A Phase 2 Randomized, Open-label Trial to Evaluate the Early Bactericidal Activity, Safety, Tolerability, and Dose-Response of Oral Alpibectir in Combination with Ethionamide, and with Ethionamide, Rifampicin, Pyrazinamide, and Ethambutol in Adults with Newly Diagnosed, Drug-Susceptible Pulmonary Tuberculosis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- EBA-TTP (0-14)
研究概览
简要总结
A multi-centre, randomized, open-label clinical trial. All treatments will be administered orally (PO) on days 1-14.
15 participants will be recruited into each treatment arm in two sequential cohorts. Each cohort will have participants enrolled onto the experimental regimen(s) or the standard of care (SOC; HRZE) control arm.
• Cohort 1 aims to generate safety data for a higher dose of alpibectir plus ethionamide 125 mg and 250 mg (arm 1: A45E125 and arm2: A45E250).
Once 5 participants have enrolled into arms 1 and 2 each, and completed 14 days of treatment, an interim safety review will be conducted to determine whether the study can advance to cohort 2.
• Cohort 2 will investigate safety of alpibectir and ethionamide (A45E250) in combination with rifampicin, pyrazinamide and ethambutol (A45E250RZE).
Participants on HRZE will serve as control for the EBA quantitative mycobacteriology in each cohort, and additionally as a safety benchmark for the A45E250RZE arm. The study is not statistically powered to make between arm comparisons of activity or safety. The treatment will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.
详细描述
This trial is designed to evaluate the antimycobacterial ejects and the safety of alpibectir in combination with other antimycobacterial agents, particularly Eto, over a 14-day period. The overarching objective is to optimise the dose of both alpibectir and ethionamide and to confirm the safety of the A45E250RZE regimen for future evaluation as an alternative regimen for INH mono-resistant TB. The data from the TASK-010 phase 2A and the ENABLE study will support evaluation of the optimal dose combination of AlpE to move forward into later phase studies. EBAs have historically been conducted between 2 and 14 days. This study will be a standard 14-day EBA design with multiple parallel and sequential treatment arms.
Cohort 1:
Arm 1 and 2: This cohort will add to the evidence base generated in the TASK-010 study (NCT05473195) to support dose optimisation of alpibectir and ethionamide (AlpE) and establish the safety of alpibectir 45 mg in humans, a dose which to date has not been evaluated.
Interim safety review: once a safety review of a subset of participants in arms 1 and 2 receiving the 45 mg dose of alpibectir is complete, cohort 2 will be permitted to begin recruiting once cohort 1 is complete.
Cohort 2:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provide written, informed consent prior to all trial-related procedures and willing to adhere to all required study procedures and restrictions for the duration of the trial.
- •Male or female, aged between 18 and 65 years, inclusive.
- •Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
- •Newly diagnosed and untreated for this episode of pulmonary TB.
- •Rifampicin- and isoniazid susceptible pulmonary TB as determined by molecular testing (GeneXpert XDR or Genotype MTBDRplus for INH).
- •A chest X-ray taken during the screening period or up to 2 weeks before screening which, in the opinion of the investigator, is consistent with TB.
- •GeneXpert positive with a quantitative readout of medium or high.
- •Ability to produce an adequate volume of sputum as estimated from an overnight sputum collection sample (estimated 10 ml or more).
- •Be of non-childbearing potential or of childbearing potential using effective methods of birth control, as defined in section 5.2 and in Appendix
- •Female Participants
- •For WOCBP who are not already receiving contraception per Appendix 1 requirements, agree to receive injectable or other contraceptive methods (per Appendix 1), to be given during screening, and at least 1 day prior to first dose of IMP.
- •Male Participants
- •Agree to ALL of the following during the study intervention period and for at least 90 days, after the last dose of study intervention:
- •Refrain from donating fresh unwashed semen
- •Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
排除标准
- •Evidence of clinically significant conditions or findings, other than TB, that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
- •Poor general condition where any delay in treatment cannot be tolerated per discretion of the investigator.
- •History of epilepsy, seizures or other neuropsychiatric disorders that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
- •Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •History of hypothyroidism
- •QTcF of >450 ms at baseline
- •Clinically significant evidence of extra-thoracic TB, as judged by the investigator.
- •History of allergy to any of the trial IMP as confirmed by the clinical judgement of the investigator.
- •Alcohol or drug abuse, that in the opinion of the investigator, is sufficient to compromise the safety or cooperation of the participant.
- •HIV positive AND:
- •CD4 < 250cells/mm3
- •On other ART regimen not listed below or, if not on ART they are not willing to wait to start treatment until completion of study regimen
- •Note: ART regimens permitted is limited to the following in line with local guidelines for 1st line ART:
- •NRTIs selected from: Emtricitabine, Lamivudine, Tenofovir
- •PLUS Dolutegravir 50 mg daily, or 50 mg twice daily if randomized to a rifampicin containing arm.
- •Participants established on ART (2 NRTIs and dolutegravir) for more than 30 days at start of screening are eligible for participation.
- •As the drug-drug interaction potential of ART has not been fully investigated with the IMP, NNRTIs (efavirenz, nevirapine) and other protease inhibitors will not be permitted in this study.
- •Female participant who is pregnant, breast-feeding, or planning to conceive a child within the anticipated period of trial participation and for at least 90 days after the last dose of study intervention. Male participant planning to conceive a child for at least 90 days, after the last dose of study intervention in the trial.
- •Treatment History
- •Participation in other clinical studies with investigational agents within 8 weeks prior to screening.
- •Treatment received for this episode of TB with any drug active against M. tb (including but not limited to isoniazid, ethambutol, cycloserine, fluoroquinolones, rifamycins, aminoglycosides, nitroimidazoles, bedaquiline, oxazolidinones, para-amino salicylic acid, pyrazinamide, thioacetazone, thioamides).
- •Treatment with immunosuppressive medications such as TNF-alpha inhibitors within 2 weeks prior to screening, or systemic corticosteroids for more than 7 days within 2 weeks prior to screening.
- •Unavoidable treatment with prohibited concomitant medications (see section 5.3.2) anticipated during administration of IMP.
- •Laboratory Safety Testing
- •Presence of hepatitis B surface antigen (HBsAg+)
- •Positive hepatitis C antibody test result (HCV IgG+)
- •Participants with the following toxicities at screening as defined by the enhanced CTCAE toxicity table:
- •creatinine >1.5 times upper limit of normal (ULN)
- •haemoglobin <8.0 g/dL
- •platelets <50x109 cells/L
- •serum potassium <3.0 mmol/L
- •alanine aminotransferase (ALT) ≥5 x ULN
- •total bilirubin >1.5 x ULN; Participants with Gilbert's syndrome can be included with total bilirubin >1.5 x ULN as long as direct bilirubin is ≤1.5xULN
- •Total white cell count <1.5 cells/L
- •Thyroid Stimulating Hormone > ULN
- •Glucose < 3.5 mmol/L
研究组 & 干预措施
Cohort 1 Arm 1 (A45E125)
Alpibectir 45 mg once daily (OD) plus Ethionamide 125 mg OD
干预措施: Alpibectir 45 mg once daily (OD) plus Ethionamide 125 mg OD (Drug)
Cohort 1 Arm 2 (A45E250)
Alpibectir 45 mg OD plus Ethionamide 250 mg OD
干预措施: Alpibectir 45 mg OD plus Ethionamide 250 mg OD (Drug)
Cohort 1 Arm 3 (HRZE)
Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based
干预措施: Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based (Drug)
Cohort 2 Arm 3 (HRZE)
Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based
干预措施: Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based (Drug)
Cohort 2 Arm 4 (A45E250RZE)
Alpibectir 45 mg OD plus Ethionamide 250 mg OD plus Rifampicin 10 mg/kg OD plus Ethambutol 20 mg/kg OD plus Pyrazinamide 25 mg/kg OD
干预措施: Alpibectir 45 mg OD plus Ethionamide 250 mg OD plus Rifampicin 10 mg/kg OD plus Ethambutol 20 mg/kg OD plus Pyrazinamide 25 mg/kg OD (Drug)
结局指标
主要结局
EBA-TTP (0-14)
时间窗: 14 days
The EBA TTP (0-14) as determined by the rate of change in log10TTP in sputum over the period day 0 (baseline sample) to Day 14 will be described using linear, bi-linear, or non-linear functions using nonlinear mixed effects modelling of log10TTP over time. Estimates of rates of change including uncertainties for each treatment group will be given and graphically illustrated.
次要结局
- EBA CFU (0-14)(14 days)
- EBA (0-2) and EBA (2-14)(2-14 days)
- Safety and tolerability(14 days)
- PK analysis - Cmax(14 days)
- Biomarkers (Sputum)(14 days)
- Biomarkers (Whole Blood)(14 days)
- Mycobacterial parameters(2-14 days)
- Drug-drug interaction - AUC (0-24)(14 days)
- PK Analysis (AUC (0-24), AUC (0-∞), AUC(0-tau)(14 days)
- PK Analysis (Tmax)(14 days)
- PK Analysis - apparent terminal half-life (t1/2)(14 days)
- PK Analysis-Descriptive Statistics(14 days)
- Drug-drug interaction - Cmax(14 days)
- Drug-drug interaction - Tmax(14 days)