Tuberculosis
Conditions
Keywords
Early bactericidal activity, Pulmonary tuberculosis, RIFAFOUR, Bedaquiline, Delamanid, GSK3036656, BTZ-043
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.
Interventions
DRUGGSK3036656
GSK3036656 was administered.
DRUGBedaquiline
Bedaquiline was administered.
DRUGDelamanid
Delamanid was administered.
DRUGRIFAFOUR e-275
RIFAFOUR e-275 was administered.
DRUGBTZ-043
BTZ-043 was administered.
DRUGPretomanid
Pretomanid was administered.
DRUGLinezolid
Linezolid was administered.
DRUGMoxifloxacin
Moxifloxacin was administered.
Sponsors
GlaxoSmithKline
Click-TB Consortium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Outcomes Assessor)
Masking description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in log10 Colony Forming Units (CFU) of Mycobacterium Tuberculosis (MTB) | At Baseline and at days 1, 2, 3, 4, 6, 8, 10, 12 and 14 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Time to Sputum Culture Positivity | At Baseline and at days 1, 2, 3, 4, 6, 8, 10, 12 and 14 | 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. |
| Number of Participants With Serious Adverse Events (SAEs) | From Day 1 to Day 28 | 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. |
| Number of Participants With Adverse Events (AE) of Grade 3 Severity or Higher | From Day 1 to Day 28 | 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. |
| 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) | From Day 1 to Day 28 | 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. |
| Number of Participants With Hematology Laboratory Values of PCI | From Day 1 to Day 28 | 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. |
| Number of Participants With Clinical Chemistry Laboratory Values of PCI | From Day 1 to Day 28 | 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. |
| Number of Participants With Vital Signs of PCI | From Day 1 to Day 28 | 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. |
Countries
South Africa
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Participant flow
Pre-assignment details
A total of 127 participants were enrolled out of which 125 started the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 33.9 YEARS STANDARD_DEVIATION 9.32 |
| Race/Ethnicity, Customized ASIAN | 0 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 11 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 14 | 0 / 15 | 0 / 16 | 0 / 14 | 0 / 3 | 0 / 16 | 0 / 13 | 0 / 14 | 0 / 11 |
| other Total, other adverse events | 9 / 9 | 11 / 14 | 10 / 15 | 12 / 16 | 11 / 14 | 1 / 3 | 12 / 16 | 8 / 13 | 11 / 14 | 9 / 11 |
| serious Total, serious adverse events | 0 / 9 | 0 / 14 | 0 / 15 | 0 / 16 | 0 / 14 | 0 / 3 | 0 / 16 | 1 / 13 | 0 / 14 | 0 / 11 |
Outcome results
None listed