A PAN-USR TB Multi-Center Trial

Southern University of Science and Technology

Status and phase: Enrolling; Phase 3

Conditions: Pulmonary Tuberculosis

Treatments: Drug: Pretomanid (Pa); Drug: Ethambutol (E); Drug: Pyrazinamide (Z); Drug: Isoniazid (H); Drug: Rifampicin (R); Drug: Linezolid (L); Drug: Moxifloxacin (M); Drug: Sitafloxacin (S); Drug: Bedaquiline (B)

Study type: Interventional

Funder types: Other

Identifiers

NCT06905522

SMART-C2405002

Details and patient eligibility

About

Tuberculosis (TB) remains a major public health issue and one of the top ten causes of death from a single infectious disease worldwide. China is among the countries with the highest TB burden, ranking third globally for total TB cases and second for drug-resistant TB cases. PAN-TB is an innovative concept in TB treatment, aiming to develop a universal regimen effective for all forms of active TB, including both drug-susceptible and drug-resistant strains. The primary goal of the PAN-TB regimen is to simplify the treatment process, reduce costs, and improve treatment success rates. The ideal Target Regimen Profile (TRP) for PAN-TB includes superior efficacy compared to standard treatment for non-drug-resistant TB, a reduced treatment duration from the current 4-6 months to 2-3 months, and improved safety and tolerability. This project aims to explore a new ultra-short-course treatment regimen for both drug-sensitive (DS-TB) and drug-resistant TB (MDR/RR-TB), which aligns with the latest trends in TB treatment both domestically and internationally. The regimen also has significant practical implications for enhancing treatment efficacy and reducing patient burden. Furthermore, the study will explore the identification of new biomarkers closely linked to treatment outcomes over the course of full-cycle therapy.

Enrollment: 610 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age range from 18 to 65 years old, regardless of gender;
2. Clinical symptoms and/or pulmonary imaging (chest X-ray or chest CT) support the diagnosis of active pulmonary tuberculosis;
3. Microbiological testing (molecular or phenotypic) confirms the presence of Mycobacterium tuberculosis, whether resistant to rifampicin or not; Recommend using respiratory specimens for GeneXpert MTB/RIF testing;
4. Voluntarily sign the informed consent form for participating in this project and be able and willing to accept follow-up visits;
5. Willing to undergo HIV testing;
6. Willing to preserve samples including DNA;
7. For women with fertility, they have a negative serum or urine pregnancy test within 3 days before enroll the study and be willing to use effective contraceptive measures during the study period. Female subjects without fertility must have records of menopause, hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. Acceptable forms of contraception include condoms, intrauterine devices, cervical caps with spermicides, and diaphragm with spermicides.

Exclusion criteria

1. 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);
2. Intolerance or allergy to any investigational drug (i.e., bedaquiline, linezolid, fluoroquinolones [including moxifloxacin, sitagliptin], pyrazinamide);
3. Resistance to any investigational drug (i.e., bedaquiline, linezolid, fluoroquinolones [including moxifloxacin, sitagliptin], pyrazinamide). 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.);
4. 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);
5. Presence of non-tuberculous mycobacteria or other microbial lung infections that affect treatment outcomes;
6. Simultaneously using drugs that affect the efficacy of this study or have contraindications for combination therapy;
7. Use of any immunosuppressive medication or systemic glucocorticoids for more than 2 weeks before screening;
8. 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;
9. Uncontrolled blood sugar in diabetes, with no likelihood of improving blood sugar status according to the judgment of the researchers;
10. HIV positive;
11. Coexisting with severe autoimmune diseases, severe liver and kidney dysfunction, psychiatric disorders, hematological disorders, or malignant tumors;
12. 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;
13. 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;
14. Women who are pregnant or breastfeeding;
15. Weight <30 kg, or ≥90 kg;
16. The patient has participated in clinical trials of other drugs within the past 3 months during the screening period;
17. Other conditions deemed unsuitable for participation in the study by the research doctors.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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610 participants in 4 patient groups

Drug-susceptible TB (A1)

Experimental group

Description:

2 months (9 weeks) BLSZ regimen: The treatment involves the use of bedaquiline (B), linezolid (L), sitafloxacin (S), and pyrazinamide (Z) throughout the entire process. At the end of 2 months (9 weeks) of treatment, if the sputum smear is still positive or if clinical symptoms have not improved, the treatment duration can be extended to 13 weeks. After the extended treatment period (3 months or 13 weeks), if the sputum smear remains positive or if clinical symptoms have not been relieved, the patient should be switched to the standard treatment regimen, and the subject should be withdrawn from the study.

Treatment:

Drug: Sitafloxacin (S)

Drug: Bedaquiline (B)

Drug: Linezolid (L)

Drug: Pyrazinamide (Z)

Drug-resistant TB (A2)

Experimental group

Description:

2 months (9 weeks) BLSZ regimen: The treatment involves the use of bedaquiline (B), linezolid (L), sitafloxacin (S), and pyrazinamide (Z) throughout the entire process. At the end of 2 months (9 weeks) of treatment, if the sputum smear is still positive or if clinical symptoms have not improved, the treatment duration can be extended to 13 weeks. After the extended treatment period (3 months or 13 weeks), if the sputum smear remains positive or if clinical symptoms have not been relieved, the patient should be switched to the standard treatment regimen, and the subject should be withdrawn from the study.

Treatment:

Drug: Sitafloxacin (S)

Drug: Bedaquiline (B)

Drug: Linezolid (L)

Drug: Pyrazinamide (Z)

Drug-susceptible TB (B)

Active Comparator group

Description:

2HRZE/4HR (26 weeks): Four drugs-isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E)-are used during the first 2 months of the intensive phase. This is followed by 4 months of consolidation treatment, during which only isoniazid and rifampicin are used.

Treatment:

Drug: Rifampicin (R)

Drug: Isoniazid (H)

Drug: Ethambutol (E)

Drug: Pyrazinamide (Z)

Drug-resistant TB (C)

Active Comparator group

Description:

6 months (26 weeks) of BPaLM: The treatment involves the use of bedaquiline (B), pretomanid (Pa), linezolid (L), and moxifloxacin (M) throughout the entire course. If the sputum culture remains positive at 4 months, or if clinical symptoms are not relieved by 6 months, or if chest CT results show worsening at 6 months, the treatment may be extended to 9 months. If the patient chooses to withdraw from the study at 6 months, they are allowed to do so.

Treatment:

Drug: Bedaquiline (B)

Drug: Moxifloxacin (M)

Drug: Linezolid (L)

Drug: Pretomanid (Pa)