Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment Trial

Study Overview
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Brief Summary
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The primary aim of this pragmatic trial is to determine the effectiveness of a Whole Genome Sequencing (WGS) Drug Sensitivity Testing (DST) strategy to guide individualised treatment of rifampicin resistant tuberculosis (RR-TB) patients. The primary objective is to determine the effectiveness of this WGS DST strategy in patients diagnosed with RR-TB. We will additionally perform an exploratory health economics evaluation of both arms, and will determine the feasibility of the WGS DST strategy.

Detailed Description
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The trial will be a single blinded randomised controlled, pragmatic, medical device trial evaluating a Whole Genome Sequencing (WGS) Drug Sensitivity Testing (DST) strategy to guide individualised treatment of rifampicin resistant tuberculosis (RR-TB) patients. A total of 248 patients diagnosed with RR-TB in the South African Free State province will by randomised to one of two trial arms. 124 patients will be assigned to the intervention arm, consisting of a WGS DST strategy for diagnosing drug resistance profile and an algorithm-determined individualised RR-TB treatment recommendation. 124 patients will be assigned to the control arm where the diagnosis of Mtb drug resistance and individualisation of RR-TB treatment will happen according to the Standard of Care (SOC) procedures.

Official Title
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Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment Trial

Conditions
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Rifampicin Resistant Tuberculosis, Drug-resistant Tuberculosis, Multidrug Resistant Tuberculosis, Pulmonary Tuberculoses

Intervention / Treatment
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* Device: WGS DST strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with RR-TB Diagnosed with pulmonary TB (PTB) or PTB plus extra-pulmonary TB (EPTB) ≥18 years of age Able to sign informed consent Not on TB treatment at time of enrolment Exclusion Criteria: Patients diagnosed EPTB without pulmonary involvement Patients with TB Meningitis or TB of the bone. Has any condition that, in the opinion of the investigator or physician, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, interfere with achieving the study objectives or compromise patient safety.

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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized Controled Phase 4 pragmatic single blinded medical device trial.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WGS DST strategy<br>WGS DST strategy for diagnosing the TB drug resistance profile and an individualised RR-TB treatment recommendation | Device: WGS DST strategy<br>* WGS DST strategy for diagnosing the TB drug resistance profile and an algorithm-determined individualised RR-TB treatment recommendation<br>|
| No Intervention: Standard of Care<br>Standard of care diagnosis of the drug resistance profile and individualised treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effectiveness of a WGS DST strategy for individualisation of RR-TB treatment | The effectiveness will be determined by the rate of change in time to positivity (TTP) over 6 months in the Mycobacterial Growth Indicator Tuber (MGIT) system [time from: Day 0 to Week 24]. The effectiveness of the WGS DST strategy will be determined by the rate of change in TTP in liquid media MGIT cultures of sputum samples collected during the first 6 months of treatment. The TTP will be used to determine the change in mycobacterial load using a non-linear mixed effect time-to-event model that provides a longitudinal representation of mycobacterial load (measured as TTP in MGIT) at weeks 2, 3, 4, 5, 6, 7, 8, 12, 16, 20 and 24 | Day 0 to month 6 (6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health economic evaluation of a WGS DST strategy for individualization of RR-TB treatment | The difference in total cost over the entire treatment period from a patients and health system perspective between a WGS strategy and SOC strategy will be assessed by comparing costing data collected at month 1 of treatment, month 6 of treatment and at the end of treatment. | Start of treatment to end of treatment (which may vary from 6 months to over 11 months) | 
| Impact of WGS strategy for individualisation of RR-TB treatment on Health related Quality of Life (HRQOL) | The difference in changes in health relates quality fo life will be assessed by comparing the change in HRQOL over time between patients randomised to the WGS and SOC strategies for individualisation of RR-TB treatment, using results of the EQ-5D-5L questionnaire collected at baseline, month 1, 2, 3, 4, 5, 6 and end of treatment. | Start of treatment to end of treatment (which may vary from 6 months to over 11 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Whole Genome Sequencing, Drug Resistant Tuberculosis