Ignite Creation Date:
2024-06-16 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 3:31 PM
Study NCT ID:
NCT06437184
Status:
RECRUITING
Last Update Posted:
2024-05-31
First Post:
2024-05-26
Brief Title:
Increased Tuberculosis Case Detection - DiOpTB
Sponsor:
Aarhus University Hospital
Organization:
Aarhus University Hospital
Study Overview
Official Title:
Increased Tuberculosis Case Detection - a Cluster-randomized Trial Combining Available Resources and Novel Strategies for High Endemic Areas
Status:
RECRUITING
Status Verified Date:
2024-07
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:
DiOpTB
Brief Summary:
As estimated by the WHO 106 million new Tuberculosis TB cases were identified in 2022- while more than three million went undetected and untreated The low detection rate illustrates the failure to recognise and diagnose TB in the current cascade of healthcare and is a major obstacle to effective TB control programs This multi-centre cluster-randomised clinical trial will evaluate the effect ie diagnostic yield of improving the point-of-care diagnostics already in place in most primary health-care centres in low-resource settings The present study will be conducted in two different geographical settings in the Western and Eastern African countries of Guinea Bissau and Ethiopia This improved clinical diagnostic pathway may improve case detection rates at primary healthcare level ensuring prompt commencement of treatment thereby diminishing transmission risk in the community and improving treatment outcomes The Optimized Diagnostic Procedure ODP will utilize instructed sputum sampling and pooling as well as computer-aided detection CAD chest X-ray CXR and additional pooled sputum sample as well as non-sputum sampling faecal and a buccaltongue swab and saliva for GeneXpert Ultra PCR Xpert as state-of-the-art add-ons to the routine diagnostic pathway for TB This adds to the key components of the WHO End TB strategy - early diagnosis - and if successful may be rapidly approved by the WHO and implemented by governments globally with potentially major public health benefits
The study will be conducted in close liaison with the national Ministries of Health and TB programs in Guinea-Bissau and Ethiopia This will facilitate any relevant findings to be taken forward for implementation into policy and practice Capacity development training and educational activities will be closely aligned to this study
The study will be conducted in close liaison with the national Ministries of Health and TB programs in Guinea-Bissau and Ethiopia This will facilitate any relevant findings to be taken forward for implementation into policy and practice Capacity development training and educational activities will be closely aligned to this study
Detailed Description:
2 Objectives 21 Primary objective
1 Diagnostic yield of active TB within ten days comparing Enhanced Usual Diagnostic Procedure EUDP to Optimized Diagnostic Procedure ODP
22 Secondary objectives
1 Number of patients treated for TB within two weeks comparing EUDP to ODP
2 The additional diagnostic yield of CAD CXR compared to Xpert and culture
3 Improved follow-up FU rates in the cascade of care ie one week and six months FU for all included and treatment start and outcome for all TB diagnosed
4 Differences in diagnostic yield of active TB between routine sputum samples instructed sputum samples and non-sputum samples faecal and saliva combined with buccaltongue swabs
5 Feasibility of including Oxford Nanopore sequencing for detection and molecular resistance patterns measured as rate of analysed samples within two weeks
3 Background In 2022 the WHO estimated that of a total 106 million new TB cases more than three million went undiagnosed and of the remaining seven million only 57 were bacteriologically confirmed 1 In sub-Saharan African settings such as Ethiopia and Guinea Bissau smear microscopy remains the major diagnostic tool in most areas despite the rollout of rapid diagnostic tests such as Xpert In a multi-centre trial by Theron et al the implementation of Xpert in African settings did indeed reduce diagnostic delay but unfortunately without any effect on the numbers who were initiated on TB treatment nor on mortality 2 The trial showed that Xpert rollout was not superior to enhanced well-equipped microscopy-based diagnostic facilities In an editorial to the Lancet written by our group it was concluded that TB elimination could be better advanced by improving currently available tools than by expanding Xpert testing to peripheral health facilities 2 3 Nevertheless when TB is diagnosed with a point of care test there is a need to ensure that correct treatment is provided However culture-based drug susceptibility testing is very scarce in high endemic areas and often takes several weeks or months to perform 4 Recently the Cryptic study 5 has shown that genotypic drug susceptibility testing gDST may guide treatment with a sensitivity and specificity well above 90 for key drugs New techniques such as MinION Oxford Nanopore Technologies have also made it possible to perform sequencing and gDST directly from sputum samples Such point-of-care-based sequencing technology is comparable in size to a USB flash drive 6 and may be attached to a laptop computer at a health centre in a high endemic area
A cluster-randomised trial implementing the TBscore recently showed a fourfold increase in case detection rate in Ethiopia but not in Guinea-Bissau 7 It identified that factors such as laboratory capacity and routines in collecting and examining sputum smear samples may have a high impact on case detection rate and could be optimized based on the available resources Surprisingly the sensitivity of sputum smear microscopy ranges from 20-80 with an average of about 50 8 which may partly be due to patient selection but also depend on considerable variability in sputum collection strategies andor laboratory procedures In a comparison of sputum collection methods by Datta et al 9 pooling of sputum and structured instructions before sampling on average led to a twofold higher diagnostic yield whereas a spot versus morning sample showed no difference A multi-centre study including Ethiopia comparing fluorescence microscopy to conventional light microscopy showed a small but significant increase in sensitivity 728 vs 65810 Further recent research has shown that buccal and tongue swabs that are easily obtained can hold valuable diagnostic potential 11 In smear-negative patients with presumed TB the available diagnostic tools in high endemic countries include CXR but standardized procedures for evaluation of CXR have been scarce Recently CAD software based on artificial intelligence algorithms such as qXR Qureai India have improved detection of microbiologically confirmed TB from 50-60 by experienced radiologists to 70-84 with a specificity of 80 by CAD 12 However a recent systematic review concluded as did the WHO that there are too few high-quality studies to fully assess its diagnostic accuracy 13 We now propose to conduct a multi-centre cluster-randomised clinical trial to evaluate whether improvements on available diagnostic resources can increase the diagnostic yield of active TB and decrease mortality for patients diagnosed with TB
4 Methods 41 Location and nature of sites The present study will be conducted in two African countries Guinea-Bissau and Ethiopia In Bissau the capital of Guinea-Bissau The Bandim Health Project has been a Health and Demographic Surveillance Site HDSS for 45 years and has a well-defined study population of approximately 100000 under continued surveillance Within the study area there are two health centres HCs from where patients with presumed TB will be enrolled Bandim HC Belem HC
In Ethiopia the study will be conducted in collaboration with the University of Gondar in the region of North-Gondar which has a population of more than two million Two health centres located in North Gondar Zone namely Azezo HC and Gondar HC will participate The Gondar University Hospital is a teaching and referral hospital and will be used for further management of severe TB cases during this study
42 Epidemiology and study population 421 Guinea-Bissau The epidemiology of TB in the Bissau study population has been extensively described 14-18 The overall incidence of TB has declined only slightly since 2004 and was estimated at 273100000 population in 2020 while TBHIV co-infection declined from 108 per 100000 to 14 per 100000 over the period 19 Smear negative cases and case fatality rate likewise declined over the period The incidence of smear positive TB remained stable at 188 per 100000 between 2004 and 2011 20 All HCs have basic laboratory facilities to carry out sputum smear microscopy and all provide TB treatment The national referral hospital for TB Hospital Raoul Follereau is located adjacent to the study area and is a close collaborating partner The incidence rate of TB in Guinea-Bissau as a whole is 361 per 100000 with a case detection rate estimated at 35 21 22
422 Ethiopia TB continues to be a major public health concern in Ethiopia fuelled by the expansion of the HIV epidemic since the 1990s According to the 2022 WHO TB report 1 Ethiopia is among high-burden countries for both TB and TBHIV and has an estimated incidence rate of 119 per 100000 and a TB mortality of 177 per 100000 21 HIV-positive TB incidence is 62 per 100000 and case detection rate is currently estimated at 73 21 22 These figures are high considering that Ethiopia is the second most populous country in Africa with an estimated total population size of more than 100 million HIV screening is carried out as a routine
43 Design The present study is designed as an open-label stepped-wedge cluster-randomised controlled trial 23 to investigate an optimized diagnostic procedure for active TB in healthcare centres in Guinea-Bissau and Ethiopia Applying the stepped-wedge design ensures that all participating HCs will implement the intervention during the study period This design is particularly useful for evaluating the population-level impact of an intervention which is of interest in this study All clusters ie HCs start with Enhanced Usual Diagnostic Procedure EUDP and are then randomized to switch to the intervention phase at predefined time points see table 1
See below for detailed description of sample size calculations
44 Bandim TBscore The Bandim TBscore TBscore Table 2 consists of five symptoms cough haemoptysis dyspnoea chest pain and night sweats and six signs pale inferior conjunctivae pulse 100 per minute positive finding at lung auscultation temperature 37C axillary body mass index BMI 1816 and mid-upper-arm circumference MUAC 220 mm200 mm 24 Each variable contributes one point while BMI and MUAC contribute an additional point if BMI16MUAC200 mm hence the maximum score is 13 The score divides patients into three severity classes SC SC-I TBscore 0-5 SC-II TBscore 6-7 and SC-III TBscore8 A simplified version of the score - TBscoreII - with a maximum score of 8 points has also been developed 25 The advantage of the latter score is that it can be performed without a physician present The TBscore has been assessed in both Gondar and Bissau and found to be a useful add on in the diagnostic cascade of care7
45 Buccal tongue swap and saliva sample Buccal and tongue samples will be collected using the Omniswab Whatman catalogue WB100035 and added to a container where patients leave a saliva sample Samples will be collected by trained laboratory staff who gently brush the inside of each cheek and then the tongue of the participant for 10 seconds with the OmniSwab The OmniSwab has a breakpoint and the head will be ejected into 500 µl buffer containing 50 mM Tris pH 80 50 mM EDTA 50 mM sucrose 100 mM NaCl and 1 SDS and transported to the laboratory at 4C 11 There the OmniSwab-collected samples will be vortexed in the saliva and the swabs heads removed One part of the sample will be analyzed using Xpert Ultrawhile the other part will be stored at - 80 C until further processing
46 Computer-aided detection chest X-ray CAD CXR applying artificial intelligence AI A preliminary study using an AI based CAD CXR software qXR Qure compared to two Ethiopian radiologists included 498 CXRs from a previously performed randomized controlled trial on the TBscore Of those the less experienced radiologist found 50 the more experienced radiologist found 100 and CAD CXR found 83 to be indicative of TB Using Xpert PCR as the gold standard for TB diagnosis the overall AUC for the CAD CXR was 084 while the less experienced radiologist performed at a sensitivity of 414 and a specificity of 941 and the experienced radiologists assessments were 552 sensitive and 850 specific The agreement between the radiologists was moderate kappa045 as was the agreement between each radiologist and the software kappa036 kappa059
In the present study we will include a mobile phone app to guide photographing analog X-ray films These photographs will then be uploaded to a locally placed box qbox and analyzed on site
47 Enrolment At all sites adult patients will be screened during consultations carried out at primary healthcare centres All patients presenting with cough of any duration sputum production or weight loss will have their TBscore assessed All participating health centres have previous experience collecting the symptoms and signs necessary for the TBscore and completing a score chart from which the TBscore can be calculated All patients with a TBscore4 will be referred for TB diagnostics Patients with 4TBscore6 will be referred to fluorescence microscopy while patients with TBscore6 will be referred to Xpert PCR The staff at the sites will receive general training in TB diagnosis and then the healthcare facilities will following a random sequence switch from Enhanced Usual Diagnostic Procedure EUDP consisting of standard TB program diagnostics but ensuring availability of all reagents to intervention ie OPD
471 Enhanced Usual Diagnostic Procedure EUDP The standard TB diagnostics in both settings consist of performing the sputum smear analysis by the clinical routine Smear-negative cases will be followed as per standard routine Figure 1A
472 The Optimized Diagnostic Procedure ODP intervention
A three-step package which involves Figure 1B
1 Oral and mobile phone-guided instructions by study staff Patients will be instructed to take several deep breaths hold their breath for a moment and repeat this several times until coughing is induced including instructions to cough deeply and vigorously whilst breathing out 26 Instructions will be presented to the participating patients on a mobile phone to ensure consistent instructions to all participants
2 Pooling of two spot sputum samples 9 Two instructed pooled spot samples will be split into two parts 27 and investigated by fluorescence microscopy 28 The other part of the pooled sputum sample will be frozen for later confirmation with batch-wise BACTEC 960 MGIT as a gold standard for microbiological diagnosis
As an add on we will analyze a subgroup of samples with the MinION to assess applicability in a low resource setting
3 Smear-negative cases at the first visit will be assessed for persisting symptoms and referred to a CXR unit Those with a CXR CAD result suggestive of active TB will be treated for TB The smear negative cases will also leave an additional instructed spot sputum sample which will be pooled and one part analyzed by Xpert Ultra and the other part by BACTEC 960 MGIT culture Additionally non-sputum sampling will be performed and analyzed by Xpert Ultra including saliva combined with buccal and tongue sample using the same swab as well as a faecal sample Xpert Ultra using the WHO-recommended direct procedure 29 In a feasibility study on the basis of intention to treat either by smear microscopy or CXRclinical grounds the participants will be asked for an additional instructed sputum sample which will extracted using EZ1 and sequenced using nanopore sequencing and the EPI2ME bioinformatic platform as previously described 6 473 Implementation of the ODP and EUDP Upon commencement of the intervention arm the staff will be trained in applying optimized diagnostic procedures
For all included patients both in the EUDP and the ODP a follow-up visit one week from first encounter will take place to ensure initiation of treatment for smear positive cases or to screen for persisting symptoms and carry out a second clinical evaluation smear negative cases Diagnosis will be according to local standards and based on smear microscopy CXR and WHO clinical criteria including for extrapulmonary cases 30 31 During the intervention the physician can overrule the TBscore if needed At all clinics both in the EUDP and ODP ie intervention phase all included patients will be referred to HIV testing at adjacent HIV-treatment clinics where pre- and post-testing counselling will be carried out
6 Sample size and statistical analyses Based on a previous study in the same setting we found that among patients with a TBscore3 there were a total of 5 smear positive cases both in Guinea-Bissau and Ethiopia Using a higher cut-off value at TBscore4 increases specificity and is estimated to increase the case detection yield to 6 based on previous data using routine sputum collection and sputum smear analysis Increasing the TBscore cut-off value thus leads to a lower referral rate of 54 of all screened instead of 73 while increasing the number of smear positive cases in the sample from 5 to 6 As both settings now use Xpert MTBRIF Ultra as the primary diagnostic method initial case rate is estimated at 8 32 Based on systematic reviews it is estimated that the diagnostic yield of an instructed sputum where two spot-samples are pooled and processed using LED microscopy will lead to an at least twofold increase in sensitivity 9 10 27 33 Adding CAD CXR onto those that are smear negative by the optimized sputum smear strategy is estimated to increase the number of patients diagnosed with TB 25-fold To show an increase in diagnostic yield using ODP from a conservative estimate of 7 to 14 with a power of 80 and a significance level of 005 two clusters in each country are needed including 132 patients per time interval of 22 weeks The estimated inclusion rate per cluster per week is 6 patients which means that it should take 66 weeks to reach a target of 1584 inclusions
Sample size was calculated using the steppedwedge function in Stata 34 The diagnostic yield time to diagnosis and treatment outcomes will be calculated
Detection rates will be compared between control EUDP and intervention ODP in a generalized linear mixed effects model taking into account time and center effect and allowing for intra-cluster correlation ie a mixed effect logistic regression for longitudinal data A similar repeated measurements model will be used to analyze and compare groups on patient characteristics
7 Timeframe Study preparations will start August 2023 with establishment of enrolment procedures and training of staff Enrolment will take place for 68 weeks from June 2024 to September 2025 End of follow-up will be April 2026 For details please see Table 3 Overall responsible body for activities planned is the PI in collaboration with local VIP and TAP personnel
8 Public health importance 81 Major advances TB case-finding remains a challenge particularly in overburdened healthcare facilities with limited access to diagnostics 35-37 A simple disease management strategy combined with improved utilization of available diagnostics may ensure that more patients with TB are treated and earlier and that those at high risk of dying are targeted appropriately with a rational use of limited resources The major advance of adding a standardized approach to patients with presumed TB will be to decrease the substantial burden of undiagnosed TB with simple means which makes it a sustainable affordable and practicable tool
82 New approach The strength of the Bandim TBscore strategy is that it guides the health care professional through a structured interview and uses the existing laboratory set-up which is of great benefit compared to other more advanced diagnostic tools The diagnostic algorithm simply utilizes what is already part of the primary healthcare setup thereby increasing the chance of being applicable in similar settings worldwide Similarly the novel technologies employed in the ODP can easily be integrated into clinical settings worldwide
83 Generalizability of trial results This trial will test implementation of a cheap readily available practical point-of-care package which requires only minor additional training of staff If shown to be effective in identifying additional TB cases use of the Bandim TBscore and improved diagnostics may be expected to be endorsed with little delay by the WHO and national governments as a standard part of TB diagnosis and management
84 Contribution to improved disease management and public health In under-funded over-burdened healthcare facilities with a large patient load presenting with co-morbidities many patients with TB remain undiagnosed and untreated 35-37 Simple clinical tools at points of care which can identify up patients with active TB may have great potential for diagnosing patients with TB early and thereby preventing TB-associated morbidity and mortality Targeting delayed TB diagnosis and TB-related mortality will add to the agenda of reducing poverty-related diseases The resources used to combat TB and the productive years lost to TB inflict a punishing toll on the economies of TB-endemic countries and helps perpetuate the cycle of poverty The majority of TB is now concentrated in the Worlds poorest countries thus effective and practicable programs to detect and cure TB early is the most feasible method of controlling the disease
85 Improvements in patient care A major strength of the Bandim TBscore is its ability to continually assess disease severity during treatment as has previously been shown by our group 25 38 39 Thus the score may be used both to enhance the number of confirmed TB cases among patients with presumed TB and serve as an easily adaptable monitoring tool during the treatment or re-evaluation of these
9 Ethical considerations Consultative approval is expected to be granted from the Regional Ethics Committee in the Central Denmark Region Denmark and permission to carry out the study will likewise be sought from the national ethics committees in Guinea-Bissau and Ethiopia Written information will be provided in the official language PortugueseAmharic and oral information will be provided to all eligible patients in the widely spoken language Portuguese CreoleAmharic Informed written consent or a fingerprint if illiterate will be kept together with case report forms
10 Capacity Building and future implications The present study will serve as a platform for relevant capacity building for good clinical practice and good clinical laboratory practice in the two African sites as well as promote a stronger linkage within Africa building on the existing links with Institutions in the EU In addition the capacity building and networking activities planned for this project aim to integrate African partners into the rapidly developing global network of TB trial sites in particular it will build a resource of patients with presumed TB with detailed clinical data which is rare among TB studies in Africa1 We have built a well-functioning infrastructure to carry out trials at the primary healthcare level which is seldom done in TB research We now aim to utilize this solid basis and our experience to improve TB case detection further
11 The Nordic collaboration and study group The Nordic collaborators in this trial have been working together since 2016 The main aim of the collaboration is to improve case finding of TB using applicable interventions in high endemic settings Capacity building is an essential part of the collaboration and all trials make efforts to involve existing structures and political elements in the settings in which they are carried out Workshops will be held throughout the trial period
Christian Morberg Wejse CW MD PhD is a consultant at the Department of Infectious Diseases Aarhus University Hospital and Professor of Cross-Cultural Medicine and Global Health at the Department of Public Health Aarhus University He has supervised more than 20 research projects in Guinea-Bissau
Thomas Schön TS MD PhD is a consultant of clinical microbiology and infectious diseases and a professor at the Department of Biomedical and Clinical Sciences Linköping University He has undertaken multiple research projects in Ethiopia and Sweden Both CW and TS have been involved in the development of the present research project and act as supervisors during the trial
Frauke Rudolf FR MD PhD is senior registrar at the Department of Infectious Diseases Aarhus University Hospital where she is responsible for TB patients and clinical associate professor at Aarhus University She has completed her PhD in Guinea-Bissau evaluating a clinical score for TB In recent years her research has focused on improving TB case detection and assessing gender differences in TB
Anita Zalisz will be working on the project in the capacity of PhD-student Anita will be responsible for supervising procedures in Bissau including data collection data entry as well as disseminating results
Mulugeta Aemero MA professor Head Tropical Infectious Diseases Research Centre CMHSCSH University of Gondar Ethiopia will be working on the project in the capacity of project collaborator in Gondar Ethiopia
Temesgen Tadesse TT MD is a physician who will be working on the project in the capacity of radiologist in Gondar Ethiopia Segenet Bizuneh SB MD is a physician who will be working on the project in the capacity of internist in Gondar Ethiopia Dessie Abebaw Angaw Assistant Professor of Epidemiology and Biostatistics will be working on the project in the capacity of project collaborator and supervisor in Gondar Ethiopia
Masresha Seyoum BSc MSc Diagnostic Coordinator at UoGCSH will be working on the project in the capacity of microbiologist in Gondar Ethiopia
Lilica Sanca LS BSc and Ebba Abate EA PhD are key personnel in Guinea-Bissau and Ethiopia respectively LS is responsible for the national refence laboratory for TB in Guinea-Bissau while EA has completed his PhD in Gondar has formerly worked as Director General Ethiopian Public Health Institute EPHI Ethiopia and is now Project Director for the North Africa Saving Lives and Livelihood Initiative Project Hope Namibia Namibia
Armando Sifna AS MD is a physician with extensive experience in TB and is part of the TB program under the ministry of health in Guinea-Bissau
12 Exploiting and disseminating the project results The standardised approach to TB management resulting from implementing the Bandim TBscore and improving available diagnostics is simple to communicate and translate into policy and WHO guidelines The national partners in this project work within the national TB programs and may disseminate project results rapidly into policy changes at the national level There are no intellectual property rights issues preventing a global dissemination of the Bandim TBscore which will be attempted through peer-reviewed publications and conference
1 Diagnostic yield of active TB within ten days comparing Enhanced Usual Diagnostic Procedure EUDP to Optimized Diagnostic Procedure ODP
22 Secondary objectives
1 Number of patients treated for TB within two weeks comparing EUDP to ODP
2 The additional diagnostic yield of CAD CXR compared to Xpert and culture
3 Improved follow-up FU rates in the cascade of care ie one week and six months FU for all included and treatment start and outcome for all TB diagnosed
4 Differences in diagnostic yield of active TB between routine sputum samples instructed sputum samples and non-sputum samples faecal and saliva combined with buccaltongue swabs
5 Feasibility of including Oxford Nanopore sequencing for detection and molecular resistance patterns measured as rate of analysed samples within two weeks
3 Background In 2022 the WHO estimated that of a total 106 million new TB cases more than three million went undiagnosed and of the remaining seven million only 57 were bacteriologically confirmed 1 In sub-Saharan African settings such as Ethiopia and Guinea Bissau smear microscopy remains the major diagnostic tool in most areas despite the rollout of rapid diagnostic tests such as Xpert In a multi-centre trial by Theron et al the implementation of Xpert in African settings did indeed reduce diagnostic delay but unfortunately without any effect on the numbers who were initiated on TB treatment nor on mortality 2 The trial showed that Xpert rollout was not superior to enhanced well-equipped microscopy-based diagnostic facilities In an editorial to the Lancet written by our group it was concluded that TB elimination could be better advanced by improving currently available tools than by expanding Xpert testing to peripheral health facilities 2 3 Nevertheless when TB is diagnosed with a point of care test there is a need to ensure that correct treatment is provided However culture-based drug susceptibility testing is very scarce in high endemic areas and often takes several weeks or months to perform 4 Recently the Cryptic study 5 has shown that genotypic drug susceptibility testing gDST may guide treatment with a sensitivity and specificity well above 90 for key drugs New techniques such as MinION Oxford Nanopore Technologies have also made it possible to perform sequencing and gDST directly from sputum samples Such point-of-care-based sequencing technology is comparable in size to a USB flash drive 6 and may be attached to a laptop computer at a health centre in a high endemic area
A cluster-randomised trial implementing the TBscore recently showed a fourfold increase in case detection rate in Ethiopia but not in Guinea-Bissau 7 It identified that factors such as laboratory capacity and routines in collecting and examining sputum smear samples may have a high impact on case detection rate and could be optimized based on the available resources Surprisingly the sensitivity of sputum smear microscopy ranges from 20-80 with an average of about 50 8 which may partly be due to patient selection but also depend on considerable variability in sputum collection strategies andor laboratory procedures In a comparison of sputum collection methods by Datta et al 9 pooling of sputum and structured instructions before sampling on average led to a twofold higher diagnostic yield whereas a spot versus morning sample showed no difference A multi-centre study including Ethiopia comparing fluorescence microscopy to conventional light microscopy showed a small but significant increase in sensitivity 728 vs 65810 Further recent research has shown that buccal and tongue swabs that are easily obtained can hold valuable diagnostic potential 11 In smear-negative patients with presumed TB the available diagnostic tools in high endemic countries include CXR but standardized procedures for evaluation of CXR have been scarce Recently CAD software based on artificial intelligence algorithms such as qXR Qureai India have improved detection of microbiologically confirmed TB from 50-60 by experienced radiologists to 70-84 with a specificity of 80 by CAD 12 However a recent systematic review concluded as did the WHO that there are too few high-quality studies to fully assess its diagnostic accuracy 13 We now propose to conduct a multi-centre cluster-randomised clinical trial to evaluate whether improvements on available diagnostic resources can increase the diagnostic yield of active TB and decrease mortality for patients diagnosed with TB
4 Methods 41 Location and nature of sites The present study will be conducted in two African countries Guinea-Bissau and Ethiopia In Bissau the capital of Guinea-Bissau The Bandim Health Project has been a Health and Demographic Surveillance Site HDSS for 45 years and has a well-defined study population of approximately 100000 under continued surveillance Within the study area there are two health centres HCs from where patients with presumed TB will be enrolled Bandim HC Belem HC
In Ethiopia the study will be conducted in collaboration with the University of Gondar in the region of North-Gondar which has a population of more than two million Two health centres located in North Gondar Zone namely Azezo HC and Gondar HC will participate The Gondar University Hospital is a teaching and referral hospital and will be used for further management of severe TB cases during this study
42 Epidemiology and study population 421 Guinea-Bissau The epidemiology of TB in the Bissau study population has been extensively described 14-18 The overall incidence of TB has declined only slightly since 2004 and was estimated at 273100000 population in 2020 while TBHIV co-infection declined from 108 per 100000 to 14 per 100000 over the period 19 Smear negative cases and case fatality rate likewise declined over the period The incidence of smear positive TB remained stable at 188 per 100000 between 2004 and 2011 20 All HCs have basic laboratory facilities to carry out sputum smear microscopy and all provide TB treatment The national referral hospital for TB Hospital Raoul Follereau is located adjacent to the study area and is a close collaborating partner The incidence rate of TB in Guinea-Bissau as a whole is 361 per 100000 with a case detection rate estimated at 35 21 22
422 Ethiopia TB continues to be a major public health concern in Ethiopia fuelled by the expansion of the HIV epidemic since the 1990s According to the 2022 WHO TB report 1 Ethiopia is among high-burden countries for both TB and TBHIV and has an estimated incidence rate of 119 per 100000 and a TB mortality of 177 per 100000 21 HIV-positive TB incidence is 62 per 100000 and case detection rate is currently estimated at 73 21 22 These figures are high considering that Ethiopia is the second most populous country in Africa with an estimated total population size of more than 100 million HIV screening is carried out as a routine
43 Design The present study is designed as an open-label stepped-wedge cluster-randomised controlled trial 23 to investigate an optimized diagnostic procedure for active TB in healthcare centres in Guinea-Bissau and Ethiopia Applying the stepped-wedge design ensures that all participating HCs will implement the intervention during the study period This design is particularly useful for evaluating the population-level impact of an intervention which is of interest in this study All clusters ie HCs start with Enhanced Usual Diagnostic Procedure EUDP and are then randomized to switch to the intervention phase at predefined time points see table 1
See below for detailed description of sample size calculations
44 Bandim TBscore The Bandim TBscore TBscore Table 2 consists of five symptoms cough haemoptysis dyspnoea chest pain and night sweats and six signs pale inferior conjunctivae pulse 100 per minute positive finding at lung auscultation temperature 37C axillary body mass index BMI 1816 and mid-upper-arm circumference MUAC 220 mm200 mm 24 Each variable contributes one point while BMI and MUAC contribute an additional point if BMI16MUAC200 mm hence the maximum score is 13 The score divides patients into three severity classes SC SC-I TBscore 0-5 SC-II TBscore 6-7 and SC-III TBscore8 A simplified version of the score - TBscoreII - with a maximum score of 8 points has also been developed 25 The advantage of the latter score is that it can be performed without a physician present The TBscore has been assessed in both Gondar and Bissau and found to be a useful add on in the diagnostic cascade of care7
45 Buccal tongue swap and saliva sample Buccal and tongue samples will be collected using the Omniswab Whatman catalogue WB100035 and added to a container where patients leave a saliva sample Samples will be collected by trained laboratory staff who gently brush the inside of each cheek and then the tongue of the participant for 10 seconds with the OmniSwab The OmniSwab has a breakpoint and the head will be ejected into 500 µl buffer containing 50 mM Tris pH 80 50 mM EDTA 50 mM sucrose 100 mM NaCl and 1 SDS and transported to the laboratory at 4C 11 There the OmniSwab-collected samples will be vortexed in the saliva and the swabs heads removed One part of the sample will be analyzed using Xpert Ultrawhile the other part will be stored at - 80 C until further processing
46 Computer-aided detection chest X-ray CAD CXR applying artificial intelligence AI A preliminary study using an AI based CAD CXR software qXR Qure compared to two Ethiopian radiologists included 498 CXRs from a previously performed randomized controlled trial on the TBscore Of those the less experienced radiologist found 50 the more experienced radiologist found 100 and CAD CXR found 83 to be indicative of TB Using Xpert PCR as the gold standard for TB diagnosis the overall AUC for the CAD CXR was 084 while the less experienced radiologist performed at a sensitivity of 414 and a specificity of 941 and the experienced radiologists assessments were 552 sensitive and 850 specific The agreement between the radiologists was moderate kappa045 as was the agreement between each radiologist and the software kappa036 kappa059
In the present study we will include a mobile phone app to guide photographing analog X-ray films These photographs will then be uploaded to a locally placed box qbox and analyzed on site
47 Enrolment At all sites adult patients will be screened during consultations carried out at primary healthcare centres All patients presenting with cough of any duration sputum production or weight loss will have their TBscore assessed All participating health centres have previous experience collecting the symptoms and signs necessary for the TBscore and completing a score chart from which the TBscore can be calculated All patients with a TBscore4 will be referred for TB diagnostics Patients with 4TBscore6 will be referred to fluorescence microscopy while patients with TBscore6 will be referred to Xpert PCR The staff at the sites will receive general training in TB diagnosis and then the healthcare facilities will following a random sequence switch from Enhanced Usual Diagnostic Procedure EUDP consisting of standard TB program diagnostics but ensuring availability of all reagents to intervention ie OPD
471 Enhanced Usual Diagnostic Procedure EUDP The standard TB diagnostics in both settings consist of performing the sputum smear analysis by the clinical routine Smear-negative cases will be followed as per standard routine Figure 1A
472 The Optimized Diagnostic Procedure ODP intervention
A three-step package which involves Figure 1B
1 Oral and mobile phone-guided instructions by study staff Patients will be instructed to take several deep breaths hold their breath for a moment and repeat this several times until coughing is induced including instructions to cough deeply and vigorously whilst breathing out 26 Instructions will be presented to the participating patients on a mobile phone to ensure consistent instructions to all participants
2 Pooling of two spot sputum samples 9 Two instructed pooled spot samples will be split into two parts 27 and investigated by fluorescence microscopy 28 The other part of the pooled sputum sample will be frozen for later confirmation with batch-wise BACTEC 960 MGIT as a gold standard for microbiological diagnosis
As an add on we will analyze a subgroup of samples with the MinION to assess applicability in a low resource setting
3 Smear-negative cases at the first visit will be assessed for persisting symptoms and referred to a CXR unit Those with a CXR CAD result suggestive of active TB will be treated for TB The smear negative cases will also leave an additional instructed spot sputum sample which will be pooled and one part analyzed by Xpert Ultra and the other part by BACTEC 960 MGIT culture Additionally non-sputum sampling will be performed and analyzed by Xpert Ultra including saliva combined with buccal and tongue sample using the same swab as well as a faecal sample Xpert Ultra using the WHO-recommended direct procedure 29 In a feasibility study on the basis of intention to treat either by smear microscopy or CXRclinical grounds the participants will be asked for an additional instructed sputum sample which will extracted using EZ1 and sequenced using nanopore sequencing and the EPI2ME bioinformatic platform as previously described 6 473 Implementation of the ODP and EUDP Upon commencement of the intervention arm the staff will be trained in applying optimized diagnostic procedures
For all included patients both in the EUDP and the ODP a follow-up visit one week from first encounter will take place to ensure initiation of treatment for smear positive cases or to screen for persisting symptoms and carry out a second clinical evaluation smear negative cases Diagnosis will be according to local standards and based on smear microscopy CXR and WHO clinical criteria including for extrapulmonary cases 30 31 During the intervention the physician can overrule the TBscore if needed At all clinics both in the EUDP and ODP ie intervention phase all included patients will be referred to HIV testing at adjacent HIV-treatment clinics where pre- and post-testing counselling will be carried out
6 Sample size and statistical analyses Based on a previous study in the same setting we found that among patients with a TBscore3 there were a total of 5 smear positive cases both in Guinea-Bissau and Ethiopia Using a higher cut-off value at TBscore4 increases specificity and is estimated to increase the case detection yield to 6 based on previous data using routine sputum collection and sputum smear analysis Increasing the TBscore cut-off value thus leads to a lower referral rate of 54 of all screened instead of 73 while increasing the number of smear positive cases in the sample from 5 to 6 As both settings now use Xpert MTBRIF Ultra as the primary diagnostic method initial case rate is estimated at 8 32 Based on systematic reviews it is estimated that the diagnostic yield of an instructed sputum where two spot-samples are pooled and processed using LED microscopy will lead to an at least twofold increase in sensitivity 9 10 27 33 Adding CAD CXR onto those that are smear negative by the optimized sputum smear strategy is estimated to increase the number of patients diagnosed with TB 25-fold To show an increase in diagnostic yield using ODP from a conservative estimate of 7 to 14 with a power of 80 and a significance level of 005 two clusters in each country are needed including 132 patients per time interval of 22 weeks The estimated inclusion rate per cluster per week is 6 patients which means that it should take 66 weeks to reach a target of 1584 inclusions
Sample size was calculated using the steppedwedge function in Stata 34 The diagnostic yield time to diagnosis and treatment outcomes will be calculated
Detection rates will be compared between control EUDP and intervention ODP in a generalized linear mixed effects model taking into account time and center effect and allowing for intra-cluster correlation ie a mixed effect logistic regression for longitudinal data A similar repeated measurements model will be used to analyze and compare groups on patient characteristics
7 Timeframe Study preparations will start August 2023 with establishment of enrolment procedures and training of staff Enrolment will take place for 68 weeks from June 2024 to September 2025 End of follow-up will be April 2026 For details please see Table 3 Overall responsible body for activities planned is the PI in collaboration with local VIP and TAP personnel
8 Public health importance 81 Major advances TB case-finding remains a challenge particularly in overburdened healthcare facilities with limited access to diagnostics 35-37 A simple disease management strategy combined with improved utilization of available diagnostics may ensure that more patients with TB are treated and earlier and that those at high risk of dying are targeted appropriately with a rational use of limited resources The major advance of adding a standardized approach to patients with presumed TB will be to decrease the substantial burden of undiagnosed TB with simple means which makes it a sustainable affordable and practicable tool
82 New approach The strength of the Bandim TBscore strategy is that it guides the health care professional through a structured interview and uses the existing laboratory set-up which is of great benefit compared to other more advanced diagnostic tools The diagnostic algorithm simply utilizes what is already part of the primary healthcare setup thereby increasing the chance of being applicable in similar settings worldwide Similarly the novel technologies employed in the ODP can easily be integrated into clinical settings worldwide
83 Generalizability of trial results This trial will test implementation of a cheap readily available practical point-of-care package which requires only minor additional training of staff If shown to be effective in identifying additional TB cases use of the Bandim TBscore and improved diagnostics may be expected to be endorsed with little delay by the WHO and national governments as a standard part of TB diagnosis and management
84 Contribution to improved disease management and public health In under-funded over-burdened healthcare facilities with a large patient load presenting with co-morbidities many patients with TB remain undiagnosed and untreated 35-37 Simple clinical tools at points of care which can identify up patients with active TB may have great potential for diagnosing patients with TB early and thereby preventing TB-associated morbidity and mortality Targeting delayed TB diagnosis and TB-related mortality will add to the agenda of reducing poverty-related diseases The resources used to combat TB and the productive years lost to TB inflict a punishing toll on the economies of TB-endemic countries and helps perpetuate the cycle of poverty The majority of TB is now concentrated in the Worlds poorest countries thus effective and practicable programs to detect and cure TB early is the most feasible method of controlling the disease
85 Improvements in patient care A major strength of the Bandim TBscore is its ability to continually assess disease severity during treatment as has previously been shown by our group 25 38 39 Thus the score may be used both to enhance the number of confirmed TB cases among patients with presumed TB and serve as an easily adaptable monitoring tool during the treatment or re-evaluation of these
9 Ethical considerations Consultative approval is expected to be granted from the Regional Ethics Committee in the Central Denmark Region Denmark and permission to carry out the study will likewise be sought from the national ethics committees in Guinea-Bissau and Ethiopia Written information will be provided in the official language PortugueseAmharic and oral information will be provided to all eligible patients in the widely spoken language Portuguese CreoleAmharic Informed written consent or a fingerprint if illiterate will be kept together with case report forms
10 Capacity Building and future implications The present study will serve as a platform for relevant capacity building for good clinical practice and good clinical laboratory practice in the two African sites as well as promote a stronger linkage within Africa building on the existing links with Institutions in the EU In addition the capacity building and networking activities planned for this project aim to integrate African partners into the rapidly developing global network of TB trial sites in particular it will build a resource of patients with presumed TB with detailed clinical data which is rare among TB studies in Africa1 We have built a well-functioning infrastructure to carry out trials at the primary healthcare level which is seldom done in TB research We now aim to utilize this solid basis and our experience to improve TB case detection further
11 The Nordic collaboration and study group The Nordic collaborators in this trial have been working together since 2016 The main aim of the collaboration is to improve case finding of TB using applicable interventions in high endemic settings Capacity building is an essential part of the collaboration and all trials make efforts to involve existing structures and political elements in the settings in which they are carried out Workshops will be held throughout the trial period
Christian Morberg Wejse CW MD PhD is a consultant at the Department of Infectious Diseases Aarhus University Hospital and Professor of Cross-Cultural Medicine and Global Health at the Department of Public Health Aarhus University He has supervised more than 20 research projects in Guinea-Bissau
Thomas Schön TS MD PhD is a consultant of clinical microbiology and infectious diseases and a professor at the Department of Biomedical and Clinical Sciences Linköping University He has undertaken multiple research projects in Ethiopia and Sweden Both CW and TS have been involved in the development of the present research project and act as supervisors during the trial
Frauke Rudolf FR MD PhD is senior registrar at the Department of Infectious Diseases Aarhus University Hospital where she is responsible for TB patients and clinical associate professor at Aarhus University She has completed her PhD in Guinea-Bissau evaluating a clinical score for TB In recent years her research has focused on improving TB case detection and assessing gender differences in TB
Anita Zalisz will be working on the project in the capacity of PhD-student Anita will be responsible for supervising procedures in Bissau including data collection data entry as well as disseminating results
Mulugeta Aemero MA professor Head Tropical Infectious Diseases Research Centre CMHSCSH University of Gondar Ethiopia will be working on the project in the capacity of project collaborator in Gondar Ethiopia
Temesgen Tadesse TT MD is a physician who will be working on the project in the capacity of radiologist in Gondar Ethiopia Segenet Bizuneh SB MD is a physician who will be working on the project in the capacity of internist in Gondar Ethiopia Dessie Abebaw Angaw Assistant Professor of Epidemiology and Biostatistics will be working on the project in the capacity of project collaborator and supervisor in Gondar Ethiopia
Masresha Seyoum BSc MSc Diagnostic Coordinator at UoGCSH will be working on the project in the capacity of microbiologist in Gondar Ethiopia
Lilica Sanca LS BSc and Ebba Abate EA PhD are key personnel in Guinea-Bissau and Ethiopia respectively LS is responsible for the national refence laboratory for TB in Guinea-Bissau while EA has completed his PhD in Gondar has formerly worked as Director General Ethiopian Public Health Institute EPHI Ethiopia and is now Project Director for the North Africa Saving Lives and Livelihood Initiative Project Hope Namibia Namibia
Armando Sifna AS MD is a physician with extensive experience in TB and is part of the TB program under the ministry of health in Guinea-Bissau
12 Exploiting and disseminating the project results The standardised approach to TB management resulting from implementing the Bandim TBscore and improving available diagnostics is simple to communicate and translate into policy and WHO guidelines The national partners in this project work within the national TB programs and may disseminate project results rapidly into policy changes at the national level There are no intellectual property rights issues preventing a global dissemination of the Bandim TBscore which will be attempted through peer-reviewed publications and conference
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