Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis

NCT ID: NCT04176250

Last Updated: 2024-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 93 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-16
• Study Completion Date: 2022-10-05

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

TBA-7371 100 mg QD

Group Type: EXPERIMENTAL

TBA-7371

Intervention Type: DRUG

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

TBA-7371 100 mg BID

Group Type: EXPERIMENTAL

TBA-7371

Intervention Type: DRUG

Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.

TBA-7371 200 mg QD

Group Type: EXPERIMENTAL

TBA-7371

Intervention Type: DRUG

Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.

TBA-7371 100 mg TID

Group Type: EXPERIMENTAL

TBA-7371

Intervention Type: DRUG

Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.

TBA-7371 400 mg QD

Group Type: EXPERIMENTAL

TBA-7371

Intervention Type: DRUG

Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.

HRZE

Group Type: ACTIVE_COMPARATOR

HRZE

Intervention Type: 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.

Interventions

TBA-7371

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

Intervention Type: DRUG

TBA-7371

Participants will receive TBA-7371 oral suspension 100 mg twice daily (BID) for 14 days.

Intervention Type: DRUG

TBA-7371

Participants will receive TBA-7371 oral suspension 200 mg QD for 14 days.

Intervention Type: DRUG

TBA-7371

Participants will receive TBA-7371 oral suspension 100 mg three times daily (TID) for 14 days.

Intervention Type: DRUG

TBA-7371

Participants will receive TBA-7371 oral suspension 400 mg QD for 14 days.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Rifafour® e-275

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gates Medical Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gates MRI

Role: STUDY_DIRECTOR

Gates Medical Research Institute

Locations

TASK

Bellville, Cape Town, South Africa

University of Cape Town (UCT) Lung Institute

Mowbray, Cape Town, South Africa

The Aurum Institute

Pretoria, Gauteng, South Africa

Perinatal HIV Research Unit (PHRU)

Jouberton, North West, South Africa

Countries

South Africa

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

Gates MRI-TBD03-201

Identifier Type: -

Identifier Source: org_study_id