PredictEndTB Signature for Individualizing Treatment in Multidrug-Resistant Tuberculosis

Personalized Therapy Durations Defined by the Blood RNA-based Model for Individualizing Treatment in Multidrug-Resistant Tuberculosis

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.

Study Overview

• Status: Terminated
• Conditions: Bacterial Infections; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Mycobacterial Infection
• Intervention / Treatment: Diagnostic test: Individualised treatment duration based on RNA transcriptomic model

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Schleswig-Holstein
    • Borstel, Schleswig-Holstein, Germany, 23845
      • Research Center Borstel
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, 2025
    • Phthisiopneumology Institute Chiril Draganiuc
• Romania
  • Bucharest, Romania
    • Marius Nasta Pulmonology Institute
• Ukraine
  • Kharkiv, Ukraine, 61000
    • Kharkiv National Medical University
  • Vinnytsia, Ukraine, 21018
    • National Pirogov Memorial Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm; The individualised treatment durations defined by the RNA transcriptomic signature-based model	Diagnostic test: Individualised treatment duration based on RNA transcriptomic model; 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.
No Intervention: Control arm; The locally accepted standard duration of treatment based on the WHO recommendation for treatment of MDR-TB patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	up to 24 months
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	up to 24 months
Proportion of patients who died from TB	This outcome measure will be used in the secondary efficacy analysis in the Intention-to-Treat population	up to 36 months
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	up to 36 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients experiencing adverse events	This outcome measure will be used in the exploratory safety analysis in the safety population	up to 24 months
Proportion of patients who experienced TB relapse that was identified on early stages	This outcome measure will be used in the safety analysis in the safety population	up to 36 months
Characteristics of the transcriptomic signatures obtained at the end of therapy time point and at follow-up visits	This outcome measure will be used in the exploratory safety analysis in the safety population	up to 36 months

Collaborators and Investigators

• Sponsor: Research Center Borstel
• Collaborators: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Jan Heyckendorf, MD, Research Center Borstel

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Actual): November 1, 2022
• Study Completion (Actual): November 1, 2022

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: March 2, 2021
• First Posted (Actual): March 5, 2021

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: tuberculosis; multidrug resistance; treatment duration
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Infections; Communicable Diseases; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Bacterial Infections
• Other Study ID Numbers: PredictEndTBSignature

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: All study data will be pseudonymised and shared with other researchers only in pseudonymised form

Drug and device information, study documents

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