PredictEndTB Signature for Individualizing Treatment in Multidrug-Resistant Tuberculosis
Primary Purpose
Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Bacterial Infections
Status
Suspended
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Individualised treatment duration based on RNA transcriptomic model
Sponsored by
About this trial
This is an interventional treatment trial for Tuberculosis, Pulmonary focused on measuring tuberculosis, multidrug resistance, treatment duration
Eligibility Criteria
Inclusion Criteria:
- Patient starting an MDR-TB treatment or within the first 4 weeks after treatment initiation and before culture conversion.
- Rifampicin resistant M. tuberculosis detected in sputum using a nucleic acid amplification test.
- New case of TB or re-treatment.
- Can give informed consent at the point of recruitment.
- Contactable (residing in the area covered by participating TB centres and possessing a landline or a mobile phone).
- Willing to participate for the entire course of the treatment and extensive follow-up.
Exclusion Criteria:
- Age <18 years old.
- Anti-MDR-TB therapy within 6 months prior to the start date of the current treatment cycle.
- HIV infection.
- Non-adherent patient with frequent interruptions.
- Patient in custodianship or guardianship.
- Late exclusion criterion: no positive cultures at inclusion and within the first 3 months of treatment.
Sites / Locations
- Research Center Borstel
- Phthisiopneumology Institute Chiril Draganiuc
- Marius Nasta Pulmonology Institute
- Kharkiv National Medical University
- National Pirogov Memorial Medical University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Experimental arm
Control arm
Arm Description
The individualised treatment durations defined by the RNA transcriptomic signature-based model
The locally accepted standard duration of treatment based on the WHO recommendation for treatment of MDR-TB patients
Outcomes
Primary Outcome Measures
Proportion of patients with favourable study outcome 12 months after treatment end
The non-inferiority of the experimental arm compared to the control arm will be established if in the Per-Protocol population the difference in proportions of patients with a favourable study outcome between study arms is greater than the lower equivalence margin of 12%. This outcome measure is assessed after up to 24 months of treatment (usually 20 months) plus 12 months of follow-up after the end of treatment.
Secondary Outcome Measures
Proportion of patients who was lost to follow-up during treatment
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Proportion of patients who had a treatment failure
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Proportion of patients who died from TB
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Proportion of patients who died of any cause
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Full Information
NCT ID
NCT04783727
First Posted
March 2, 2021
Last Updated
September 8, 2022
Sponsor
Research Center Borstel
Collaborators
Ludwig-Maximilians - University of Munich
1. Study Identification
Unique Protocol Identification Number
NCT04783727
Brief Title
PredictEndTB Signature for Individualizing Treatment in Multidrug-Resistant Tuberculosis
Official Title
Personalized Therapy Durations Defined by the Blood RNA-based Model for Individualizing Treatment in Multidrug-Resistant Tuberculosis
Study Type
Interventional
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Suspended
Why Stopped
Change in WHO recommendations for standard of care (control arm); war in Ukraine where two study sites are located.
Study Start Date
April 1, 2021 (Actual)
Primary Completion Date
November 2025 (Anticipated)
Study Completion Date
March 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Research Center Borstel
Collaborators
Ludwig-Maximilians - University of Munich
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
PredictEndTB signature is a non-inferiority, prospective, parallel-group open-label randomized controlled trial evaluating the efficacy of individualised antituberculous treatment durations that utilize the transcriptomic signature-based model compared to the standardised twenty months treatment in a cohort of multidrug-resistant tuberculosis patients.
Detailed Description
This study is a non-inferiority, prospective, parallel-group open-label randomized controlled trial. Three hundred forty-two HIV-negative patients diagnosed with pulmonary tuberculosis (TB) and starting a new anti-multidrug-resistant tuberculosis (MDR-TB) treatment cycle will be included in the study. Two randomized arms of 171 patients each will be recruited over the two-year period, each patient will be followed-up over the entire course of anti-TB treatment and one year after the end of therapy. Regular study visits will include physical examination, collection of sputum, blood and urine and filling in the study questionnaire. On the collected specimens standard bacteriological and blood tests, as well as extended immunological analysis, will be performed. In the experimental group, an RNA transcriptomic analysis using RNA-Seq technology will also be performed.
In the control arm, the patients will receive a standardised World Health Organization recommended 20 months treatment while in the experimental arm the treatment duration will be guided by the transcriptomic signature-based model.
Treatment outcomes and level of TB relapse and survival within the follow-up period will be compared between the experimental and control arms. The efficacy of biomarker-guided treatment therapy will be assessed by a comparison of the proportions of favourable study outcome between two arms.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Bacterial Infections, Mycobacterial Infection
Keywords
tuberculosis, multidrug resistance, treatment duration
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Masking Description
During the treatment, both Participant and Care Provider will be masked but once the treatment end is achieved, they will be unmasked, and study participation is continued.
Allocation
Randomized
Enrollment
342 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Experimental arm
Arm Type
Experimental
Arm Description
The individualised treatment durations defined by the RNA transcriptomic signature-based model
Arm Title
Control arm
Arm Type
No Intervention
Arm Description
The locally accepted standard duration of treatment based on the WHO recommendation for treatment of MDR-TB patients
Intervention Type
Diagnostic Test
Intervention Name(s)
Individualised treatment duration based on RNA transcriptomic model
Intervention Description
Anti-MDR-TB treatment with standard drugs and individual treatment duration guided by the RNA transcriptomic model; may be shorter or longer than standard WHO-recommended treatment duration of 20 months.
Primary Outcome Measure Information:
Title
Proportion of patients with favourable study outcome 12 months after treatment end
Description
The non-inferiority of the experimental arm compared to the control arm will be established if in the Per-Protocol population the difference in proportions of patients with a favourable study outcome between study arms is greater than the lower equivalence margin of 12%. This outcome measure is assessed after up to 24 months of treatment (usually 20 months) plus 12 months of follow-up after the end of treatment.
Time Frame
up to 36 months
Secondary Outcome Measure Information:
Title
Proportion of patients who was lost to follow-up during treatment
Description
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Time Frame
up to 24 months
Title
Proportion of patients who had a treatment failure
Description
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Time Frame
up to 24 months
Title
Proportion of patients who died from TB
Description
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Time Frame
up to 36 months
Title
Proportion of patients who died of any cause
Description
This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population
Time Frame
up to 36 months
Other Pre-specified Outcome Measures:
Title
Proportion of patients experiencing adverse events
Description
This outcome measure will be used in the exploratory safety analysis in the safety population
Time Frame
up to 24 months
Title
Proportion of patients who experienced TB relapse that was identified on early stages
Description
This outcome measure will be used in the safety analysis in the safety population
Time Frame
up to 36 months
Title
Characteristics of the transcriptomic signatures obtained at the end of therapy time point and at follow-up visits
Description
This outcome measure will be used in the exploratory safety analysis in the safety population
Time Frame
up to 36 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patient starting an MDR-TB treatment or within the first 4 weeks after treatment initiation and before culture conversion.
Rifampicin resistant M. tuberculosis detected in sputum using a nucleic acid amplification test.
New case of TB or re-treatment.
Can give informed consent at the point of recruitment.
Contactable (residing in the area covered by participating TB centres and possessing a landline or a mobile phone).
Willing to participate for the entire course of the treatment and extensive follow-up.
Exclusion Criteria:
Age <18 years old.
Anti-MDR-TB therapy within 6 months prior to the start date of the current treatment cycle.
HIV infection.
Non-adherent patient with frequent interruptions.
Patient in custodianship or guardianship.
Late exclusion criterion: no positive cultures at inclusion and within the first 3 months of treatment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan Heyckendorf, MD
Organizational Affiliation
Research Center Borstel
Official's Role
Principal Investigator
Facility Information:
Facility Name
Research Center Borstel
City
Borstel
State/Province
Schleswig-Holstein
ZIP/Postal Code
23845
Country
Germany
Facility Name
Phthisiopneumology Institute Chiril Draganiuc
City
Chisinau
ZIP/Postal Code
2025
Country
Moldova, Republic of
Facility Name
Marius Nasta Pulmonology Institute
City
Bucharest
Country
Romania
Facility Name
Kharkiv National Medical University
City
Kharkiv
ZIP/Postal Code
61000
Country
Ukraine
Facility Name
National Pirogov Memorial Medical University
City
Vinnytsia
ZIP/Postal Code
21018
Country
Ukraine
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
All study data will be pseudonymised and shared with other researchers only in pseudonymised form
Citations:
PubMed Identifier
33574078
Citation
Heyckendorf J, Marwitz S, Reimann M, Avsar K, DiNardo AR, Gunther G, Hoelscher M, Ibraim E, Kalsdorf B, Kaufmann SHE, Kontsevaya I, van Leth F, Mandalakas AM, Maurer FP, Muller M, Nitschkowski D, Olaru ID, Popa C, Rachow A, Rolling T, Rybniker J, Salzer HJF, Sanchez-Carballo P, Schuhmann M, Schaub D, Spinu V, Suarez I, Terhalle E, Unnewehr M, Weiner J 3rd, Goldmann T, Lange C. Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model. Eur Respir J. 2021 Sep 2;58(3):2003492. doi: 10.1183/13993003.03492-2020. Print 2021 Sep.
Results Reference
background
PubMed Identifier
34331877
Citation
Heyckendorf J, Reimann M, Marwitz S, Lange C; DZIF-TB cohort study group. Pathogen-free diagnosis of tuberculosis. Lancet Infect Dis. 2021 Aug;21(8):1066. doi: 10.1016/S1473-3099(21)00337-6. No abstract available.
Results Reference
background
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PredictEndTB Signature for Individualizing Treatment in Multidrug-Resistant Tuberculosis
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