Trial Outcomes & Findings for Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (NCT NCT04176250)

The study was conducted in South Africa.

This was a dose escalation, controlled, randomized study to evaluate safety, early bactericidal activity (EBA) and pharmacokinetics (PK) of TBA-7371 in adult participants with rifampicin-sensitive pulmonary tuberculosis (TB). Participants were randomized 5:1 to TBA-7371 or HRZE. Data are presented by intervention.

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis

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.

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.

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 (0-2) and BACFU (2-14) values were indicative of a reduction in log10CFU from Baseline, i.e., bactericidal activity. The lower the mean BACFU (0-2) and BACFU (2-14), the greater the reduction given it is negative. Positive mean BACFU (0-2) and BACFU (2-14) values indicated an increase in log10CFU from Baseline.

Overnight sputum samples were collected daily. Bacterial burden was assessed on each sputum sample by time to positivity (TTP; hours) in MGIT system. Baseline TTP measure was taken as the average of Day -2 and Day -1 TTP values. TTP values from subsequent overnight sputum samples (Day 1 to 14) were used to assess changes in bacterial burden during the Study Treatment Phase (bactericidal activity). BATTP was the average change of time to (sputum culture) Positivity (hours) per day in MGIT system per day over 14 days. Positive mean BATTP values were indicative of an increase in TTP from Baseline. The higher the Mean BATTP, the greater the increase given it is positive. Negative mean BATTP values indicated a reduction in TTP from Baseline.

Overnight sputum samples were collected daily. Bacterial burden was assessed on each sputum sample by LAM assay in picograms/mL. Baseline log10LAM measure was taken as the average of Day -2 and Day -1 log10LAM values. Log10LAM values from subsequent overnight sputum samples (Day 1 to 14) were used to assess changes in bacterial burden during the Study Treatment Phase (bactericidal activity). Negative mean BALAM values were indicative of a reduction in log10 LAM from Baseline. The lower the Mean BALAM, the greater the reduction given it is negative. Positive mean BALAM values indicated an increase in log10 LAM from Baseline.

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. Number of participants reporting any AEs is presented.

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. Clinical signs and symptoms that constitute AEs 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 who experienced grade \>=3 AEs by preferred term is presented.

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. Number of participants reporting Reporting AEs is presented by Severity: Mild- Grade 1 (An event that is usually transient in nature and generally does not interfere with normal activities), Moderate-Grade 2 (An AE that is sufficiently discomforting to interfere with normal activities) and Severe- ≥Grade 3 (An AE that is incapacitating and prevents normal activities). The higher the grade, the more severe the symptoms.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with use of a study intervention, whether or not considered related to study intervention. An AE is considered related to study intervention if there was a reasonable possibility that the study intervention contributed to the AE.

Eye symptoms were assessed by non-leading questions delivered by trained staff based on a standardized script. A participant with multiple eye symptoms within a preferred term was counted once. Number of participants with any new eye symptom in one or both eyes is presented. All the eye symptoms have been included in the adverse events section of this study.

Average duration of eye symptoms in one or both eyes that were observed after screening for an individual participant was computed as the average duration of all symptoms using the number of symptoms as denominator. Average duration of new eye symptoms in one of both eyes was measured in Hours.

Any day that a participant reported an eye symptom in one or both eyes after screening was counted toward the number of days of having eye symptoms in the study for that participant. Total Number of Days with New Eye Symptoms in One or Both Eyes is presented.

The visual acuity scores were converted to logarithm to the base 10 of the minimum angle of resolution (logMAR) scale for analyzing change from Baseline. LogMar scale was computed as logMAR = -log(visual acuity score in decimal scale). In logMAR scale, lower scores corresponded to better vision, and as acuity became worse, the value of the logMAR increased. Worst logMAR score was defined to be the highest value of logMAR scores measured on left and right eyes at a given time point. The International Classification of Diseases 11 for distance vision impairment used was: Normal: Equal to or better than 20/40; Mild: Worse than 20/40 and equal to or better than 20/70; Moderate: Worse than 20/70 and equal to or better than 20/200; Severe: Worse than 20/200 and equal to or better than 20/400; Blindness: Worse than 20/400. Baseline was defined as the last assessment at screening. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Color vision abnormality was defined as the most severe of protan, deutan, or tritan color deficiency in one or both eyes at a given time point. The degree of severity of color vision deficiency was graded as mild, moderate, severe. The severity of color vision abnormality was assigned to the highest degree of severity of the 3 color vision deficits. Number of participants with color vision abnormality in one or both eyes is presented.

HR was measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

SBP and DBP were measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

12-lead ECG was recorded after at least 10 minutes of supine rest to measure HR. Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

HR, SBP and DBP were measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Number of participants with ≥25% intraday increase in HR, ≥25% intraday decrease in SBP, ≥25% intraday decrease in DBP at any intraday time is presented.

HR was measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Mean number of days with ≥25% increase in HR from Baseline is presented.

SBP and DBP were measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Mean number of days with ≥25% decrease in SBP and decrease in DBP from Baseline is presented.

12-lead ECG was recorded once at each time point after at least 10 minutes of supine rest to assess PR interval, QRS duration, QT interval, QT Corrected for HR Using Fridericia's Method (QTcF) interval and RR interval. Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

HR was measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

SBP and DBP were measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Eye symptoms were assessed by non-leading questions delivered by trained staff based on a standardized script. A participant with multiple eye symptoms within a preferred term was counted once. Severe eye symptoms were events with grade 3 intensity or greater. Number of participants with new eye symptoms in any eye including: any, severe and serious is presented.

The visual acuity scores were converted to logMAR scale for analyzing change from Baseline. LogMar scale was computed as logMAR = -log(visual acuity score in decimal scale). In logMAR scale, lower scores corresponded to better vision, and as acuity became worse, the value of the logMAR increased. Worst logMAR score was defined to be the highest value of logMAR scores measured on left and right eyes at a given time point. The International Classification of Diseases 11 classification for distance vision impairment used was: Normal: Equal to or better than 20/40; Mild: Worse than 20/40 and equal to or better than 20/70; Moderate: Worse than 20/70 and equal to or better than 20/200; Severe: Worse than 20/200 and equal to or better than 20/400; Blindness: Worse than 20/400. Baseline was defined as the last assessment at screening. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Color vision abnormality was defined as the most severe of protan, deutan, or tritan color deficiency in one or both eyes at a given time point. The degree of severity of color vision deficiency was graded as mild, moderate, severe. The severity of color vision abnormality was assigned to the highest degree of severity of the 3 color vision deficits. Number of participants with color vision abnormality in one or both eyes is presented.

HR was measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

SBP and DBP were measured twice as follows: after 10 minutes supine ("manual, supine") and after 2 (±0.5) minutes standing ("manual, 2-minute standing"). Baseline was measured on Day 1 before the first dose of study medication was administered. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

The visual acuity scores were converted to logMAR scale for analyzing change from Baseline. LogMar scale was computed as logMAR = -log(visual acuity score in decimal scale). In logMAR scale, lower scores corresponded to better vision, and as acuity became worse, the value of the logMAR increased. Worst logMAR score was defined to be the highest value of logMAR scores measured on left and right eyes at a given time point. The International Classification of Diseases 11 classification for distance vision impairment used was: Normal: Equal to or better than 20/40; Mild: Worse than 20/40 and equal to or better than 20/70; Moderate: Worse than 20/70 and equal to or better than 20/200; Severe: Worse than 20/200 and equal to or better than 20/400; Blindness: Worse than 20/400. Baseline was defined as the last assessment at screening. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Color vision abnormality was defined as the most severe of protan, deutan, or tritan color deficiency in one or both eyes at a given time point. The degree of severity of color vision deficiency was graded as mild, moderate, severe. The severity of color vision abnormality was assigned to the highest degree of severity of the 3 color vision deficits. Number of participants with color vision abnormality in one or both eyes is presented.

Blood samples were collected from participants for analysis of following hematology parameters: Erythrocytes, Hemoglobin, Hematocrit, Leukocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (e.g. High to High) or whose value became normal, were recorded in the 'To Normal or No Change' category. Baseline was defined as the last assessment at screening. Only the abnormal values were reported where normal to high and normal to low changes were reported.

Blood samples were collected from participants for analysis of following hematology parameters; Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Bilirubin, Creatinine, Urea Nitrogen, Sodium and Potassium. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (e.g. High to High) or whose value became normal, were recorded in the 'To Normal or No Change' category. Baseline was defined as the last assessment at screening. Only the abnormal values were reported where normal to high and normal to low changes were reported.

Blood samples were collected from participants for analysis of following serum coagulation: Prothrombin time, Activated Partial Thromboplastin Time and Prothrombin International Normalized Ratio. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (e.g. High to High) or whose value became normal, were recorded in the 'To Normal or No Change' category. Baseline was defined as the last assessment at screening. Only the abnormal values were reported where normal to high and normal to low changes were reported.

Urine samples were collected to measure urine specific gravity. Baseline was defined as the last assessment at screening. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Urine samples were collected to measure urine pH. Baseline was defined as the last assessment at screening. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.

Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis. Tau represents the dosing interval of 24 hours.