NCT05007821

已完成

2 期

A Phase II, Prospective, Randomized, Multicenter Trial to Evaluate the Efficacy and Safety/Tolerability of Two Linezolid Dosing Strategies in Combination With a Short Course Regimen for the Treatment of Drug-Resistant Pulmonary Tuberculosis

National Institute of Allergy and Infectious Diseases (NIAID)25 个研究点分布在 7 个国家目标入组 138 人2022年9月27日

适应症Tuberculosis, Multidrug-Resistant Tuberculosis Tuberculosis, Pulmonary

干预措施Delamanid 300 mg Clofazimine 300 mg Clofazimine 100 mg Bedaquiline 200 mg Bedaquiline 100 mg Linezolid 600 mg Linezolid 1200 mg (QD)Linezolid 1200 mg (TIW)

概览

阶段: 2 期
干预措施: Delamanid 300 mg
疾病 / 适应症: Tuberculosis, Multidrug-Resistant
发起方: National Institute of Allergy and Infectious Diseases (NIAID)
入组人数: 138
试验地点: 25
主要终点: Cumulative probability of sputum culture conversion
状态: 已完成
最后更新: 昨天

概览研究者入排标准研究组 & 干预措施结局指标研究点相似试验

概览

简要总结

The purpose of the study was to evaluate the efficacy (how well the medicines work) and tolerability (whether participants stop treatment because of side effects from a drug) of an anti-TB treatment regimen that compared two doses of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). This study also measured the level of LZD and BDQ in the participants' blood.

详细描述

When the study was designed, there was currently no "standard of care" or single standardized treatment regimen recommended for everyone with drug resistant-tuberculosis (DR-TB). Current DR-TB treatments were not well tolerated and often had side effects. There was a need to identify drugs with enough anti-TB activity (treatment against TB) and good safety profiles that could improve outcomes in the treatment of DR-TB. The main purpose of this study was to evaluate the efficacy and tolerability of a new shorter course anti-TB treatment regimen that compared two dosing strategies of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). As a secondary aim, the study assessed the safety (the level and type of side effects from a drug or treatment) of the combination of these drugs. Everyone in the study took BDQ, DLM, and CFZ once a day for the entire treatment period. The difference between the two treatment groups in the study was in how participants took the fourth drug: LZD. Participants in group A took one dose of LZD once a day for the entire treatment period. Participants in group B took a higher dose of LZD once a day for 4 weeks and then took that higher dose of LZD just three times a week for the rest of the treatment period.

注册库

clinicaltrials.gov

开始日期

2022年9月27日

结束日期

2026年1月13日

最后更新

昨天

研究类型

Interventional

研究设计

Parallel

性别

All

研究者

发起方

National Institute of Allergy and Infectious Diseases (NIAID)

责任方

Sponsor

入排标准

入选标准

•Newly diagnosed pulmonary drug-resistant tuberculosis (DR-TB), with resistance to at least rifampicin or rifampin (which is a drug used in the therapy of tuberculosis) confirmed from a sputum specimen collected within 60 days prior to entry.
•HIV-1 infection status documented as either absent or present.
•For participants living with HIV, either currently on an antiretroviral therapy (ART) regimen or willing and able to start ART within 30 days after entry.
•Efavirenz or etravirine (drugs used to treat HIV) must be discontinued prior to a participant's starting anti-TB medications. For participants on efavirenz or etravirine, they must be willing and able to discontinue these at least 7 days prior to initiating study TB medications.
•For participants living with HIV, CD4+ cell (a type of white blood cell) count greater than or equal to 50 cells/mm3 obtained within 60 days prior to study entry.
•For females of reproductive potential, negative serum or urine pregnancy test.
•Females of reproductive potential who are participating in sexual activity that could lead to pregnancy must agree to use two of the following forms of birth control while receiving TB study medications and for 30 days after stopping study medications:
•Male or female condoms
•Diaphragm or cervical cap (with spermicide, if available)
•Intrauterine device (IUD) or intrauterine system (IUS)

排除标准

•Documentation of clinically significant (as judged by the study doctor) active infections (including HIV-related opportunistic infections) other than TB and HIV requiring treatment within 30 days prior to entry.
•Evidence of clinically significant (as judged by the study doctor) metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric, endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) that would interfere with study medications or procedures.
•Inability to take oral medications.
•Suspected or documented TB involving the central nervous system, clinically significant renal TB or TB pericarditis, or current extrapulmonary TB involving other organ systems that might interfere with study medications or procedures, as judged by the study doctor.
•Prior treatment with one or more of the study drugs at any time in the past for an episode of DR-TB that is not the qualifying episode or treatment for more than 7 cumulative days with one or more of the study drugs within 30 days prior to entry for the qualifying episode of DR-TB.
•History of allergy or hypersensitivity to any of the study drugs or medications in the same class as the study drugs.
•Known or suspected current alcohol and/or drug abuse that is, in the opinion of the study doctor, sufficient to compromise the safety and/or cooperation of the participant.
•Receipt of any investigational drugs within 60 days prior to entry.
•Known history of prolonged QT syndrome (heart rhythm condition that can potentially cause fast, chaotic heartbeats) or current prolonged QT interval on screening electrocardiogram (a medical test that detects cardiac (heart) abnormalities).
•Known history of clinically significant cardiac arrhythmia (a condition in which the heart beats with an irregular or abnormal rhythm) requiring medication or clinically significant electrocardiogram (ECG) abnormality, in the opinion of the study doctor, within 60 days prior to entry.

研究组 & 干预措施

Arm A

Everyone in the study took bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) once a day for the entire treatment period. Arm A participants took linezolid (LZD) once a day for the entire treatment period. * Weeks 1-26: LZD 600 mg once daily (QD) * Weeks 1-2: BDQ 200 mg QD + DLM 300 mg QD + CFZ 300 mg QD * Weeks 3-8: BDQ 200 mg QD + DLM 300 mg QD + CFZ 100 mg QD * Weeks 9-26: BDQ 100 mg QD + DLM 300 mg QD + CFZ 100 mg QD

干预措施: Delamanid 300 mg

Arm A

干预措施: Clofazimine 300 mg

Arm A

干预措施: Clofazimine 100 mg

Arm B

Everyone in the study took bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) once a day for the entire treatment period. Arm B participants took a higher dose of linezolid (LZD) once a day for 4 weeks and then took that higher dose of LZD just three times a week for the rest of the treatment period. * Weeks 1-4: LZD 1200 mg once daily (QD) * Weeks 5-26: LZD 1200 mg three times per week (TIW) * Weeks 1-2: BDQ 200 mg QD + DLM 300 mg QD + CFZ 300 mg QD * Weeks 3-8: BDQ 200 mg QD + DLM 300 mg QD + CFZ 100 mg QD * Weeks 9-26: BDQ 100 mg QD + DLM 300 mg QD + CFZ 100 mg QD

干预措施: Clofazimine 100 mg

Arm B

干预措施: Delamanid 300 mg

Arm A

干预措施: Bedaquiline 200 mg

Arm B

干预措施: Bedaquiline 200 mg

Arm A

干预措施: Bedaquiline 100 mg

Arm B

干预措施: Bedaquiline 100 mg

Arm A

干预措施: Linezolid 600 mg

Arm B

干预措施: Linezolid 1200 mg (QD)

Arm B

干预措施: Linezolid 1200 mg (TIW)

Arm B

干预措施: Clofazimine 300 mg

结局指标

主要结局

Cumulative probability of sputum culture conversion

时间窗: Up to 26 weeks

Cumulative probability of permanent discontinuation of at least one anti-TB drug due to adverse events, intolerance, or death

时间窗: Up to 26 weeks

Time to 26 Weeks Stable Culture Conversion in Liquid Media

时间窗: Up to 26 weeks

Time of stable liquid culture conversion was the visit corresponding to the 1st of 2 consecutive MTB-neg cultures obtained at least 7 days apart without an intervening MTB-pos culture. Inability to produce sputum with or without induction was considered an MTB-neg culture. A participant was MTB-pos at a visit if at least 1 of the liquid cultures was MTB-pos. A participant was MTB-neg at a visit if both liquid cultures were MTB-neg or if 1 liquid culture was MTB-neg and the other was missing or indeterminate. If the 1st MTB-neg liquid culture was at week 26, then conversion was met. If a participant did not convert by week 26, they were censored at their last culture result. If a participant died (any cause except trauma), they were censored at week 26 (worst possible outcome). Within-arm Kaplan-Meier estimates of proportions at week 26 and the Cox proportional hazards regression model hazard ratio were calculated; between-arm differences were tested with the log rank test.

Proportion of Participants With Permanent Discontinuation of At Least One Anti-TB Drug Due To Adverse Events, Intolerance, Or Death

时间窗: Up to 26 weeks

Time of permanent discontinuation of at least one anti-TB drug due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with at least one anti-TB drug or study visits, or due to participant request was the corresponding date of discontinuation. If a participant did not permanently discontinue at least one anti-TB drug due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with at least one anti-TB drug or study visits, or due to participant request by week 26, they were censored at the date of permanent treatment discontinuation of all study drugs or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with permanent discontinuation were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula.

次要结局

Proportion of doses taken during the treatment period(Up to 26 weeks)
Cumulative probability of sputum culture conversion(At week 38)
Cumulative probability of treatment-related adverse events(Up to 26 weeks)
Linezolid minimum plasma concentration (Cmin)(At week 4)
Linezolid maximum plasma concentration (Cmax)(At week 4)
Cumulative probability of permanent discontinuation of LZD due to AEs, intolerance, or death; temporary discontinuation of LZD for any reason; and dose reduction of LZD(Up to 26 weeks)
Linezolid time to reach maximum plasma concentration (Tmax)(At week 4)
Linezolid area under the concentration-time curve (AUC)(At week 4)
Delamanid minimum plasma concentration (Cmin)(At week 4)
Delamanid area under the concentration-time curve (AUC)(At week 4)
Delamanid apparent oral clearance (CL/F)(At week 4)
Linezolid apparent oral clearance (CL/F)(At week 4)
Cumulative probability of unfavorable TB treatment outcome(At week 72)
Delamanid maximum plasma concentration (Cmax)(At week 4)
Delamanid time to reach maximum plasma concentration (Tmax)(At week 4)
Proportion of Participants Achieving Stable Liquid Culture Conversion(At week 8)
Proportion of Participants Achieving Stable Liquid Culture Conversion(At week 16)
Proportion of Participants Achieving Stable Liquid Culture Conversion(At week 26)
Proportion of Participants Achieving Stable Liquid Culture Conversion(At week 38)
Proportion of Participants With Permanent Discontinuation of LZD Due To Adverse Events, Intolerance, or Death(Up to 26 weeks)
Proportion of Participants With Temporary Discontinuation of LZD For Any Reason(Up to 26 weeks)
Proportion of Participants With LZD Dose Reduction(Up to 26 weeks)
Proportion of Participants With Treatment-Related Adverse Events(Up to 26 weeks)
Proportion of Participants With Unfavorable TB Treatment Outcome(At week 26)
Proportion of Participants With Unfavorable TB Treatment Outcome(At week 38)
Proportion of Participants With Unfavorable TB Treatment Outcome(At week 72)
Pharmacokinetic Parameter for Linezolid: Minimum Plasma Concentration (Cmin)(At week 4)
Pharmacokinetic Parameter for Linezolid: Maximum Plasma Concentration (Cmax)(At week 4)
Pharmacokinetic Parameter for Linezolid: Time to Reach Maximum Plasma Concentration (Tmax)(At week 4)
Pharmacokinetic Parameter for Linezolid: Area Under the Concentration-time Curve (AUC)(At week 4)
Pharmacokinetic Parameter for Linezolid: Apparent Oral Clearance (CL/F)(At week 4)
Pharmacokinetic Parameter for Delamanid: Minimum Plasma Concentration (Cmin)(At week 4)
Pharmacokinetic Parameter for Delamanid: Maximum Plasma Concentration (Cmax)(At week 4)
Pharmacokinetic Parameter for Delamanid: Time to Reach Maximum Plasma Concentration (Tmax)(At week 4)
Pharmacokinetic Parameter for Delamanid: Area Under the Concentration-time Curve (AUC)(At week 4)
Pharmacokinetic Parameter for Delamanid: Apparent Oral Clearance (CL/F)(At week 4)
Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Minimum Plasma Concentration (Cmin)(At week 4)
Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Maximum Plasma Concentration (Cmax)(At week 4)
Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Time to Reach Maximum Plasma Concentration (Tmax)(At week 4)
Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Area Under the Concentration-time Curve (AUC)(At week 4)
Pharmacokinetic Parameter for Delamanid Metabolite (DM-6705): Apparent Oral Clearance (CL/F)(At week 4)
Number of Participants With >90% Directly Observed Therapy Doses Taken During the Treatment Period(Up to 26 weeks)