Ultra-Short Regimen for Elderly DS-TB

Official title

A Ultrashort Regimen for Drug-susceptible Pulmonary Tuberculosis in Elderly Patients: A Multicenter Randomized Controlled Trial

Overview

Tuberculosis (TB) remains one of the leading global public health concerns and is among the top ten causes of death from a single infectious agent. China ranks third worldwide in total TB burden, with a substantial proportion of cases classified as drug-susceptible TB (DS-TB). Despite the availability of effective standard treatment regimens, the current 6-month therapy duration poses challenges in terms of patient adherence, resource allocation, and overall treatment success. In recent years, ultrashort-course regimens for DS-TB have been proposed and evaluated in clinical studies, showing promising results in improving adherence, reducing treatment duration, and maintaining or even enhancing treatment efficacy. However, these regimens have primarily been studied in younger populations, with limited data available for elderly patients. Older adults often present with age-related physiological changes, multiple comorbidities, and an increased risk of adverse drug reactions, which may affect both the efficacy and safety of treatment. Therefore, this study aims to assess the therapeutic effectiveness and safety profile of a novel ultrashort-course regimen for drug-susceptible pulmonary TB specifically in patients aged 65 years and older.

Interventions

• Drug Bedaquiline (B)
  The initial dose of bedaquiline is 400 mg daily for 2 weeks, followed by 200 mg three times a week.
• Drug Sitafloxacin (S)
  200mg once daily
• Drug Linezolid (L)
  600mg once daily
• Drug Pyrazinamide (Z)
  20-30 mg/kg/day; 1000 mg for patients weighing \<50 kg, 1500 mg for patients weighing ≥50 kg but \<75 kg, and 2000 mg for patients weighing ≥75 kg.
• Drug Isoniazid (H)
  4-6 mg/kg once daily, 300 mg once daily
• Drug Rifampicin (R)
  8-12 mg/kg once daily, 450 mg for patients weighing \<50 kg, 600 mg for patients weighing ≥50 kg but \<75 kg, and 750 mg for patients weighing ≥75 kg.
• Drug Ethambutol (E)
  15-25 mg/kg once daily, 750 mg once daily

Primary outcome measures

• Unfavorable outcomes [Time frame: 12 months (52 weeks)]
• Percentage of patients with treatment interruption [Time frame: 2 months (9 weeks)]

Secondary outcome measures (6)

• Sputum culture conversion rate [Time frame: 2 months (9 weeks) after randomization]
• Serious adverse events or grade 3 or higher adverse events (short-term) [Time frame: 12 months (52 weeks) after randomization]
• Serious adverse events or grade 3 or higher adverse events (mid-term) [Time frame: 18 months (78 weeks) after randomization]
• Adverse events during treatment [Time frame: 26 weeks]
• Percentage of patients with QTcF prolongation [Time frame: 26 weeks]
• Percentage of Patients with liver function damage [Time frame: 26 weeks]

Eligibility criteria

Inclusion criteria

• Aged 65 years or older, regardless of gender
• Clinical symptoms and/or pulmonary imaging (chest X-ray or chest CT) support the diagnosis of active pulmonary tuberculosis;
• Microbiological testing (molecular or phenotypic) confirms the presence of Mycobacterium tuberculosis, and susceptible to rifampicin; Recommend using respiratory specimens for GeneXpert MTB/RIF testing;
• Voluntarily sign the informed consent form for participating in this project and be able and willing to accept follow-up visits;
• Willing to undergo HIV testing;
• Willing to preserve samples including DNA;

Exclusion criteria

• Prior to this study, patients who were diagnosed with active pulmonary tuberculosis and had received anti-tuberculosis treatment (including first-line and second-line anti-tuberculosis drugs);
• Intolerance or allergy to any investigational drug (i.e., bedaquiline, linezolid, pyrazinamide, etc);
• Resistance to any investigational drug (i.e., bedaquiline, linezolid, pyrazinamide, etc). The following detection methods can be used: tNGS or other drug sensitivity testing methods (such as GeneXpert MTB/XDR, dissolution curve method, phenotypic drug sensitivity, etc.);
• Suffering from hematogenous disseminated tuberculosis or coexisting with extrapulmonary tuberculosis (as specified in this study, the scope of pulmonary tuberculosis includes: simple pulmonary tuberculosis, pulmonary tuberculosis + tuberculous pleurisy/bronchial tuberculosis/mediastinal lymph node tuberculosis. Extrapulmonary tuberculosis refers to tuberculosis other than the chest-related types mentioned above);
• Presence of non-tuberculous mycobacteria or other microbial lung infections that affect treatment outcomes;
• Simultaneously using drugs that affect the efficacy of this study or have contraindications for combination therapy;
• Use of any immunosuppressive medication or systemic glucocorticoids for more than 2 weeks before screening;
• Any medication currently used or planned to be used that is known to significantly prolong the QTc interval, including but not limited to: amiodarone, amitriptyline, chloroquine, chlorpromazine, cisapride, dipyridamole, itraconazole, procaine, quinidine, or sotalol;
• Uncontrolled blood sugar in diabetes, with no likelihood of improving blood sugar status according to the judgment of the researchers;
• HIV positive;
• Coexisting with severe autoimmune diseases, severe liver and kidney dysfunction, psychiatric disorders, hematological disorders, or malignant tumors;
• Laboratory parameters within 14 days prior to recruitment: (1) Serum AST and ALT levels ≥ 3 times the upper limit of normal (ULN); (2) Blood creatinine ≥ 2 times ULN; (3) Hemoglobin ≤ 70 g/L; (4) Platelet count ≤ 50 × 10\^9/L; (5) Blood potassium levels are ≥ 5.5 mmol/L or ≤ 3.5 mmol/L;
• ECG QTcF ≥450 ms (allowing for one re-test during the screening phase to reassess eligibility for inclusion); Presence of one or more risk factors that could cause QT interval prolongation, such as arrhythmia, myocardial ischemia, etc.; history or family history of long QT syndrome;
• Weight <30 kg, or ≥90 kg;
• The patient has participated in clinical trials of other drugs within the past 3 months during the screening period;
• Other conditions deemed unsuitable for participation in the study by the research doctors.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Paton NI, Cousins C, Suresh C, Burhan E, Chew KL, Dalay VB, Lu Q, Kusmiati T, Balanag VM, Lee SL, Ruslami R, Pokharkar Y, Djaharuddin I, Sugiri JJR, Veto RS, Sekaggya-Wiltshire C, Avihingsanon A, Sarin R, Papineni P, Nunn AJ, Crook AM; TRUNCATE-TB Trial Team. Treatment Strategy for Rifampin-Susceptible Tuberculosis. N Engl J Med. 2023 Mar 9;388(10):873-887. doi: 10.1056/NEJMoa2212537. Epub 2023 Fe PMID 36808186

Identifiers

NCT: NCT07076225 · USRElderly

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗