Early Bactericidal Activity, Safety & Tolerability of Oral GSK3036656 in a Dual Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin Susceptible Pulmonary Tuberculosis

NCT05382312 | Completed Phase 2 Results

• 1 other identifier: 214912
• Study Type: interventional
• Target: 127
• Locations: 1 country
• Sites: 1

Brief Summary

This study measured the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics of GSK3036656 in combination with either delamanid, bedaquiline or BTZ-043 and delamanid in combination with bedaquiline or standard of care, for 14 days, in participants with newly diagnosed sputum smear positive drug-sensitive pulmonary tuberculosis. Participants reverted to the standard treatment (RIFAFOUR e-275) once the study treatment (Day 1 to Day 14) was completed.

Conditions

Tuberculosis

Keywords

Early bactericidal activity; Pulmonary tuberculosis; RIFAFOUR; Bedaquiline; Delamanid; GSK3036656; BTZ-043

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in log10 Colony Forming Units (CFU) of Mycobacterium Tuberculosis (MTB)

  Baseline was defined as the mean of Day -2 and Day -1. If data was available at only one of these timepoints, then that value was used as baseline.

  At Baseline and at days 1, 2, 3, 4, 6, 8, 10, 12 and 14

Secondary Outcomes (10)

• Change From Baseline in Time to Sputum Culture Positivity

  At Baseline and at days 1, 2, 3, 4, 6, 8, 10, 12 and 14

• Number of Participants With Serious Adverse Events (SAEs)

  From Day 1 to Day 28

• Number of Participants With Adverse Events (AE) of Grade 3 Severity or Higher

  From Day 1 to Day 28

• Number of Participants With Adverse Events Related to Study Treatment

  From Day 1 to Day 28

• Number of Participants Withdrawn From the Treatment Due to Adverse Events

  From Day 1 to Day 28

Study Arms (10)

GSK3036656 + Bedaquiline

EXPERIMENTAL

Participants received GSK3036656 20 milligram (mg) + bedaquiline 400 mg once daily for 14 days; loading doses: 50 mg GSK3036656 (Day 1), 700 mg bedaquiline (Day 1), 500 mg (Day 2), then 400 mg daily (Days 3-14).

Drug: GSK3036656; Drug: Bedaquiline

GSK3036656 + Delamanid

EXPERIMENTAL

Participants received GSK3036656 20 mg + delamanid 300 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.

Drug: GSK3036656; Drug: Delamanid

Delamanid + Bedaquiline

EXPERIMENTAL

Participants received delamanid 300 mg + bedaquiline 400 mg once daily for 14 days; bedaquiline loading doses: 700 mg (Day 1), 500 mg (Day 2), then 400 mg daily (Days 3-14).

Drug: Bedaquiline; Drug: Delamanid

Standard of care for drug-sensitive tuberculosis (DS - TB)_Cohort 1

EXPERIMENTAL

Participants received Rifafour e-275 (or equivalent generic) once daily for 14 days.

Drug: RIFAFOUR e-275

GSK3036656 + BTZ-043

EXPERIMENTAL

Participants received GSK3036656 20 mg + BTZ-043 1000 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.

Drug: GSK3036656; Drug: BTZ-043

Standard of care for DS - TB_Cohort 2

EXPERIMENTAL

Participants received Rifafour e-275 (or equivalent generic) once daily for 14 days.

Drug: RIFAFOUR e-275

GSK3036656 + Pretomanid

EXPERIMENTAL

Participants received GSK3036656 20 mg + pretomanid 200 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.

Drug: GSK3036656; Drug: Pretomanid

GSK3036656 + Linezolid

EXPERIMENTAL

Participants received GSK3036656 20 mg + linezolid 600 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.

Drug: GSK3036656; Drug: Linezolid

GSK3036656 + moxifloxacin

EXPERIMENTAL

Participants received GSK3036656 20 mg + moxifloxacin 400 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.

Drug: GSK3036656; Drug: Moxifloxacin

Standard of care for DS TB_Cohort 3

EXPERIMENTAL

Participants received Rifafour e-275 (or equivalent generic) once daily for 14 days.

Drug: RIFAFOUR e-275

Interventions

GSK3036656 DRUG

GSK3036656 was administered.

GSK3036656 + BTZ-043; GSK3036656 + Bedaquiline; GSK3036656 + Delamanid; GSK3036656 + Linezolid; GSK3036656 + Pretomanid; GSK3036656 + moxifloxacin

Bedaquiline DRUG

Bedaquiline was administered.

Delamanid + Bedaquiline; GSK3036656 + Bedaquiline

Delamanid DRUG

Delamanid was administered.

Delamanid + Bedaquiline; GSK3036656 + Delamanid

RIFAFOUR e-275 DRUG

RIFAFOUR e-275 was administered.

Standard of care for DS - TB_Cohort 2; Standard of care for DS TB_Cohort 3; Standard of care for drug-sensitive tuberculosis (DS - TB)_Cohort 1

BTZ-043 DRUG

BTZ-043 was administered.

GSK3036656 + BTZ-043

Pretomanid DRUG

Pretomanid was administered.

GSK3036656 + Pretomanid

Linezolid DRUG

Linezolid was administered.

GSK3036656 + Linezolid

Moxifloxacin DRUG

Moxifloxacin was administered.

GSK3036656 + moxifloxacin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants were 18 to 65 years of age inclusive, at the time of signing the informed consent.
• Participants had:
• A new episode of untreated, rifampicin-susceptible pulmonary tuberculosis (TB)
• A chest X-ray picture consistent with pulmonary TB
• At least one sputum sample positive on direct microscopy for acid-fast bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease \[IUATLD\]/World Health Organization \[WHO\] scale) or positive on a molecular test (at least medium positive for MTB on Xpert MTB/Rif)
• A normal echocardiogram, or an echocardiogram with normal left ventricular function with at most trace to mild valvular regurgitation, and no valvular stenosis
• A creatinine clearance greater than or equal to (\>=) 90 mL/minute (Cockcroft-Gault formula)
• Male participants were eligible to participate if they agreed to barrier precautions until 90 days after the last dose.
• A female participant was eligible to participate if she was not pregnant or breastfeeding and was a woman of non-childbearing potential (WONCBP) or a woman of childbearing potential (WOCBP) using a highly effective contraceptive method. A WOCBP had to have a negative urine or serum pregnancy test, as required by local regulations, before the first dose of study intervention. Only participants who were at least 25 years of age, and females of non-childbearing potential, were eligible for the positron emission tomography-computed tomography (PET-CT) assessments.
• Participants were capable of giving signed informed consent.

You may not qualify if:

• There was evidence of a clinically significant condition or abnormality (as judged by the Investigator) (other than the indication being studied) that might have compromised safety or the interpretation of trial efficacy or safety endpoints.
• There was clinically significant evidence of extrathoracic TB, as judged by the Investigator.
• QTc interval corrected for heart rate by Fridericia's formula (QTcF) was greater than (\>) 450 milliseconds (msec).
• There was arterial hypertension with systolic BP \>=160 mm Hg or diastolic BP \>=100 mm Hg. Participants with well-controlled hypertension could be included if they were using amlodipine for the duration of the study.
• Participants had vitiligo.
• Participants were receiving QT-prolonging drugs, including but not limited to fluoroquinolones, macrolides, and clofazimine.
• HIV-infected participants who:
• had a cluster of differentiation (CD)4+ count \<350 cells/microliters;
• had received antiretroviral therapy medication within the last 30 days;
• had received oral or intravenous antifungal medication within the last 30 days;
• or had an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection or malignancy in the last 12 months (except pulmonary TB).
• Hepatitis B surface antigen (HBsAg) was present, or the Hepatitis C antibody test result at screening was positive.
• Participants had diabetes (Type 1 or 2), point-of-care glycated hemoglobin (HbA1c) above 6.5%, or random glucose over 11.1 millimoles (mmol)/L.
• There were diseases or conditions in which the use of delamanid or bedaquiline was contraindicated.
• Participants had abnormal laboratory values at screening, as graded by the enhanced Common Terminology Criteria for Adverse Events (CTCAE version 5, 2017).

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Click-TB Consortium: collaborator

Study Sites (1)

GSK Investigational Site

Bellville, 7530, South Africa

Location

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary

Interventions

GSK656; bedaquiline; OPC-67683; 2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; pretomanid; Linezolid; Moxifloxacin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  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
• Masking Details: All laboratory staff involved in analyzing and reporting the microbiological endpoints (logarithm to base10 \[log10\] colony forming units \[CFU\] counts and time to sputum culture positivity) were unaware of treatment assignments.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2022
• First Posted: May 19, 2022
• Study Start: July 26, 2022
• Primary Completion: May 27, 2025
• Study Completion: May 27, 2025
• Last Updated: June 17, 2026
• Results First Posted: June 17, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

ZA (1)