Change in WHO recommendations for standard of care (control arm); availability of new shorter treatment regimens for MDR-TB; war in Ukraine where two study sites are located; key trial team members left the team.

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.

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.

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.

All study data will be pseudonymised and shared with other researchers only in pseudonymised form

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.