GSK233705 is a high-affinity specific muscarinic receptor (mAChR) antagonist which is being developed for the treatment of chronic obstructive pulmonary disease. This is a randomised, double-blind, placebo-controlled, dose ascending, parallel group study to examine the safety, tolerability, pharmacokinetics and pharmacodynamics of twice daily inhaled doses of GSK233705B for 7 days, in COPD subjects.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
DIAGNOSTIC
Enrollment
23
GSK Investigational Site
Eindhoven, Netherlands
GSK Investigational Site
Harderwijk, Netherlands
GSK Investigational Site
Utrecht, Netherlands
GSK Investigational Site
Zuidlaren, Netherlands
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
Time frame: Up to follow-up (approximately 45 days)
Summary of Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Blood pressure was measured subsequent to 12 lead electrocardiogram (ECG). Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.
Time frame: Up to Day 7 (24 hours post-dose)
Summary of Mean Heart Rate
Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.
Time frame: Up to Day 7 (24 hour post dose)
Maximum Value of SBP and DBP (0-4 Hour) for the Morning Dose
Blood pressure was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (0-4 hour)
Maximum Value of Heart Rate (0-4 Hour) for the Morning Dose
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Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (0-4 hour)
Weighted Mean of SBP and DBP (0-4 Hour) for the Morning Dose
Blood pressure was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (0-4 hour)
Weighted Mean of Heart Rate (0-4 Hour) for the Morning Dose
Heart rate was measured subsequent to 12 lead ECG. Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (0-4 hour)
Number of Participants With Abnormal 12-lead ECG Findings
Single measurements were taken at all time points. The pre-dose values were classed as Baseline. Data for number of participants with normal, abnormal not clinically significant and abnormal clinically significant is presented. It was assessed on Baseline (triplicate), 15, 30 minutes, 1.5, 4, 8 and 24 hours on Day 1 and 7.
Time frame: Up to Day 7 (24 hour post dose)
Maximum Value (0-4 Hour) for the Morning Dose of ECG Parameters Corrected According to Fredericia's Formula (QTcF) and Corrected According to Bazett's Formula (QTc B)
Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (0-4 hour)
Weighted Mean (0-4 h) for the Morning Dose of ECG Parameters QTcF and QTc B
Baseline was defined as the mean of the three planned pre-dose measurements. It was assessed on pre-dose, 15, 30 minutes, 1.5 and 4 hours on Day 1 and 7. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (0-4 hour)
Summary of Mean Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC)
It was assessed on 1, 2, 4, 9, 12 and 24 hours on Days 1 and 7. Also on Day 7, it was measured on 0 hour (Baseline). At all time points 3 measurements were taken and formal statistical analysis was carried out on the derived maximum readings. Data for adjusted mean is presented as least square mean.
Time frame: Up to Day 7 (24-hour post dose)
Number of Participants Who Used Rescue Medication
Inhaled salbutamol was used as a rescue medication. Participants were required to keep a diary of their rescue medication (total number of salbutamol doses taken) over the entire 7-day treatment period. Diaries were reviewed by the Investigator when participants were admitted to the unit on Days 1, 2, 7 and 8.
Time frame: Up to Day 7
Number of Participants With Abnormalities in Chemistry Data of Clinical Concern
Clinical chemistry parameters included urea, potassium, aspartate aminotransferase (AST), total bilirubin, creatinine, creatine kinase, chloride, alanine aminotransferase (ALT), uric acid, glucose, gamma glutamyltransferase (GGT), albumin, sodium, phosphorus inorganic, calcium, alkaline phosphatase (ALP) and total protein. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours). Data for parameters with above and below the potential clinical concern (PCI) is provided.
Time frame: Up to Day 7
Number of Participants With Abnormalities in Hematology Data of Clinical Concern
Hematology parameters included platelet count, red blood cell (RBC) count, mean corpuscular volume (MCV), total neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours). Data for parameters with above and below the PCI is provided.
Time frame: Up to Day 7
Summary of Microscopy Data for Participants With Abnormal Urinalysis Dipstick Results
Urinalysis parameters included protein, blood, ketones, glucose, bilirubin, urobilinogen, leukocyte esterase, specific gravity, nitrites and pH. Sediment microscopy was performed only on urine samples showing an abnormality on the dipstick. Microscopy was performed for: WBC, RBC, hyaline casts, granular casts and cellular casts. It was assessed on Day 1 (pre-dose, 24 hours) and Day 7 (pre-dose, 24 hours).
Time frame: Up to Day 7 (pre dose)
Summary of Mean (0-24 Hour) and Maximum (0-24 Hour) Heart Rate Measured Using 24 Hour Using Holter ECG Data
Holter monitors were switched on immediately prior to dosing (up to 15mins pre-dose) so as to capture Holter ECG data from the 24 hour period following dosing. It was assessed on Day 1 and 7.
Time frame: Up to Day 7
Plasma Concentrations of GSK233705
Blood samples were collected at indicated time points. 12 hour pharmacokinetic (PK) sampling was before evening dose.
Time frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose
Urine Concentrations of GSK233705
Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study and consolidated data is presented as 0-12 hours and 12-24 hours. 12 hour pharmacokinetic sampling was before evening dose.
Time frame: Day 1 and 7 throughout 24 hours
Derived Plasma PK Parameters-area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau)
Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning samples.
Time frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose
Derived Plasma PK Parameters-area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-t)
Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning sample as adjusted geometric mean.
Time frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose
Derived PK Plasma Parameters-area Under Concentration-maximum Observed Plasma Concentration (Cmax)
Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning and evening samples as adjusted geometric mean.
Time frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose
Derived PK Plasma Parameters-area Under Concentration-time of Maximum Observed Plasma Concentration (T-max), Half-life (T-half) and Last Time Point Where the Concentration is Above the Limit of Quantification (T-last)
Blood samples were collected at indicated time points. 12 hour PK sampling was before evening dose. Data presented for morning and evening samples.
Time frame: Day 1 and 7 morning: pre-dose, 5, 15 minutes, 1, 6 and 12 hours post-dose and Day 1 and 7 evening: pre-dose, 5 and 30 post-dose
Derived Urine Pharmacokinetic (PK) Parameters-area Under the Plasma Concentration-amount of Drug Excreted Unchanged in Urine (Ae)
Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study and consolidated data presented as AM dose and PM dose. 12 hour pharmacokinetic sampling was before evening dose.
Time frame: Day 1 and 7 throughout 24 hours
Derived Urine PK Parameters-area Under Concentration-fraction of Dose Excreted Unchanged in Urine (Fe)
Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study and consolidated data presented as 0-12 hours and 12-24 hours. 12 hour pharmacokinetic sampling was before evening dose.
Time frame: Day 1 and 7 throughout 24 hours
Derived Urine PK Parameters-area Under Concentration-renal Clearance (Clr)
Urine GSK233705 pharmacokinetic excretion rate-time data is presented. Urine samples were collected throughout study. 12 hour pharmacokinetic sampling was before evening dose.
Time frame: Day 1 and 7 throughout 24 hours