A Study on the Short-course Treatment Regimen Containing Pretomanid for Drug-resistant Tuberculosis

Study Design Type This study is a prospective, randomized controlled trial aimed at evaluating the efficacy and safety of different treatment regimens for patients with drug-resistant tuberculosis (RR-TB).

Study Subjects Patients with MDR/RR-TB who meet the inclusion and exclusion criteria will be enrolled in this study. Deviation from the inclusion and exclusion criteria is not allowed as it may compromise the scientific integrity, regulatory acceptability, or safety of the study participants. Therefore, it is crucial to adhere to the criteria specified in the study protocol.

Study Population Study Population: Male or female patients aged ≥12 years, with newly diagnosed or retreated pulmonary tuberculosis, and no contraindications to the study drugs.

Planned Enrollment 200 cases, 100 cases in each group. Inclusion and Exclusion Criteria

Inclusion Criteria:

The study participant (or their legal guardian if the participant lacks legal capacity) voluntarily signs the informed consent form before enrollment.

The study participant (and their guardian) indicates willingness to complete all study steps and intervention cycles.

Male or female, aged ≥12 years, and weighing ≥30 kilograms. Confirmed pulmonary tuberculosis by microbiological diagnosis, with molecular or phenotypic drug susceptibility test results within the last 3 months confirming rifampicin resistance, and confirmed by sputum culture results at enrollment.

For women of childbearing age, not pregnant, willing to undergo a pregnancy test with a negative result, and willing to use highly effective contraceptive measures from signing the informed consent until 3 months after the end of the study treatment.

For men of childbearing age, using condoms or other methods to ensure effective contraception for their sexual partners.

Women who are breastfeeding are willing to stop breastfeeding from signing the informed consent until 3 months after the end of the study treatment.

Willing to undergo HIV testing, and if the result is positive, willing to receive antiretroviral therapy.

Exclusion Criteria:

Previous treatment with bedaquiline (BDQ) or delamanid (DLM) for more than 28 days.

Concurrent hematogenous disseminated pulmonary tuberculosis or severe extrapulmonary tuberculosis (including gastrointestinal tuberculosis, genitourinary tuberculosis, bone and joint tuberculosis, tuberculous meningitis, etc.) as determined by the investigator.

Currently using prohibited drugs as specified in the study protocol, and the investigator believes that the priority of continuing the drug is higher than participating in this study from the perspective of patient benefit.

Known hypersensitivity to any drug in the study protocol. Currently participating in any other drug clinical trial. Cardiovascular disease risk at screening: QTcF interval \> 480 milliseconds; history of clinically significant arrhythmia within 60 days before enrollment as determined by the investigator, and the investigator believes that participation in the study may increase the risk; decompensated heart failure; grade 3 hypertension and not reaching the control target; thyroid dysfunction; abnormal serum calcium, magnesium, or potassium levels.

History of optic neuropathy or peripheral neuropathy, and the investigator believes that progression/deterioration may occur during the study or the participant is not suitable for the study.

Liver disease manifestations at screening: active viral hepatitis; decompensated liver cirrhosis.

Kidney disease history or related manifestations at screening: unstable or rapidly progressive kidney disease; moderate/severe renal impairment or end-stage renal disease; male serum creatinine ≥ 133 μmol/L, female serum creatinine ≥ 124 μmol/L.

Other laboratory abnormalities: hemoglobin level \< 8.0 g/dL; platelet count \< 75,000/mm³; absolute neutrophil count \< 1000/mm³; aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \> 3×ULN; total bilirubin \> 2×ULN, or \> 1.5×ULN with other liver enzyme abnormalities; albumin \< 30 g/L. Researchers believe that study participants are unable to complete the study process or that participation in the study is unsafe for the participants.

Study Process

This study plans to include RR-TB patients aged ≥12 years. Under the guidance of rapid molecular drug susceptibility test results for fluoroquinolones (FQs), patients will be randomly divided into two groups:

Experimental group: treated with a regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin for 6 months.

Control group:

For FQ-sensitive patients, treated with a regimen of bedaquiline, delamanid, linezolid, and levofloxacin for 6 months.

For FQ-resistant patients, treated with a regimen of bedaquiline, delamanid, linezolid, and clofazimine for 6 months.

For patients with unknown FQ susceptibility results, treated with a regimen of bedaquiline, delamanid, linezolid, levofloxacin, and clofazimine for 6 months.

The study duration includes the screening period, treatment period, post-treatment follow-up period, and extended follow-up period. The study treatment is selected based on FQ susceptibility results. Patients with negative sputum culture at 16 weeks continue for 24 weeks, and those with positive sputum culture continue for 36 weeks. Visit frequency: every 4 weeks during the treatment period and every 8 weeks during the post-treatment follow-up period.

Observation Indicators

Outcome and endpoint definitions:

Benign outcomes during the treatment period:

Cure: completing 80% or more of the required medication dose within 28 weeks after the start of study treatment, with no evidence of treatment failure, and negative MTB culture in the last two sputum specimens (collected at least 14 days apart) at the end of treatment.

Completion of treatment: completing 80% or more of the required medication dose within 28 weeks after the start of study treatment, with no evidence of treatment failure, but no evidence of negative MTB culture in two sputum specimens collected at least 14 days apart at the end of treatment.

Benign outcomes during the post-treatment follow-up period:

Cure: negative MTB sputum culture at 72 weeks after enrollment. Negative sputum culture at the last visit before loss to follow-up: if lost to follow-up before 72 weeks after enrollment and the last MTB sputum culture before loss to follow-up is negative.

Benign outcomes during the extended follow-up period:

Cure: negative MTB sputum culture at 108 weeks after enrollment. Negative sputum culture at the last visit before loss to follow-up: if lost to follow-up before 108 weeks after enrollment and the last MTB sputum culture before loss to follow-up is negative.

Adverse outcomes:

Death: death due to any cause. Drug change: permanent replacement or addition of at least one drug due to any reason, except for adjustments based on baseline drug susceptibility.

• Favorable outcomes during the follow - up period after treatment [Срок оценки: From the beginning of the treatment until 72 weeks.]
• Favorable outcomes with an extended follow - up period [Срок оценки: Follow - up was conducted until 108 weeks after enrollment.]
• Unfavorable outcome [Срок оценки: From the time of enrollment until the 108th week of follow - up]