Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis

NCT04176250 | Completed Phase 2 Results DMC

• 1 other identifier: Gates MRI-TBD03-201
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Pulmonary Tuberculosis

Keywords

Rifampicin-sensitive pulmonary tuberculosis; TBA-7371; Pulmonary tuberculosis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (43)

• 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

• 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

• 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

• Number of Participants Reporting Any Adverse Events (AEs)

  Up to Day 15

• Number of Participants Reporting Grade >=3 AEs by Preferred Term

  Up to Day 15

Study Arms (6)

TBA-7371 100 mg QD

EXPERIMENTAL

Drug: TBA-7371

TBA-7371 100 mg BID

EXPERIMENTAL

Drug: TBA-7371

TBA-7371 200 mg QD

EXPERIMENTAL

Drug: TBA-7371

TBA-7371 100 mg TID

EXPERIMENTAL

Drug: TBA-7371

TBA-7371 400 mg QD

EXPERIMENTAL

Drug: TBA-7371

HRZE

ACTIVE COMPARATOR

Drug: HRZE

Interventions

TBA-7371 DRUG

Participants will receive TBA-7371 oral suspension 100 milligram (mg) once daily (QD) for 14 days.

TBA-7371 100 mg QD

HRZE DRUG

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.

Also known as: Rifafour® e-275

HRZE

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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:
• uveitis;
• color vision deficiency;
• amblyopia;
• 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.

Sponsors & Collaborators

• Gates Medical Research Institute: lead

Study Sites (4)

TASK

Bellville, Cape Town, 7530, South Africa

Location

University of Cape Town (UCT) Lung Institute

Mowbray, Cape Town, 7700, South Africa

Location

The Aurum Institute

Pretoria, Gauteng, 0087, South Africa

Location

Perinatal HIV Research Unit (PHRU)

Jouberton, North West, 2574, South Africa

Location

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Study Director
• Organization: Gates MRI

clinical.trials@gatesmri.org

+1 857 702 2108

Study Officials

• Gates MRI

  Gates Medical Research Institute

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2019
• First Posted: November 25, 2019
• Study Start: January 16, 2020
• Primary Completion: October 5, 2022
• Study Completion: October 5, 2022
• Last Updated: April 11, 2024
• Results First Posted: April 11, 2024

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share

Locations

ZA (4)