Drug-resistant Tuberculosis, Pulmonary Tuberculosis, Rifampin-resistant Tuberculosis
Conditions
Keywords
Drug-resistant tuberculosis, BDLL, Chinese Population, Short regimen
Brief summary
This is an investigational, prospective, multicenter, single-arm, open label trial. The goal of this clinical trial is to evaluate the efficacy and safety of a 6-month all-oral regimen, consisting of Bedaquiline (BDQ, B), Delamanid (DLM, D), Linezolid (LZD, L), Levofloxacin (LFX) or Clofazimine (CFZ, C), or BDLLfxC regimen, to treat rifampin-resistant pulmonary tuberculosis (RR-TB) in Chinese teenagers and adults (aged 12 years or above). The main questions it aims to answer are: * Is BDLLfxC regimen effective to treat RR-TB in Chinese participants? * Is BDLLfxC regimen safe in Chinese RR-TB participants? Participants will take BDLLfxC regimen to treat their RR-TB. There will be no additional hospital visits, laboratory tests or radiological examinations other than routine clinical practice.
Interventions
DRUGbedaquiline
400 milligrams (mg) daily for 2 weeks(w), then 200mg three times a week for 22 weeks (w)
DRUGdelamanid
* for participants weighing up to 33.9 kilograms (kg): 50mg two times a day for 24w * for participants weighing 34kg or above: 100mg two times a day for 8w, then 200mg daily for 16w
DRUGlinezolid
* for participants weighing up to 33.9kg: 450mg daily; * for participants weighing 34kg or above: 600mg daily; for 24w if a negative culture is obtained from sputum collected at 16w, or else for 36w
DRUGLevofloxacin
Only for participants with confirmed fluoroquinolone-susceptible TB or unknown fluoroquinolone susceptibility: * for participants weighing up to 33.9kg: 500mg daily * for participants weighing 34kg to 49.9kg: 750 daily * for participants weighing 50kg or above: 1000mg daily for 24w if a negative culture is obtained from sputum collected at 16w, or else for 36w
DRUGClofazimine
Only for participants with confirmed fluoroquinolone-resistant TB or unknown fluoroquinolone susceptibility: 100mg daily, for 24w if a negative culture is obtained from sputum collected at 16w, or else for 36w
Sponsors
Beijing Chest Hospital
Huashan Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants are willing to sign informed consent of this trial, those without capacity for civil conduct need their legal guardian to sign * Participants (and their legal guardian if applicable) are willing to cooperate to complete all trial procedures * Male or female, 12 years or older, weight ≥ 30kg * Confirmed pulmonary tuberculosis with resistance to rifampin by phenotypic or genotypic susceptibility testing within 3 months, and must be re-confirmed by sputum culture sampled at trial inclusion * Women with childbearing potential should not be pregnant, confirmed by a volunteered negative pregnancy test, and are willing to use effective contraceptive method from giving consent to 3 months after study treatment * Men with childbearing potential must be willing to use condom or other effective contraceptive methods to avoid their sex partners from being pregnant * Women in breastfeeding period must be willing to discontinue breastfeeding from giving consent to 3 months after study treatment * Participants are willing to take HIV test, and willing to take appropriate antiretroviral therapy if positive
Exclusion criteria
* Previously use of Bedaquiline or Delamanid for at least 28 days * Concomitant hematogenous disseminated tuberculosis, or severe pulmonary tuberculosis in investigator's opinion (including tuberculosis of the digestive system, osteoarticular tuberculosis or tuberculous meningitis) * Currently using any drug that has been prohibited in the protocol * History of allergic action to any of the study drugs * Currently participating in any other clinical trials * Cardiovascular risk at screening: (1) QTcF more than 480 milliseconds (ms); (2) History of clinically significant arrythmia, and at investigator's opinion, participation in this study will increase the risk; (3) Decompensated heart failure; (4) Grade 3 high blood pressure and the goals of treatment have not been reached; (5) Abnormal thyroid function; (6) Abnormal serum Ca, Mg or K level; (7) Other conditions with cardiovascular risks in investigator's opinion. * History of optic neuropathy or peripheral neuropathy, and the investigator considers that the condition may progress or deteriorate by participating in the study, or inappropriate to participate * Hepatic disorders at screening: (1) Active viral hepatitis: HBsAg positive or HBV DNA \>1000 CPs/mL, with elevated AST or ALT or HCV RNA positive; (2) Decompensated cirrhosis * Renal disorders at screening: (1) Unstable or rapidly progressive renal disease; (2) Moderate / severe renal disfunction or end-stage renal disease (eGFR\< 60 mL/min/1.73 m2); (3) Serum creatinine ≥133 μmol/L(1.5 mg/mL) in men, or ≥124 μmol/L (1.4 mg/mL) in women * Other abnormal laboratory test: (1) Hemoglobin \< 8.0g/dL; (2) Platelet \<75,000/mm3; (3) Absolute neutrophil count \<1000/mm3; (4) Aspartate transaminase (AST) or alanine aminotransferase (ALT) \>3×upper limit of normal (ULN); (5) Total bilirubin (TBil) \>2×ULN, or \>1.5×ULN together with abnormal AST or ALT; (6) Albumin \<30g/L * The investigator considers that the participant is not able to complete the study process, or the participation is not safe.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with favorable outcomes in both treatment and follow-up period | Up to 72 weeks after start of treatment | Favorable outcome in treatment period (up to 28 weeks after start of treatment): a participant's outcome will be defined as favorable if it meets any of the following below and has not been defined as unfavorable before, 1. . Cured: complete at least 80% of total required dose per protocol, with negative culture results of last two sputum samples (collected 14 days apart) ; 2. . Treatment completed: complete at least 80% of total required dose per protocol, with NO negative culture results of last two sputum samples (collected 14 days apart); Favorable outcome in follow-up period (from end of treatment to 72 weeks after start of treatment): a participant's outcome will be defined as favorable if it meets any of the following below and has not been defined as unfavorable before, (1). Cured: sputum culture negative at 72 weeks from start of treatment; (2). Culture negative when last seen: loss to follow-up before 72 weeks, with negative sputum culture when last seen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with grade 3 or 4 adverse effect | Up to 72 weeks after start of treatment | Adverse effect will be graded using Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. |
| Proportion of participants with favorable outcomes in treatment period, follow-up period and prolonged follow-up period, respectively | Up to 108 weeks after start of treatment | The definitions of favorable outcome in treatment and follow-up period are as described in primary outcome. Favorable outcome in prolonged follow-up period (from end of treatment to 108 weeks after start of treatment): a participant's outcome will be defined as favorable if it meets any of the following below and has not been defined as unfavorable before, (1). Cured: sputum culture negative at 108 weeks from start of treatment; (2). Culture negative when last seen: loss to follow-up before 108 weeks, with negative sputum culture when last seen. |
| Time to culture conversion | Up to 72 weeks after start of treatment | Time from start of treatment to the first time that obtained two consecutive negative sputum culture results, and the sputum samples must be collected 14 days apart. The date when first sputum sample is collected will be recorded as the date for culture conversion. |
Countries
China
Outcome results
None listed