Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment Trial (SMARTT)

Aurum Institute, University of Stellenbosch, University of the Free State, Free State Department of Health

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.

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.

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

WGS DST strategy for diagnosing the TB drug resistance profile and an individualised RR-TB treatment recommendation

WGS DST strategy for diagnosing the TB drug resistance profile and an algorithm-determined individualised RR-TB treatment recommendation

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

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.

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.

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.

The analysable individual patient data (IPD) will be made available, including WGS data (to be published on the European Nucleotide Archive (ENA)) and de-identified clinical and demographic IPD. This ensures an adit trial for summary results reporting, enables re-analyses of trial data and the possibility for combining the data with others for novel investigations.

WGS: available on European Nucleotide Archive (ENA) Other data: access will be provided to researchers who have obtained Institutional Review Board (IRB) approval for analyses

Van Rie A, De Vos E, Costa E, Verboven L, Ndebele F, Heupink TH, Abrams S; SMARTT team; Fanampe B, Van der Spoel Van Dyk A, Charalambous S, Churchyard G, Warren R. Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial. Trials. 2022 Oct 8;23(1):864. doi: 10.1186/s13063-022-06793-w.