Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial

Annelies Van Rie, Elise De Vos, Emilyn Costa, Lennert Verboven, Felex Ndebele, Tim H Heupink, Steven Abrams, SMARTT team, Boitumelo Fanampe, Anneke Van der Spoel Van Dyk, Salome Charalambous, Gavin Churchyard, Rob Warren, Noriah Maraba, Heeran Makkan, Trevor Beattie, Zandile Rachel Sibeko, S'thabiso Bohlela, Pulane Segwaba, Emmanuel Ayodeji Ogunbayo, Nomadlozi Mhlambi, Felicia Wells, Leen Rigouts, Gary Maartens, Francesca Conradie, John Black, Sam Potgieter, Annelies Van Rie, Elise De Vos, Emilyn Costa, Lennert Verboven, Felex Ndebele, Tim H Heupink, Steven Abrams, SMARTT team, Boitumelo Fanampe, Anneke Van der Spoel Van Dyk, Salome Charalambous, Gavin Churchyard, Rob Warren, Noriah Maraba, Heeran Makkan, Trevor Beattie, Zandile Rachel Sibeko, S'thabiso Bohlela, Pulane Segwaba, Emmanuel Ayodeji Ogunbayo, Nomadlozi Mhlambi, Felicia Wells, Leen Rigouts, Gary Maartens, Francesca Conradie, John Black, Sam Potgieter

Abstract

Background: Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition.

Methods: This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective.

Discussion: This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings.

Trial registration: ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.

Keywords: Clinical trial; Drug resistance; Pragmatic; Strategy trial; Treatment recommender; Tuberculosis; Whole-genome sequencing.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Strategy for whole genome sequencing-guided drug resistance profile determination and automated individualized treatment recommendation
Fig. 2
Fig. 2
Schedule of screening, enrolment, interventions, and assessments. *Assessments listed are limited to the study-specific assessments. In addition to these, several assessments are performed on all study participants as per standard of care procedures. W, week; M, month; MGIT, Mycobacteria Growth Incubator Tube. ** Individualization of treatment occurs when drug susceptibility test results become available (whole genome sequencing for the experimental arm; line probe assays and phenotypic drug susceptibility test for standard of care arm). This is expected to occur a median of 5 to 6 weeks after the start of treatment. ***Closeout is performed at month 6 for patients who receive a 6-month treatment regimen

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