Clinical trial NCT05382312: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Tuberculosis
Keywords: Early bactericidal activity
Pulmonary tuberculosis
RIFAFOUR
Bedaquiline
Delamanid
GSK3036656
BTZ-043
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Click-TB Consortium
First posted: 2022-05-19
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: This study aims to measure the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics with GSK3036656 in combination with either delamanid or bedaquiline or BTZ-043, 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 will revert to the standard treatment (RIFAFOUR® e-275) once the study treatment (Day 1 to Day 14) has been completed.


Eligibility criteria: Inclusion Criteria:

* Participants must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
* Participants who have:

  1. 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. Normal echocardiogram or echocardiogram with normal left ventricular function with at most trace to mild valvular regurgitation is allowed and no valvular stenosis.
  5. A creatinine clearance greater than or equal to (\>=)90 mL/minute (Cockroft-Gault formula).
* Male participants are eligible to participate if they agree to barrier precautions until 90 days after last dose.
* A female participant is eligible to participate if she is not pregnant or breast feeding and is a woman of non-childbearing potential (WONCBP) or a woman of childbearing potential (WOCBP) using a contraceptive method that is highly effective. A WOCBP must have a negative pregnancy test urine or serum as required by local regulations before the first dose of study intervention. Only participants who are at least 25 years of age (and females of non-childbearing potential) will be eligible for the positron emission tomography-computed tomography (PET-CT) assessments.
* Capable of giving signed informed consent.

Exclusion Criteria:

* Evidence of a clinically significant (as judged by the Investigator) condition or abnormality (other than the indication being studied) that might compromise safety or the interpretation of trial efficacy or safety endpoints.
* Clinically significant evidence of extrathoracic TB as judged by the Investigator.
* QTc interval corrected for heart rate by Fridericia's formula (QTcF) greater than (\>)450 milliseconds (msec).
* Arterial hypertension with Systolic BP \>=160 mm Hg or diastolic BP \>=100 nm Hg. Participants with well-controlled hypertension may be included if they are using amlodipine for the duration of the study.
* Participants with vitiligo.
* Participants receiving any QT prolonging drugs, including but not limited to fluoroquinolones, macrolides and clofazimine.
* HIV infected participants:

  1. having a cluster of differentiation (CD)4+ count \<350 cells/microliters;
  2. having received any antiretroviral therapy medication within the last 30 days;
  3. or having received oral or intravenous antifungal medication within the last 30 days;
  4. or with an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection or malignancies in the last 12 months (except pulmonary TB).
* Presence of Hepatitis B surface antigen (HBsAg) or Positive Hepatitis C antibody test result at screening.
* Participants with diabetes (Type 1 or 2), point of care glycated hemoglobin (HbA1c) above 6.5%, or random glucose over 11.1 millimoles (mmol)/L
* Any diseases or conditions in which use of delamanid or bedaquiline is contraindicated.
* Participants with abnormal laboratory values at screening as graded by the enhanced Common Terminology Criteria for Adverse Events (CTCAE version 5 2017).

Primary outcomes:
measure: Change from Baseline in log10 CFU of Mycobacterium tuberculosis (MTB) (per milliliters of respiratory sputum samples)
timeFrame: Baseline and up to Day 14
Secondary outcomes:
measure: Change from Baseline in time to sputum culture positivity
timeFrame: Baseline and up to Day 14
measure: Number of participants with serious adverse events
timeFrame: Up to Day 28
measure: Number of participants with adverse events of Grade 3 severity or higher
timeFrame: Up to Day 28
measure: Number of participants with adverse events related to study drug
timeFrame: Up to Day 28
measure: Number of participants withdrawn from the treatment due to adverse events
timeFrame: Up to Day 28
measure: Number of participants withdrawn from the study due to adverse events
timeFrame: Up to Day 28
measure: Number of participants with electrocardiogram (ECG) values of potential clinical importance (PCI)
timeFrame: Up to Day 28
measure: Number of participants with hematology laboratory values of PCI
timeFrame: Up to Day 28
measure: Number of participants with clinical chemistry laboratory values of PCI
timeFrame: Up to Day 28
measure: Number of participants with vital signs of PCI
timeFrame: Up to Day 28
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: