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

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Tuberculosis

Treatments: Drug: GSK3036656; Drug: RIFAFOUR e-275; Drug: BTZ-043; Drug: Delamanid; Drug: Bedaquiline

Study type: Interventional

Funder types: Industry; Other

Identifiers

NCT05382312

214912

Details and patient eligibility

About

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.

Enrollment: 127 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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127 participants in 5 patient groups

Participants receiving GSK3036656+bedaquiline

Experimental group

Treatment:

Drug: Bedaquiline

Drug: GSK3036656

Participants receiving GSK3036656+delamanid

Experimental group

Treatment:

Drug: Delamanid

Drug: GSK3036656

Participants receiving bedaquiline+delamanid

Experimental group

Treatment:

Drug: Bedaquiline

Drug: Delamanid

Participants receiving RIFAFOUR e-275

Experimental group

Treatment:

Drug: RIFAFOUR e-275

Participants receiving GSK3036656+BTZ-043

Experimental group

Treatment:

Drug: BTZ-043

Drug: GSK3036656