NCT04176250已完成2 期
A Phase 2a, Dose Escalation, Controlled, Randomized Study to Evaluate Safety, Early Bactericidal Activity (EBA) and Pharmacokinetics of TBA-7371 in Adult Patients With Rifampicin-sensitive Pulmonary Tuberculosis
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 93
- 试验地点
- 4
- 主要终点
- Number of Participants Reporting ≥Grade 3 Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The purpose of this study is to assess the safety, early bactericidal activity (EBA) and pharmacokinetics of TBA-7371 in adult participants with rifampicin-sensitive tuberculosis and select dose regimen(s) for future studies.
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
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants between 18 to 60 years of age inclusive at the time of signing the informed consent.
- •Body weight within 40 and 100 kilogram (inclusive).
- •Untreated, rifampicin-sensitive pulmonary tuberculosis, as defined by all of the following:
- •isoniazid urine screen negativity
- •sputum smear positivity on direct microscopy for acid-fast bacilli, defined as at least 1+ on the International Unit Against Tuberculosis and Lung Disease/ World Health Organization scale
- •chest X-rays which in the opinion of the investigator is consistent with tuberculosis (TB).
- •Mycobacterium tuberculosis (Mtb) positivity on molecular test (GeneXpert®)
- •rifampicin sensitivity on molecular test (GeneXpert®).
- •Participants must be able to produce at least 10 milliliter of sputum during the overnight sputum collection (day -7 to -3 or day -2 of the Screening Phase).
- •Female and male participants should be of non-childbearing potential or using an effective method of birth control.
- •Non-childbearing potential is defined as follows:
- •participant is not heterosexually active or practices sexual abstinence, OR
- •female participant or sexual partner has undergone bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy, OR
- •female participant or sexual partner has been postmenopausal with a history of no menses for at least 12 consecutive months, OR
- •male participant or sexual partner has undergone vasectomy or bilateral orchidectomy at least three months prior to screening, OR
- •male participant with pregnant sexual partner (for duration of the study) who does not have any other sexual partners.
- •An effective method of birth control is defined as follows:
- •double barrier method, which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together), OR
- •barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female participant or partner, AND
- •participant willing to continue practicing one of the above-mentioned birth control methods throughout 14-day Study Treatment Phase and for 4 weeks after the last dose of study medication or discontinuation from study medication in case of early withdrawal.
- •Participants must be capable of giving signed informed consent, which includes agreeing to compliance with the requirements and restrictions listed in the informed consent form and the protocol.
排除标准
- •Need for immediate effective anti-TB treatment as judged by the investigator.
- •Evidence and/or history of extra-thoracic TB (e.g. miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis, ocular TB), as judged by the investigator.
- •Evidence and/or history in the last 5 years of one or any combination of the following:
- •color vision deficiency;
- •visual acuity worse than 20/25 after correction in either eye;
- •any known eye disease or prior eye surgery;
- •any systemic condition with ocular manifestations (i.e. Marfan, syphilis, diabetes, Beçhet, Vogt-Koyanagi-Harada, Lyme, or chronic inflammatory condition such as sarcoidosis, rheumatoid arthritis, psoriatic arthritis)
- •Evidence and/or history in the last 5 years of clinically significant medical condition(s) as judged by the investigator, including malignancies and unstable or uncontrolled hypertension.
- •Any current medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the participant will comply with the protocol.
- •For Human Immunodeficiency Virus infected participants:
- •CD4+ count <350 cells/microliter, OR
- •Acquired Immune Deficiency Syndrome-defining opportunistic infection or malignancies (except pulmonary TB).
- •Seated systolic/diastolic blood pressure assessed as vital sign [i.e. not from electrocardiogram (ECG)] is less than 95/40 millimeters of Mercury (mmHg) or greater than 145/95 mmHg at screening. Out-of-range blood pressure may be repeated twice with at least 5 minutes intervening.
- •Seated heart rate assessed as vital sign (i.e. not from ECG) is lower than 40 beats per minute (bpm) or higher than 110 bpm at screening. Out-of-range heart rate may be repeated twice with at least 5 minutes intervening.
- •A clinically significant ECG abnormality at screening. NOTE: The following can be considered not clinically significant:
- •mild first-degree atrio-ventricular block (P-R interval <0.23 seconds);
- •right or left axis deviation;
- •incomplete right bundle branch block;
- •isolated left anterior fascicular block (left anterior hemiblock) in young athletic participants.
- •A list of commonly used prohibited medications with the features described below are prohibited:
- •Use of medications active against Mtb within 3 months prior to the first dose of study drug.
- •Use of systemic immunosuppressive medications within 14 days prior to the first dose of study drug.
- •Use of strong inhibitors or strong inducers of cytochrome P450 (CYP) enzymes within 14 days prior to the first dose of study drug.
- •Use of inhibitors of phosphodiesterase (PDE) enzymes within 14 days prior to the first dose of study drug.
- •Use of medications known to affect the eye within 3 months prior to the first dose of study drug.
- •For Human Immunodeficiency Virus positive participants, use of medications listed in the protocol within 3 months prior to the first dose of study drug.
- •Participation in other clinical study(-ies) with investigational agent(s) within 6 months prior to trial start.
- •The following laboratory values from blood collected during the Screening Phase, which represent Grade 2 or higher abnormalities per Division of Acquired Immune Deficiency Syndrome (DAIDS) Toxicity Table Version 2.1, will be cause for exclusion:
- •Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≥ 2.5x upper limit of normal (ULN) for local laboratory values
- •Total bilirubin ≥ 1.6x ULN
- •Creatinine ≥ 1.3x ULN
- •Hemoglobin < 10 grams per deciliter (g/dL) [male] or 9.5 g/dL [female]
- •White Blood Cells < 2,000 /cubic millimeter (mm3)
- •Platelets ≤ 100,000 /mm3
- •International normalized ratio of prothrombin time (INR) ≥ 1.5x ULN
- •Partial thromboplastin time (PTT) ≥ 1.66 ULN
- •Prothrombin time (PT) ≥ 1.25x ULN
- •Grade 2 or higher abnormalities in other laboratory parameters from blood or urine Grade 1 abnormalities, or abnormalities from laboratory parameters not included in the DAIDS Toxicity Table Version 2.1, may lead to exclusion if the investigator considers them clinically significant.
- •History of allergy or hypersensitivity to any of the study drugs or related substances.
- •Positive urine drug screening for cocaine AND/OR amphetamines AND/OR opiates AND/OR methamphetamines. Note: screening will also be conducted for cannabinoids and results documented in the case report form; however, a positive test for cannabinoids is not an exclusion criterion.
- •Female participants currently pregnant or lactating/nursing; OR having positive serum pregnancy test during the Screening Phase OR planning a pregnancy within the 1 month after first dose of study drug.
研究组 & 干预措施
TBA-7371 100 mg TID
Experimental
干预措施: TBA-7371 (Drug)
TBA-7371 400 mg QD
Experimental
干预措施: TBA-7371 (Drug)
TBA-7371 200 mg QD
Experimental
干预措施: TBA-7371 (Drug)
TBA-7371 100 mg QD
Experimental
干预措施: TBA-7371 (Drug)
TBA-7371 100 mg BID
Experimental
干预措施: TBA-7371 (Drug)
HRZE
Active Comparator
干预措施: HRZE (Drug)
结局指标
主要结局
Number of Participants Reporting ≥Grade 3 Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Up to Day 15
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Clinical signs and symptoms that constitute AEs/SAEs were classified by the investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 3), potentially life threatening (Grade 4), death (Grade 5). Number of participants reporting one or more severe AEs (≥grade 3) and SAEs is presented.
Average Change Per Day (Slope) of Log Colony Forming Units (CFU) Counts From Day 0 to Day 14 (BACFU [0-14]) to Assess Bactericidal Activity
时间窗: Day 0 to Day 14
Overnight sputum samples were collected daily. Bacterial burden was assessed on each sputum sample by CFU on solid culture media. Baseline log10CFU measure was taken as the average of Day -2 and Day -1 log10CFU values. Log10CFU values from subsequent overnight sputum samples (Day 1 to Day 14) were used to assess changes in bacterial burden during the Study Treatment Phase (bactericidal activity). BACFU was the average change in log10CFU count per day over the 14 day Study Treatment Phase. Negative mean BACFU (0-14) values were indicative of a reduction in log10CFU from Baseline, i.e., bactericidal activity. The lower the mean BACFU (0-14) the greater the reduction given it is negative. Positive mean BACFU (0-14) values indicated an increase in log10CFU from Baseline.
次要结局
- Average Change Per Day (Slope) of the log10 Sputum Lipoarabinomannan (LAM) Measurements From Day 0 to Day 14 (BALAM [0-14]), From Day 0 to Day 2 (BALAM [0-2]) and From Day 2 to Day 14 (BALAM [2-14]) to Assess Bactericidal Activity(Day 0 to Day 14, Day 0 to Day 2 and Day 2 to Day 14)
- Change From Baseline in Heart Rate (HR)(Baseline and up to Day 15)
- Change From Baseline in HR as Measured by Electrocardiogram (ECG)(Baseline and at Day 15)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline and up to Day 15)
- Number of Participants With Shift From Baseline in Clinical Chemistry Parameters(Day 3, Day 7, Day 15 and Day 42)
- Number of Participants With Shift From Baseline in Serum Coagulation Parameters(Day 3, Day 7, Day 15 and Day 42)
- Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Last Quantifiable Concentration (AUClast) After Administration of TBA7371(Days 1, 7 and 14)
- Minimum Observed Plasma Concentration (Cmin) After Administration of TBA7371(Days 7 and 14)
- Average Change Per Day (Slope) of Log CFU Counts From Day 0 to Day 2 (BACFU [0-2]) and From Day 2 to Day 14 (BACFU [2-14]) to Assess Bactericidal Activity(Day 0 to Day 2 and Day 2 to Day 14)
- Number of Participants Reporting Grade >=3 AEs by Preferred Term(Up to Day 15)
- Number of Participants Reporting AEs (Presented by Severity)(Up to Day 15)
- Number of Participants Experiencing AEs Related to Study Intervention(Up to Day 15)
- Total Number of Days With New Eye Symptoms in One or Both Eyes(Up to Day 15)
- Number of Participants With ≥25% Intraday Increase in HR, ≥25% Intraday Decrease in SBP, ≥25% Intraday Decrease in DBP at Any Intraday Time(Day 1 and up to Day 15)
- Average Change Per Day(Slope)of Time to Sputum Culture Positivity(TTP) in Mycobacteria Growth Indicator Tube (MGIT) System From Day0 to Day14 (BATTP[0-14]),From Day0 to Day2(BATTP[0-2]), and From Day2 to Day14(BATTP [2-14]) to Assess Bactericidal Activity(Day 0 to Day 14, Day 0 to Day 2 and Day 2 to Day 14)
- Number of Participants Reporting Any Adverse Events (AEs)(Up to Day 15)
- Number of Participants With Any New Eye Symptom in One or Both Eyes(Up to Day 15)
- Average Duration of New Eye Symptom in One or Both Eyes(Up to Day 15)
- Change From Baseline in Electrocardiogram (ECG) Parameters(Baseline and up to Day 15)
- Change From Baseline in SBP and DBP(Baseline and at Day 28 and Day 42)
- Maximum Observed Serum Concentration (Cmax) After Administration of TBA7371(Days 1, 7 and 14)
- Time at Last Quantifiable Concentration (Tlast) After Administration of TBA7371(Days 1, 7 and 14)
- Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUCinf) After Administration of TBA7371(Day 1)
- Half-life (T1/2) After Administration of TBA7371(Days 1, 7 and 14)
- Change From Baseline in Visual Acuity Score(Baseline and up to Day 42)
- Number of Participants With Color Vision Abnormality in One or Both Eyes(Up to Day 42)
- Mean Number of Days With ≥25% Increase in HR From Baseline(Baseline (Day 1) and up to Day 15)
- Mean Number of Days With ≥25% Decrease in SBP and Decrease in DBP From Baseline(Baseline (Day 1) and up to Day 15)
- Number of Participants With Shift From Baseline in Hematology Parameters(Day 3, Day 7, Day 15 and Day 42)
- Time at Maximum Plasma Concentration (Tmax) After Administration of TBA7371(Days 1, 7 and 14)
- Last Quantifiable Concentration (Clast) After Administration of TBA7371(Days 1, 7 and 14)
- Change From Baseline in HR(Baseline and at Day 28 and Day 42)
- Change From Baseline in Urinalysis Parameter: Urine Potential of Hydrogen (pH)(Baseline and at Day 3, Day 7 and Day 42)
- Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Tau (AUCtau) After Administration of TBA7371(Days 1, 7 and 14)
- Accumulation Ratio After Administration of TBA7371(Days 7 and 14)
- Number of Participants With New Eye Symptoms in Any Eye(Day 1, Day 4, Day 7, Day 10, Day 14 and 15)
- Change From Baseline in Urinalysis Parameter: Urine Specific Gravity(Baseline and at Day 3, Day 7 and Day 42)
研究者
研究点 (4)
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