Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: Drug: TBA-7371; Drug: TBA-7371; Drug: TBA-7371; Drug: TBA-7371; Drug: TBA-7371; Drug: HRZE

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Cape Town
    • Bellville, Cape Town, South Africa, 7530
      • TASK
    • Mowbray, Cape Town, South Africa, 7700
      • University of Cape Town (UCT) Lung Institute
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0087
      • The Aurum Institute
  • North West Province
    • Jouberton, North West Province, South Africa, 2574
      • Perinatal HIV Research Unit (PHRU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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:

  1. isoniazid urine screen negativity
  2. 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
  3. chest X-rays which in the opinion of the investigator is consistent with tuberculosis (TB).
  4. Mycobacterium tuberculosis (Mtb) positivity on molecular test (GeneXpert®)
  5. 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:

    1. participant is not heterosexually active or practices sexual abstinence, OR
    2. female participant or sexual partner has undergone bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy, OR
    3. female participant or sexual partner has been postmenopausal with a history of no menses for at least 12 consecutive months, OR
    4. male participant or sexual partner has undergone vasectomy or bilateral orchidectomy at least three months prior to screening, OR
    5. 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:

    1. 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
    2. barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female participant or partner, AND
    3. 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.

Exclusion Criteria:

• 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:

  1. uveitis;
  2. color vision deficiency;
  3. amblyopia;
  4. visual acuity worse than 20/25 after correction in either eye;
  5. any known eye disease or prior eye surgery;
  6. 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:

  1. CD4+ count <350 cells/microliter, OR
  2. 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:

  1. mild first-degree atrio-ventricular block (P-R interval <0.23 seconds);
  2. right or left axis deviation;
  3. incomplete right bundle branch block;
  4. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TBA-7371 100 mg QD	Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.
Experimental: TBA-7371 100 mg BID	Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.
Experimental: TBA-7371 200 mg QD	Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.
Experimental: TBA-7371 100 mg TID	Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.
Experimental: TBA-7371 400 mg QD	Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.; Drug: TBA-7371; Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.
Active Comparator: HRZE	Drug: HRZE; Participants will receive Isoniazid [H] / rifampicin [R] / pyrazinamide [Z] / ethambutol [E] (HRZE), a fixed dose combination tablet QD for 14 days, based on weight as 40-54 kilograms (kg): 3 tablets; 55-70 kg: 4 tablets and 71 kg and over: 5 tablets.; Other Names: Rifafour® e-275

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Day 0 to Day 14
Number of Participants Reporting ≥Grade 3 Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Up to Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Day 0 to Day 2 and Day 2 to Day 14
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	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.	Day 0 to Day 14, Day 0 to Day 2 and Day 2 to Day 14
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	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.	Day 0 to Day 14, Day 0 to Day 2 and Day 2 to Day 14
Number of Participants Reporting Any Adverse Events (AEs)	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.	Up to Day 15
Number of Participants Reporting Grade >=3 AEs by Preferred Term	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.	Up to Day 15
Number of Participants Reporting AEs (Presented by Severity)	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.	Up to Day 15
Number of Participants Experiencing AEs Related to Study Intervention	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.	Up to Day 15
Number of Participants With Any New Eye Symptom in One or Both Eyes	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.	Up to Day 15
Average Duration of New Eye Symptom in One or Both Eyes	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.	Up to Day 15
Total Number of Days With New Eye Symptoms in One or Both Eyes	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.	Up to Day 15
Change From Baseline in Visual Acuity Score	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.	Baseline and up to Day 15
Number of Participants With Color Vision Abnormality in One or Both Eyes	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.	Up to Day 15
Change From Baseline in Heart Rate (HR)	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.	Baseline and up to Day 15
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	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.	Baseline and up to Day 15
Change From Baseline in HR as Measured by Electrocardiogram (ECG)	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.	Baseline and at 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	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.	Day 1 and up to Day 15
Mean Number of Days With ≥25% Increase in HR From Baseline	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.	Baseline (Day 1) and up to Day 15
Mean Number of Days With ≥25% Decrease in SBP and Decrease in DBP From Baseline	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.	Baseline (Day 1) and up to Day 15
Change From Baseline in Electrocardiogram (ECG) Parameters	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.	Baseline and up to Day 15
Change From Baseline in HR	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.	Baseline (Day 1) and at Day 4, Day 7, Day 10 and Day 14
Change From Baseline in SBP and DBP	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.	Baseline (Day 1) and at Day 4, Day 7, Day 10 and Day 14
Number of Participants With New Eye Symptoms in Any Eye	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.	Day 1, Day 4, Day 7, Day 10, Day 14 and 15
Change From Baseline in Visual Acuity Score	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.	Baseline, Day 1, Day 4, Day 7, Day 10 and Day 14
Number of Participants With Color Vision Abnormality in One or Both Eyes	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.	Day 1, Day 4, Day 7, Day 10 and Day 14
Change From Baseline in HR	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.	Baseline and at Day 28 and Day 42
Change From Baseline in SBP and DBP	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.	Baseline and at Day 28 and Day 42
Change From Baseline in Visual Acuity Score	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.	Baseline and up to Day 42
Number of Participants With Color Vision Abnormality in One or Both Eyes	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.	Up to Day 42
Number of Participants With Shift From Baseline in Hematology Parameters	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.	Day 3, Day 7, Day 15 and Day 42
Number of Participants With Shift From Baseline in Clinical Chemistry Parameters	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.	Day 3, Day 7, Day 15 and Day 42
Number of Participants With Shift From Baseline in Serum Coagulation Parameters	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.	Day 3, Day 7, Day 15 and Day 42
Change From Baseline in Urinalysis Parameter: Urine Specific Gravity	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.	Baseline and at Day 3, Day 7 and Day 42
Change From Baseline in Urinalysis Parameter: Urine Potential of Hydrogen (pH)	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.	Baseline and at Day 3, Day 7 and Day 42
Maximum Observed Serum Concentration (Cmax) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 1, 7 and 14
Time at Maximum Plasma Concentration (Tmax) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 1, 7 and 14
Last Quantifiable Concentration (Clast) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 1, 7 and 14
Time at Last Quantifiable Concentration (Tlast) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 1, 7 and 14
Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUCinf) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Day 1
Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Last Quantifiable Concentration (AUClast) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 1, 7 and 14
Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Tau (AUCtau) After Administration of TBA7371	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.	Days 1, 7 and 14
Minimum Observed Plasma Concentration (Cmin) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis. Mean and standard deviation for Cmin could not be calculated due to high proportion of NQ values (>30% of values were imputed)	Days 7 and 14
Half-life (T1/2) After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 1, 7 and 14
Accumulation Ratio After Administration of TBA7371	Blood samples were collected at indicated time points for pharmacokinetic analysis of TBA7371. PK parameters were analyzed using standard non-compartmental analysis.	Days 7 and 14

Collaborators and Investigators

• Sponsor: Bill & Melinda Gates Medical Research Institute
• Investigators: Study Director: Gates MRI, Bill & Melinda Gates Medical Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2020
• Primary Completion (Actual): October 5, 2022
• Study Completion (Actual): October 5, 2022

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: November 21, 2019
• First Posted (Actual): November 25, 2019

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: October 4, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: TBA-7371; Pulmonary tuberculosis; Rifampicin-sensitive pulmonary tuberculosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary
• Other Study ID Numbers: Gates MRI-TBD03-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No