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

A Parallel Group, Phase 2A, Randomised, Open Label Treatment Study to Assess the Early Bactericidal Activity, Safety and Tolerability of GSK3036656 Administered as a Two Drug Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin-susceptible Pulmonary Tuberculosis

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: GSK3036656; Drug: Bedaquiline; Drug: Delamanid; Drug: RIFAFOUR e-275; Drug: BTZ-043; Drug: Pretomanid; Drug: Linezolid; Drug: Moxifloxacin

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Bellville, South Africa, 7530
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants were 18 to 65 years of age inclusive, at the time of signing the informed consent.

• Participants had:

  1. A new episode of untreated, rifampicin-susceptible pulmonary tuberculosis (TB)
  2. A chest X-ray picture consistent with pulmonary TB
  3. 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)
  4. A normal echocardiogram, or an echocardiogram with normal left ventricular function with at most trace to mild valvular regurgitation, and no valvular stenosis
  5. 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.

Exclusion Criteria:

• 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:

  1. had a cluster of differentiation (CD)4+ count <350 cells/microliters;
  2. had received antiretroviral therapy medication within the last 30 days;
  3. had received oral or intravenous antifungal medication within the last 30 days;
  4. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GSK3036656 + Bedaquiline; 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; GSK3036656 was administered.; Drug: Bedaquiline; Bedaquiline was administered.
Experimental: GSK3036656 + Delamanid; Participants received GSK3036656 20 mg + delamanid 300 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.	Drug: GSK3036656; GSK3036656 was administered.; Drug: Delamanid; Delamanid was administered.
Experimental: Delamanid + Bedaquiline; 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; Bedaquiline was administered.; Drug: Delamanid; Delamanid was administered.
Experimental: Standard of care for drug-sensitive tuberculosis (DS - TB)_Cohort 1; Participants received Rifafour e-275 (or equivalent generic) once daily for 14 days.	Drug: RIFAFOUR e-275; RIFAFOUR e-275 was administered.
Experimental: GSK3036656 + BTZ-043; Participants received GSK3036656 20 mg + BTZ-043 1000 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.	Drug: GSK3036656; GSK3036656 was administered.; Drug: BTZ-043; BTZ-043 was administered.
Experimental: Standard of care for DS - TB_Cohort 2; Participants received Rifafour e-275 (or equivalent generic) once daily for 14 days.	Drug: RIFAFOUR e-275; RIFAFOUR e-275 was administered.
Experimental: GSK3036656 + Pretomanid; Participants received GSK3036656 20 mg + pretomanid 200 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.	Drug: GSK3036656; GSK3036656 was administered.; Drug: Pretomanid; Pretomanid was administered.
Experimental: GSK3036656 + Linezolid; Participants received GSK3036656 20 mg + linezolid 600 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.	Drug: GSK3036656; GSK3036656 was administered.; Drug: Linezolid; Linezolid was administered.
Experimental: GSK3036656 + moxifloxacin; Participants received GSK3036656 20 mg + moxifloxacin 400 mg once daily for 14 days; 50 mg GSK3036656 loading dose on Day 1.	Drug: GSK3036656; GSK3036656 was administered.; Drug: Moxifloxacin; Moxifloxacin was administered.
Experimental: Standard of care for DS TB_Cohort 3; Participants received Rifafour e-275 (or equivalent generic) once daily for 14 days.	Drug: RIFAFOUR e-275; RIFAFOUR e-275 was administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Time to Sputum Culture Positivity	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
Number of Participants With Serious Adverse Events (SAEs)	An SAE was defined as any untoward medical occurrence that, at any dose, resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, caused a congenital anomaly/birth defect, or was any other situation identified according to medical or scientific judgment.	From Day 1 to Day 28
Number of Participants With Adverse Events (AE) of Grade 3 Severity or Higher	An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not it was considered related to the study intervention. The intensity of AEs was assessed using the Division of Acquired Immunodeficiency Syndrome (DAIDS) criteria Version 2.1, where grades were defined based on numeric criteria as follows: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: potentially life-threatening; Grade 5: death. A higher grade indicated greater severity. Any = occurrence of the event regardless of intensity grade.	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
Number of Participants Withdrawn From the Study Due to Adverse Events		From Day 1 to Day 28
Number of Participants With Electrocardiogram (ECG) Values of Potential Clinical Importance (PCI)	PCI ECG values were defined as any ECG findings which, in the opinion of the investigator or medical monitor, would have interfered with the safety of the individual participant. The ECG measurements analyzed were PR Interval, QRS Duration, and QTcF Interval. A value was reported as "high" for a period if it had shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it had shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it had remained unchanged (e.g., High to High), or as "To W/in Range" if it had been within range.	From Day 1 to Day 28
Number of Participants With Hematology Laboratory Values of PCI	The analyzed hematology parameters were hematocrits, hemoglobin, lymphocytes, neutrophils, and platelets. A value was reported as "high" for a period if it had shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it had shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it had remained unchanged (e.g., High to High), or as "To W/in Range" if it had been within range.	From Day 1 to Day 28
Number of Participants With Clinical Chemistry Laboratory Values of PCI	The chemistry parameters analyzed were glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, calcium, creatinine, potassium, and sodium. A value was reported as "high" for a period if it had shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it had shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it had remained unchanged (e.g., High to High), or as "To W/in Range" if it had been within range.	From Day 1 to Day 28
Number of Participants With Vital Signs of PCI	The analyzed vital signs were systolic blood pressure, diastolic blood pressure, pulse rate. A value was reported as "high" for a period if it had shifted from "low" or "within range" (W/in) at the start of the treatment period but was "high" during or at the end of the same treatment period. A value was reported as "low" for a period if it had shifted from "high" or "W/in" at the start of the treatment period but was "low" during or at the end of the same treatment period. A value was reported as "No Change" if it had remained unchanged (e.g., High to High), or as "To W/in Range" if it had been within range.	From Day 1 to Day 28

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: Click-TB Consortium
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2022
• Primary Completion (Actual): May 27, 2025
• Study Completion (Actual): May 27, 2025

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 19, 2022

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Pulmonary tuberculosis; Bedaquiline; Early bactericidal activity; GSK3036656; Delamanid; BTZ-043; RIFAFOUR
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Acids, Acyclic; Carboxylic Acids; Amides; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Acetamides; Acetates; Oxazolidinones; Oxazoles; Linezolid; Moxifloxacin; GSK656; bedaquiline; OPC-67683; pretomanid; 2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one
• Other Study ID Numbers: 214912

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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