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    Summary
    EudraCT Number:2020-004084-10
    Sponsor's Protocol Code Number:T001018N
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2022-05-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2020-004084-10
    A.3Full title of the trial
    Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment; a pragmatic randomised controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Sequencing Tuberculosis bacteria's DNA and its use for Resistant Tuberculosis Treatment; a pragmatic randomised controlled trial
    A.3.2Name or abbreviated title of the trial where available
    SMARTT-trial
    A.4.1Sponsor's protocol code numberT001018N
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFlemisch Fund for Scientific Research - Fonds voor Wetenschappelijk Onderzoek
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFons voor Wetenschappelijk Onderzoek
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFlemisch Fund for Scientific Research
    B.5.2Functional name of contact pointFWO
    B.5.3 Address:
    B.5.3.1Street AddressEgmontstraat 5
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1000
    B.5.3.4CountryBelgium
    B.5.4Telephone number00322512 91 10
    B.5.5Fax number00322512 58 90
    B.5.6E-mailtbm@fwo.be
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameWhole Genome Sequencing (WGS) for identification of the drug resistance profile of M.tb
    D.3.2Product code All Department of Health (SA) approved RR-TB drugs
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeWhole Genome Sequencing (WGS) (as a diagnostic (medical device) for the identification of the drug resistance profile of Mycobacterium tuberculosis (Mtb).
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rifampicin resistant (RR-TB) and drug resistant (DR-TB) tuberculosis
    E.1.1.1Medical condition in easily understood language
    Rifampicin resistant (RR-TB) and drug resistant (DR-TB) tuberculosis
    E.1.1.2Therapeutic area Health Care [N] - Health Services Administration [N04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10049031
    E.1.2Term Genotype drug resistance test
    E.1.2System Organ Class 10022891 - Investigations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10048723
    E.1.2Term Multiple-drug resistance
    E.1.2System Organ Class 10018065 - General disorders and administration site conditions
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10059866
    E.1.2Term Drug resistance
    E.1.2System Organ Class 10018065 - General disorders and administration site conditions
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10004052
    E.1.2Term Bacterial resistance
    E.1.2System Organ Class 100000004862
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10038637
    E.1.2Term Resistance bacterial
    E.1.2System Organ Class 100000004862
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10028152
    E.1.2Term Multi-antibiotic resistance
    E.1.2System Organ Class 100000004862
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10070974
    E.1.2Term Antibiotic resistance test
    E.1.2System Organ Class 10022891 - Investigations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to determine the effectiveness of a Whole Genome Sequencing (WGS) Drug Sensitivity Testing (DST) strategy in patients with rifampicin Resistant tuberculosis (RR-TB).
    E.2.2Secondary objectives of the trial
    —Secondary effectiveness:
    - Relapse rate (recurrence of RR-TB disease) in the first year after treatment completion
    - Probability of TB free survival free 12 months after RR-TB treatment completion
    —Exploratory effectiveness:
    - proportion of patients with 4 or more effective drugs in their 'final' treatment regimen
    - turnaround time for complete DST profile
    -median time between initiation of standard regimen and initiation of the individualized treatment regimen.
    -Quality of Life (QOL), change in QOL, and pill burden.
    —health economic evaluation of a WGS DST strategy for individualization of RR-TB treatment
    —Exploratory feasibility objective: To determine the feasibility of a WGS DST strategy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Diagnosed with RR-TB on Xpert Ultra
    Justification: The target population for the use of WGS if people with confirmed rifampicin resistant TB. Xpert Ultra is the initial test used for diagnosis of TB and RR-TB in South Africa.
    - Diagnosed with pulmonary TB (PTB) or PTB plus extra-pulmonary TB (EPTB)
    Justification: To assess the main outcome measure (time to culture conversion) weekly samples must be collected for Mtb culture. This is only possible in people with PTB.
    - ≥18 years of age
    Justification: collection of sputum samples in children is difficult and children most often have paucibacillary TB. We therefore propose to limit the study to adults with RR-TB.
    - Able to sign informed consent
    Justification: This is not an emergency research study. All people will thus need to complete the written informed consent process before any trial related procedure.
    - Not on TB treatment at time of enrolment
    Justification: There are two main reasons to limit enrolment to people not yet on TB treatment at time of enrolment: (1) In this phase IV pragmatic trial, we aim to study the use of WGS as this will most be implemented in routine care. We believe that WGS would be the first ‘reflex’ DST assay that will be performed after a RR-TB diagnosis. WGS would thus occur in people not yet on TB treatment, (2) On treatment, the myco-bacterial burden rapidly decreases, possibly reducing the success rate of WGS.
    E.4Principal exclusion criteria
    - Patients diagnosed EPTB without pulmonary involvement
    Justification: the primary endpoint of the trial is time to culture conversion. This requires collection of weekly samples for Mtb culture. This is not feasible and too burdensome for patients with EPTB without pulmonary TB as this would require weekly collection of an invasive sample.
    - Patients with TB Meningitis or TB of the bone.
    Justification: the treatment of patients with TB meningitis or TB of the bone is complicated and should always be decided by a exert committee. For optimal safety of these patients, they will be excluded from participation in this trial.
    - 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.
    Justification: this exclusion criteria aims to ensure optimal patient safety and scientific rigor.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be time to culture conversion. Specifically, we will use a non-linear mixed effects model to analyse the repeated measurements of time to culture positivity in liquid media, as this is the most powerful method to assess time to culture conversion.

    The primary analysis will be an intent to treat analysis. The intent to treat study population is defined as all participants who were enrolled and randomized to one of the two arms. In the intent-to-treat analysis, all participants allocated to the experimental (WGS DTS strategy) arm will remain in this arm, independent of whether the WGS was successful (interpretable result) and independent of whether the individualized treatment suggested by the treatment recommender algorithm was implemented by the physician in charge of patient care.
    For the primary analysis, we will compare time to culture conversion between the two arms using a non-linear mixed effects model for optimal use of the serial culture data collected during treatment. This method is more powerful for the characterization of differences in mycobacterial response to treatment compared to the classical Kaplan-Meier survival curves or the estimation of hazard ratios.
    We will perform several sensitivity analyses
    - standard Kaplan Meyer analysis and log rank test to compare time to stable culture conversion between the SOC and WGS and treatment algorithm-arm
    - modified intent-to-treat analysis excluding patients with culture negative/contaminated result at baseline
    - modified intent-to-treat analysis excluding patients in whom the physician decided not to implement the individualized treatment regimen as suggested by the treatment recommender algorithm
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be time to culture conversion, analysing the repeated measurements of time to culture positivity in liquid media. Repeated culture sampling will happen at the baseline (pre-treatment) visit, at w2, 3, 4, 5, 6, 8, and then monthly following treatment initiation until treatment completion.
    E.5.2Secondary end point(s)
    Secondary effectiveness endpoints:
    - Relapse rate (recurrence of RR-TB disease) in the first year after treatment completion
    - Probability of TB free survival free 12 months after RR-TB treatment completion

    Exploratory effectiveness endpoints:
    - Proportion of patients with 4 or more effective drugs in their 'final' treatment regimen
    - Turnaround time for complete DST profile
    - Median time between initiation of standard regimen and initiation of the individualized treatment
    regimen.
    - Quality of Life (QOL), change in QOL, and pill burden.

    Health Economic assessment:
    Outcome measures: Patient socio-economic status, household assets and treatment-related costs will be collected by using a questionnaire, adapted from a validated tool to estimate TB patient costs.
    Mean incremental costs incurred by patients randomized to the WGS vs SOC arm
    - Mean incremental cost to the health system of a WGS DST strategy compared to SOC
    - Mean changes in health related quality of life (HRQOL) during treatment in patients randomized to the WGS and SOC arm
    - Patient costs by category (direct medical costs, transport, food and accommodation costs, and cost of
    guardians/accompanying persons and lost time) in patients randomized to the WGS and SOC arm
    - Costs related to SAE in patients randomized to the WGS and SOC arm

    Feasibility of a WGS DST strategy Outcome measures:
    - Proportion of samples where WGS is successful (directly on sputum, liquid and solid media)
    - Proportion of participants in whom the WGS DST-guided individualized treatment recommendation is
    prescribed
    E.5.2.1Timepoint(s) of evaluation of this end point
    All patients will be followed up during treatment and for 12-month after treatment completion as per South African guidelines.
    The QOL questionnaire will happen at the baseline visit, and then monthly until treatment completion. The health economics questionnaire will be asked at week 4, 24, and at the end of treatment.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Medical device trial assessing Whole Genome Sequencing (WGS) (as a diagnostic (medical device) for the identification of the drug resistance profile of Mycobacterium tuberculosis (Mtb).
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard of Care for determining the M.tb drug resistance profile
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    South Africa
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS:
    All patients will be followed up during treatment and for 12-month after treatment completion as per South African guidelines.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 248
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 248
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None. All participants will be followed-up according to standard routine procedures for treatment, management, and follow-up of patients with drug-resistant tuberculosis.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation The Aurum institute
    G.4.3.4Network Country South Africa
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Public Health Clinics from the Free State Department of Health
    G.4.3.4Network Country South Africa
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation National Health Laboratory System - Bloemfontein, South Africa
    G.4.3.4Network Country South Africa
    G.4 Investigator Network to be involved in the Trial: 4
    G.4.1Name of Organisation Stellenbosch University
    G.4.3.4Network Country South Africa
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: South Africa
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