E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rifampicin resistant (RR-TB) and drug resistant (DR-TB) tuberculosis |
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E.1.1.1 | Medical condition in easily understood language |
Rifampicin resistant (RR-TB) and drug resistant (DR-TB) tuberculosis |
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E.1.1.2 | Therapeutic area | Health Care [N] - Health Services Administration [N04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10049031 |
E.1.2 | Term | Genotype drug resistance test |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10048723 |
E.1.2 | Term | Multiple-drug resistance |
E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059866 |
E.1.2 | Term | Drug resistance |
E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004052 |
E.1.2 | Term | Bacterial resistance |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038637 |
E.1.2 | Term | Resistance bacterial |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028152 |
E.1.2 | Term | Multi-antibiotic resistance |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070974 |
E.1.2 | Term | Antibiotic resistance test |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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). |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other 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).
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard of Care for determining the M.tb drug resistance profile |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial 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
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LVLS: All patients will be followed up during treatment and for 12-month after treatment completion as per South African guidelines. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 4 |