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

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.

Study Overview

• Status: Recruiting
• Conditions: Drug-resistant Tuberculosis; Rifampicin Resistant Tuberculosis; Pulmonary Tuberculoses; Multidrug Resistant Tuberculosis
• Intervention / Treatment: Device: WGS DST strategy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 248
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Elise De Vos, MSc; Phone Number: 0032477715350; Email: elise.devos@uantwerpen.be
• Study Contact Backup: Name: Annelies Van Rie, PhD, MD; Email: annelies.vanrie@uantwerpen.be

Study Locations

• South Africa
  • Free State
    • Bloemfontein, Free State, South Africa
      • Recruiting
      • Free State Department of Health Clinics
      • Contact: Salome Charalambous, PhD; Phone Number: +27 10 590 1389; Email: SCharalambous@auruminstitute.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: HEALTH_SERVICES_RESEARCH
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: WGS DST strategy; WGS DST strategy for diagnosing the TB drug resistance profile and an individualised RR-TB treatment recommendation	Device: WGS DST strategy; WGS DST strategy for diagnosing the TB drug resistance profile and an algorithm-determined individualised RR-TB treatment recommendation
NO_INTERVENTION: Standard of Care; Standard of care diagnosis of the drug resistance profile and individualised treatment

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Universiteit Antwerpen
• Collaborators: Aurum Institute; University of Stellenbosch; University of the Free State; Free State Department of Health
• Investigators: Principal Investigator: Gavin Churchyard, PhD, MD, Aurum Institute; Principal Investigator: Annelies Van Rie, PhD, MD, Universiteit Antwerpen; Principal Investigator: Rob M Warren, PhD, Stellenbosch University, MRC; Principal Investigator: Salome Charalambous, PhD, Aurum Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 21, 2021
• Primary Completion (ANTICIPATED): December 1, 2022
• Study Completion (ANTICIPATED): January 1, 2025

Study Registration Dates

• First Submitted: April 22, 2021
• First Submitted That Met QC Criteria: August 17, 2021
• First Posted (ACTUAL): August 23, 2021

Study Record Updates

• Last Update Posted (ACTUAL): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 14, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Whole Genome Sequencing; Drug Resistant Tuberculosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: AUR1-11-248; T001018N (OTHER_GRANT: TBM FWO); 2020-004084-10 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: From publication of the results of the primary up to 5 years thereafter
• IPD Sharing Access Criteria: 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No