Utility of Sputum Induction and Novel Technologies to Improve TB Diagnosis in a High HIV Prevalence Primary Care Setting

Study Overview
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Brief Summary
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This study will investigate the benefit of using Sputum induction for TB diagnosis in a primary care clinic for adult TB suspects that are either unable to produce a sputum sample (sputum scarce) or on initial diagnostic work-up have 2 negative sputum smear samples (WHO standard for frontline TB diagnosis). The investigators hypothesize that acquiring an induced sputum sample for smear microscopy and liquid TB culture will decrease time-to-diagnosis and time-to-treatment initiation in smear negative/sputum scarce TB patients in a primary care clinic in a resource-limited high TB HIV prevalent setting.

Detailed Description
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Tuberculosis is on the increase in Africa. A key area of weakness in TB control efforts is the inability to make a rapid diagnosis. This is, in part, due to the inability to obtain representative biological samples and the non-availability of cheap, effective, rapid and field-friendly diagnostic tools. Indeed, in HIV positive patients, where the sensitivity of sputum smear is as low as 20%, culture results take several weeks and a significant proportion of patients do not expectorate sputum. Sputum induction for the diagnosis of TB has been evaluated in several studies, has been shown to have a good yield, feasibility and safety when performed correctly, and with diagnostic comparability to bronchoscopy. Few studies have evaluated the performance of induced sputum outside of the hospital environment and the tolerability, yield and performance outcome of sputum induction in a primary care facility has yet to be evaluated. The objective of this study is two-fold. We seek to evaluate, through a randomized controlled trial, the feasibility, performance outcomes and impact on time-to-diagnosis and -treatment of sputum induction, in a high HIV prevalence primary care setting, for the diagnosis of smear negative/ sputum scarce TB. We hypothesize that acquiring an induced sputum sample for smear microscopy and liquid TB culture will decrease time-to-diagnosis and time-to-treatment initiation in smear negative/sputum scarce TB patients in a primary care clinic in a resource-limited high TB HIV prevalent setting. We will also evaluate the potential incremental benefit of novel technologies to improve the rapidity and diagnostic yield using induced sputum samples (Xpert MTB/RIF assay, microscopic observation drug susceptibility testing (MODS) and the Genotype MTB DRplus line probe assay).

Official Title
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A Randomised Control Trial of Sputum Induction, and New and Emerging Technologies in a High HIV Prevalence Primary Care Setting

Conditions
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Tuberculosis

Intervention / Treatment
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* Procedure: Sputum induction
* Procedure: standard routine expectorated sputum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 2x smear negative or sputum scarce TB suspects Primary care patient (not referred by doctor) Adult patients (>18 years) Able to provide informed consent Exclusion Criteria: Not meeting inclusion criteria <18 years Unable to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sputum induction<br>Enrolled patients receive sputum induction (using ultrasonic nebulisation with hypertonic saline) | Procedure: Sputum induction<br>* Ultrasonic nebulisation 3% hypertonic saline nebulised for duration of 20 mins<br>|
| Active Comparator: No sputum induction<br>Enrolled patients randomised to this study arm will receive an observed expectorated sputum collection attempt. Research nurses train study patients on the method of producing sputum spontaneously. | Procedure: standard routine expectorated sputum<br>* Patients in the control group are trained by the research staff to produce sputum but no device is utilized. Sputum is spontaneously expectorated where possible<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-treatment initiation | Time-specific proportion of patients initiated on TB treatment between study arms Time-points to be analysed include 3, 5, 7, 10, 14, 21, 48 days from enrollment. | Up to 48 days after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic yield of sputum culture | Difference in diagnostic yield of a single sputum TB culture between study arms. This will compare the single induced or expectorated sputum sample collected at study enrollment. | Up to 2 months after enrollment | 
| Diagnostic yield and accuracy of sputum smear microscopy | Difference in diagnostic yield and accuracy of a single sputum TB smear between study arms. This will compare the single induced or expectorated sputum sample collected at study enrollment. Liquid TB culture will be used as the reference standard for assessment of diagnostic accuracy Fluorescence smear microscopy will be performed on auramine-O stained concentrated samples | Up to 2 months after enrollment | 
| Feasibility of sputum induction in primary care clinics | Feasibility and robustness of performing sputum induction in primary care clinics (measures include - sputum induction failure rates, turn-around-time, user appraisals and evaluation) | 2 years | 
| Safety and tolerability of sputum induction performed in primary care clinics | Side-effects of sputum induction procedures Number of induced sputum procedures terminated because of patient side-effects and safety | 2 years | 
| Diagnostic yield and accuracy of additional diagnostics including Xpert MTB/RIF assay, MODS and Genotype MTBDRplus | Difference in diagnostic yield and accuracy of Xpert MTB/RIF, MODS liquid culture and the Genotype MTBDRplus on a single induced or expectorated sputum sample collected at enrollment. Liquid TB culture will be used as the reference standard for diagnostic accuracy measures. | 2 years | 
| Cost-analysis of sputum induction for primary care clinics | Based on diagnostic accuracy measures of different diagnostic tests between the induced sputum and standard care groups, cost-of-diagnosis will be calculated and compared | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, diagnosis, sputum induction, primary care