalent to the average per capita income in the country Health care personnel time will be valuated based on average salaries from information provided by facility management in each setting
2 Prevalence of microbiologically confirmed and clinically diagnosed active TB - detected as part of the initial contact investigation who initiate LTBI treatment within 3 months of the index TB patient starting active TB treatment will be compared between all three arms
3 Prevalence of positive TST 5 mm or 10 mm cut-points by age group - 0-4 for Brazil only 5-10 11-17 18-24 25-34 years and older in Standard and GX Strategies This is simple descriptive analysis - and will be presented as overall prevalence in the specified age groups plus stratified by country
4 Incidence of serious adverse events related to LTBI therapy Adverse events are relatively rare dichotomous outcomes As such Poisson regression will be used to compare the occurrence of the adverse events between each of the two experimental arms and the conventional arm To account for clustering by household GEE with an exchangeable correlation structure and empirical standard errors will be used Investigators will compare in the same way - the occurrence of grade 1-2 adverse events reported by study investigators
5 Completion of LTBI therapy - defined as taking at least 80 of doses in 120 of allowed time For 6H this means taking at least 144 doses within 216 days for 4R this means 96 doses within 144 days and for 3HR - 72 doses within 108 days Since this is a dichotomous outcome the primary analysis will use logistic regression with an identity link and estimated via GEE to account for clustering by household An exchangeable correlation structure and empirical standard errors will be used The proportion completing treatment in each experimental arm against the standard arm will be compared
6 Sensitivity and specificity of CXR reading by usual providers in each study site For this analysis the reference standard will be the readings by the external CXR review
7 Active TB - defined as treatment initiated for active TB - detected only as a result of the CXR done in persons who could not produce a sputum sample
At a recent United Nations high level conference on TB a target was set that more than 30 million individuals should be treated for LTBI over the next 5 years This ambitious goal will require massive scaling up of LTBI diagnosis and treatment - which will be challenging if not impossible with current approaches to diagnosis and treatment of latent TB Two aspects of management of LTBI - need for CXR and need for TST - are controversial as both can create important barriers to LTBI initiation thereby reducing the individual as well as public health benefits of treatment For TST difficulties in training and quality assurance of administration and reading and a global shortage of tuberculin material have reduced uptake CXR was recommended by WHO in its 2018 guidelines for LTBI management as part of investigations to rule our active TB however CXR services are not accessible in many settings and even if accessible the cost for a CXR often falls on patients and is often prohibitively expensive An alternate strategy is to use GeneXpert equipment with the Xpert MTBRif test hereafter labelled GX to replace CXR to exclude prevalent active TB
Study Objectives
To compare outcomes from three different strategies for the management of HIV uninfected persons aged 5-50 years who are HH contacts of newly diagnosed microbiologically confirmed active pulmonary TB 0-5 years only in Brazil
Design
This will be a cluster randomized trial with three arms of equal size clusters will be defined as all the household contacts of patients with newly diagnosed active pulmonary TB The first eligible member of the HH who provides signed informed consent to participate will be randomized to one of the three strategies All subsequently enrolled members of the same HH will be assigned to the same study arm
Study participants will be randomized to one of three different study arms
1 Standard care control arm Participants will receive symptom screening and tuberculin skin testing TST If symptom screen positive andor TST positive they undergo chest x-rays CXR If CXR abnormal they undergo microbiological investigation If CXR normal or if microbiological investigation negative TST positive receive latent TB infection LTBI treatment If microbiological investigation is positive they will be offered treatment for active TB For children under 5 years of age in Brazil sputum induction will be performed for bacteriological investigation
2 GeneXpert GX Participants follow an algorithm similar to the standard care however participants with positive symptom screen andor positive TST will receive GX ie GX replaces CXR in standard care algorithm GX positive are considered to have active TB TST positive and GX negative receive LTBI treatment If an individual is not able to provide sputum they will undergo a CXR
3 CXR for allNoTST Participants will receive symptom screening and CXR No TST will be performed If CXR abnormal or symptom positive they undergo microbiological investigation If the CXR is normal andor microbiological investigations negative - they receive LTBI treatment as per national guidelines If microbiological investigation is positive they will be offered treatment for active TB
Population and Setting
HIV uninfected persons aged 5-50 years who are household contacts newly diagnosed microbiologically confirmed active pulmonary TB can participate in the study The planned number of household contacts to recruit is about 1434 in total or about 455 for each of the three arms The study will take place in five cities in two countries Benin Cotonou and Porto Novo and Brazil Rio de Janeiro Manaus and Porto Alegre In each city clinics will be selected that are representative of the diagnostic facilities and capacities available in most clinics in the country For Brazil only they will include under 5 HIV uninfected
Study duration
Study participants will be recruited over a period of 18 months Participants will be followed until LTBI treatment is completed 4-6 months depending on what treatment is given
Outcomes
Primary Outcome
Of those eligible measured or estimated for LTBI therapy the proportion starting therapy within 3 months of the index TB patient starting active TB treatment
Secondary outcomes
1 Societal costs health system and patient costs of the full cascade of care - from initial identification to LTBI therapy completion
2 Prevalence of microbiologically confirmed and clinically diagnosed active TB - detected as part of the initial contact investigation who initiate LTBI treatment within 3 months of the index TB patient starting active TB treatment
3 Prevalence of positive TST 5 mm or 10 mm - overall and by age group
4 Incidence of grade 1-4 adverse events related to LTBI therapy
5 Proportion who complete LTBI therapy - defined as having taken at least 80 of doses in 120 of allowed time
6 Sensitivity and specificity of CXR reading by usual providers in each study site reference standard will be readings by external reviewers
7 Prevalence of active TB diagnosed using CXR in participants who cannot produce a sputum sample
8 Applicable for Brazil only To evaluate the applicability and performance of material for bacteriological investigation obtained from induced sputum in children under 5 years of age
Statistical analyses
Primary analysis The primary outcome is the proportion starting LTBI therapy of those eligible measured or estimated for latent TB therapy Eligible will be defined as aged 5-50 years HIV uninfected and TST 5mm For the no TST arm the expected prevalence for HIV uninfected HH contacts aged 5 years and older will be estimated from age-specific prevalence of positive TST among HH contacts tested in the other two arms This expected prevalence will be used to estimate the proportion eligible for LTBI therapy in the no TST arm Treatment initiation will be defined as being given a prescription for LTBI therapy or dispensed the first month of pills needed for LTBI therapy Since this is a dichotomous outcome the primary analysis will be a logistic regression using an identity link and estimated via generalized estimating equations GEE to account for clustering by household An exchangeable correlation structure and empirical standard errors will be used The proportion starting LTBI therapy within 3 months of the index TB patient starting active TB treatment will be compared in each experimental arm against the standard arm
Secondary analyses
1 Societal costs health system and patient costs of the full cascade of care - from initial identification to LTBI therapy completion will be considered Using all relevant cost components and an ingredients approach differences in health system costs will be assessed for each of the strategies Patient time will be valuated based on an assumption of income equivalent to the average per capita income in the country Health care personnel time will be valuated based on average salaries from information provided by facility management in each setting
2 Prevalence of microbiologically confirmed and clinically diagnosed active TB - detected as part of the initial contact investigation who initiate LTBI treatment within 3 months of the index TB patient starting active TB treatment will be compared between all three arms
3 Prevalence of positive TST 5 mm or 10 mm cut-points by age group - 0-4 for Brazil only 5-10 11-17 18-24 25-34 years and older in Standard and GX Strategies This is simple descriptive analysis - and will be presented as overall prevalence in the specified age groups plus stratified by country
4 Incidence of serious adverse events related to LTBI therapy Adverse events are relatively rare dichotomous outcomes As such Poisson regression will be used to compare the occurrence of the adverse events between each of the two experimental arms and the conventional arm To account for clustering by household GEE with an exchangeable correlation structure and empirical standard errors will be used Investigators will compare in the same way - the occurrence of grade 1-2 adverse events reported by study investigators
5 Completion of LTBI therapy - defined as taking at least 80 of doses in 120 of allowed time For 6H this means taking at least 144 doses within 216 days for 4R this means 96 doses within 144 days and for 3HR - 72 doses within 108 days Since this is a dichotomous outcome the primary analysis will use logistic regression with an identity link and estimated via GEE to account for clustering by household An exchangeable correlation structure and empirical standard errors will be used The proportion completing treatment in each experimental arm against the standard arm will be compared
6 Sensitivity and specificity of CXR reading by usual providers in each study site For this analysis the reference standard will be the readings by the external CXR review
7 Active TB - defined as treatment initiated for active TB - detected only as a result of the CXR done in persons who could not produce a sputum sample
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None