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A 2 Part Study Examining Doses Of GSK961081 In Healthy Volunteers And Then In COPD Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00478738
First received: May 24, 2007
Last updated: February 1, 2017
Last verified: January 2017
  Purpose
GSK961081 has previously been administered to healthy subjects in a nebulised formulation and the first part of this study which will be conducted in healthy subjects proposes to bridge the change from nebulised to DPI formulation of GSK961081 before administration to patients. The second part of the study will be conducted in COPD patients and aims to assess the safety and bronchodilator profile of GSK961081 over 24 hours, during 14 days dosing.

Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive Drug: GSK961081 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Double Blind (masked roles unspecified)
Primary Purpose: Treatment
Official Title: A Study to Assess the Pharmacokinetics of Single Escalating Doses of Inhaled GSK961081 DPI (a Dual Pharmacophore) in Healthy Subjects (Part 1) and a Randomised, Double-blind, Double Dummy, Crossover (Incomplete Block) Study to Assess the Safety, Tolerability, Pharmacodynamics (Pulmonary and Systemic) and Pharmacokinetics of 14 Days Dosing With Inhaled GSK961081 DPI Compared With Placebo and Tiotropium Plus Salmeterol in Patients With COPD (Part 2)

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Part 1: Summary of area under the GSK961081 concentration-time curve (AUC) after a single dose [ Time Frame: Pre-dose (0.0 hour [h]) and 15, 30, 45 minutes (M), 1, 2, 3, 4, 6, 8, 12 and 24 h post dose of each treatment period ]
    Plasma samples for PK analysis were drawn on Day (D) 1 at indicated time points. The AUC from time zero (0M) to 2h (AUC 0-2) was area under the plasma concentration-time curve over the 2h time period. AUC(0-6) was area under the plasma concentration-time curve from 0M to 6h. AUC(0-t) was area under the plasma concentration-time curve from 0M to last quantifiable concentration. The AUC extrapolated to infinity (inf) (AUC[0-inf]) was calculated as the sum of AUC(0-t) and Ct/lambda z, where Ct is the observed GSK961081 concentration obtained from the log-linear regression analysis of the last quantifiable time-point and lambda z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. The number of time points used in the estimation of lambda z. Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the PK population.

  • Part 1: Summary of maximum observed concentration (Cmax) of GSK961081 after a single dose [ Time Frame: Pre-dose (0.0h) and 15, 30, 45 M, 1, 2, 3, 4, 6, 8, 12 and 24 h post dose of each treatment period ]
    Plasma samples for PK analysis were drawn on D1 at indicated time points. The first occurrence of the maximum observed GSK961081 concentration determined directly from the raw concentration-time data after each single dose. All participants were present at the time of measurement.

  • Part 1: Summary of last observed plasma concentration (t-last), time of maximum observed concentration (t-max) and terminal elimination half-life (t-half) [ Time Frame: Pre-dose (0.0h) and 15, 30, 45 M, 1, 2, 3, 4, 6, 8, 12 and 24 h post dose of each treatment period ]
    Plasma samples for PK analysis were drawn on D1 at indicated time points. The t-last and t-max was determined directly from the raw concentration-time data after each single dose. The t-half was obtained as the ratio of ln2/lambda z, where ln(2) is the natural logarithm of 2 (approximately 0.693) and lambda z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data after each single dose. Data for adjusted mean is presented as least square mean. Only those participants available at the specified time points were analyzed (represented by n=x,x,x in the category titles). Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the All Subjects population.

  • Part 2: Forced Expiratory Volume in 1 second (FEV1) over 24 hours post-dose on D1 and 14 [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Lung function tests (FEV1) was recorded whilst the participant was in a sitting position (if taken whilst the participant was on the bed, their legs should be over the edge). All lung function tests was repeated, until three technically acceptable measurements were made. Each measurement should be done at least 1 M apart. Participants must be resting in the body box for at least 30 seconds prior to any assessments. The FEV1 was measured at 15, 30 M, 1, 4, 12 and 24 h post dose of each treatment period on D1 and 14. Data for adjusted mean is presented as least square mean. Only those participants available at the specified time points were analyzed (represented by n=x,x,x,x in the category titles). Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the All Subjects population. Data for adjusted mean is presented as least square mean.


Secondary Outcome Measures:
  • Part 1: Number of participants with Adverse Events (AE) and Serious adverse events (SAE) [ Time Frame: Up to 16 weeks ]
    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. Refer to the general AE/SAE module for a list of AEs and SAEs.

  • Part 1: Mean values for urea, sodium, potassium, cholesterol, chloride, high density lipids-cholesterol (HDLC), and triglyceride [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.

  • Part 1: Mean values for creatinine and total bilirubin [ Time Frame: Up to D1of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.

  • Part 1: Mean values for total protein and albumin [ Time Frame: Up to D1of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.

  • Part 1: Mean values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine kinase and gamma glutamyl transferase (GGT). All participants were present at the time of measurement. [ Time Frame: Up to D1of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1 pre-dose and 24h post dose in Part 1 of study. All participants were present at the time of measurement.

  • Part 1: Mean values for platelet and white blood cell (WBC) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Mean values for hemoglobin and mean corpuscle hemoglobin concentration (MCHC) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Mean values for hematocrit [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Mean values for mean corpuscle volume (MCV) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Mean values for mean corpuscle hemoglobin (MCH) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Mean values for reticulocytes, total neutrophil, lymphocyte, monocyte, eosinophil and basophil [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Mean values for red blood cells (RBC) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated hematology tests on D1 pre-dose and 24h post dose in Part 1 of study.

  • Part 1: Summary of Results of Statistical Serial Time point Analysis of FEV1 Data-Treatment Differences [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Lung function tests (FEV1) was recorded whilst the participant was in a sitting position (if taken whilst the participant was on the bed, their legs should be over the edge). All lung function tests was repeated, until three technically acceptable measurements were made. Each measurement should be done at least 1 M apart. Participants must be resting in the body box for at least 30 seconds prior to any assessments. FEV1 measurements were taken after sGaw measurements. The FEV1 was measured at 15, 1, 4, 12 and 24 h post dose of each treatment period on D1. Data for adjusted mean is presented as least square mean. All participants were present at the time of measurement.

  • Part 1: Change from Baseline derived Electrocardiogram (ECG) parameters- QT interval corrected according to Bazzet's formula (QTcF) and QT interval corrected according to Fridericia's formula (QTcB) Maximum value (0-4 h) [ Time Frame: Up to D1of each treatment period (up to 16 weeks) ]
    ECG measurements were made with the participants in a supine position having rested in this position for at least 10 M before each reading. Data is presented as maximum value 0-4 h of each treatment period on D1. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where, RR interval (milliseconds [msec]) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.

  • Part 1: Change from Baseline derived ECG parameters-QTc(F) and QTc(B) Weighted mean (0-4 h)-Part [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    ECG measurements was made with the participants in a supine position having rested in this position for at least 10 M before each reading. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where, RR interval (msec) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points (0- 4 h) calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 1: Mean supine systolic blood pressure (SBP) maximum value (0-4 h) [ Time Frame: Up to D1of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. SBP was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1.Three baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.

  • Part 1: Mean supine diastolic blood pressure (DBP) minimum change (0-4 h) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. DBP was measured with an automatic measuring device. Data is presented as minimum change 0-4 h of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean. Data for adjusted mean is presented as least square mean.

  • Part 1: Mean supine SBP and supine DBP Weighted mean (0-4 h) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. It was measured at 0- 4 h post dose of each treatment period on D1. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 1: Change from Baseline supine heart rate maximum value (0-4 h) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.

  • Part 1: Change from Baseline supine heart rate Weighted mean (0-4 h) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. It was measured at 0-4 h post dose of each treatment period on D1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 1: Maximum change in postural SBP and DBP (0-4h) [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Maximum change in postural SBP and DBP (0-4 h) was derived as post dose standing reading minus post dose supine reading. Data for adjusted mean is presented as least square mean.

  • Part 1: Maximum change from Baseline value (0-4h) for glucose [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Data is presented as maximum value of glucose at 0-4 h of each treatment period on D1. Blood samples were collected for measurement of glucose at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Data for adjusted mean is presented as least square mean.

  • Part 1: Minimum change from Baseline value (0-4h) for potassium [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Data is presented as minimum change for potassium at 0-4 h of each treatment period on D1. Blood samples were collected for measurement of potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Data for adjusted mean is presented as least square mean.

  • Part 1: Maximum change from Baseline value (0-4h) for potassium [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of glucose at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The data for maximum change from Baseline for potassium was not analyzed.

  • Part 1: Weighted mean change from baseline (0-4h) for glucose and potassium [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of glucose and potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 1: Number of participants with abnormal Holter ECG findings as a function of cardiac monitoring [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Holter monitoring (24 h) was conducted at screening and after each dose during. Holter tapes were analyzed locally at site. A screening visit was taken place within 28 days of the first dosing occasion. Participants with abnormal (not clinically significant [NCS]), abnormal (clinically significant [CS]) and no result were presented.

  • Part 1: Number of participants with abnormal Lead II ECG findings as a function of cardiac monitoring [ Time Frame: Up to D1 of each treatment period (up to 16 weeks) ]
    Lead II ECG monitoring (via telemetry) will be recorded from pre-dose until 6 h after the dose. Participants with abnormal (NCS), abnormal (CS) and no result were presented.

  • Part 2: Number of participants with AE and SAE [ Time Frame: Up to 16 weeks ]
    An AE was defined as any untoward MO in a participant temporally associated with the use of a 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. Refer to the general AE/SAE module for a list of AEs and SAEs.

  • Part 2: Mean values for urea, sodium, potassium, cholesterol, chloride, high density lipids-cholesterol (HDLC), and triglyceride [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for creatinine and total bilirubin [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for total protein and albumin [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for AST, ALT, ALP, creatine kinase and GGT [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for hemoglobin and MCHC [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for hematocrit [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for MCV [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for MCH [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for total neutrophil, lymphocyte, monocyte, eosinophil and basophil [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for platelets and WBC [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for RBC [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7, 14 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Mean values for reticulocytes [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of indicated laboratory biochemistry tests on D1, 4, 7 pre-dose and 24h post dose on D14 in Part 2 of study.

  • Part 2: Change from Baseline derived ECG parameters- QTcF and QTcB Maximum value (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    ECG measurements were made with the participants in a supine position having rested in this position for at least 10 M before each reading. Data is presented as maximum value of glucose at 0-4 h of each treatment period on D1 and D14. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where, RR interval (msec) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Baseline value was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.

  • Part 2: Change from Baseline derived ECG parameters-QTcF and QTcB Weighted mean (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    ECG measurements was made with the participants in a supine position having rested for at least 10 M before reading. Data is presented as maximum value of glucose at 0-4 h of each treatment period on D1 and D14. The QTcB was derived automatically by the machine. The QTcF was manually derived by dividing QT interval with cube root of division of RR interval by 1000. Where RR interval (msec) was calculated as square of QT interval divided by QTcB, which was multiplied by 1000. The change from Baseline was calculated by subtracting the Baseline values from the post-randomization values. Baseline value was defined as the mean of three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points (0-4 h) calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 2: Maximum change from Baseline value (0-4h) for potassium [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of glucose at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1 and D14. The data for maximum change from Baseline was not analyzed.

  • Part 2: Ambulatory blood pressure: maximum, minimum, time to maximum, time to minimum and weighted mean for systolic and diastolic blood pressure, and weighted mean arterial pressure over 0-8 and 8-24 h after dosing on Days 1 and 14 [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Ambulatory blood pressure was monitored over 0-8 h and 8-24 h after dosing of each treatment period on D1 and D14. The data for ambulatory blood pressure was not analyzed.

  • Part 2: Number of participants with abnormal Holter ECG findings as a function of cardiac monitoring [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Holter monitoring (24 h) was conducted at screening and on D1 and 14 of each treatment period. Holter tapes were analyzed locally at site. A screening visit was taken place within 28 days of the first dosing occasion. Participants with abnormal (not clinically significant), abnormal (clinically significant) and no result were presented.

  • Part 2: Number of participants with abnormal Lead II ECG findings as a function of cardiac monitoring [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Lead II ECG monitoring (via telemetry) will be recorded from pre-dose until 8 h after the dose on D1 and D14 of each treatment period. Participants with abnormal (not clinically significant), abnormal (CS) and no result were presented.

  • Part 2: Mean supine SBP maximum value (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. SBP was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1 and D14. The baseline was defined as the mean of the three pre-dose measurements on D1 and D14 for each treatment period. Data for adjusted mean is presented as least square mean.

  • Part 2: Mean supine DBP minimum change (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. DBP was measured with an automatic measuring device. Data is presented as minimum change 0-4 h of each treatment period on D1 and D14. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean. Data for adjusted mean is presented as least square mean.

  • Part 2: Mean supine SBP and supine DBP Weighted mean (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. It was measured at 0- 4 h post dose of each treatment period on D1 and D14. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 2: Change from Baseline supine heart rate maximum value (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1 and D14. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Data for adjusted mean is presented as least square mean.

  • Part 2: Change from Baseline supine heart rate Weighted mean (0-4 h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. Heart rate was measured with an automatic measuring device. It was measured at 0-4 h post dose of each treatment period on D1 and D14. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 2: Maximum change in postural SBP and DBP (0-4h) [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Participants were required to rest in the supine position for at least 10 M before each reading. SBP and DBP were measured with an automatic measuring device. Data is presented as maximum value 0-4 h of each treatment period on D1 and D14. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. Maximum change in postural SBP and DBP (0-4h) was derived as post dose standing reading minus post dose supine reading. Data for adjusted mean is presented as least square mean.

  • Part 2: Minimum change from Baseline value (0-4h) for potassium [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Data is presented as minimum change for potassium at 0-4 h of each treatment period on D1 and D14. Blood samples were collected for measurement of potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1 and D14. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Data for adjusted mean is presented as least square mean.

  • Part 2: Weighted mean change from baseline (0-4h) for potassium [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    Blood samples were collected for measurement of glucose and potassium at pre-dose (0.0), 30 M, 1, 2 and 4 h post dose of each treatment period on D1 and D14. The Baseline was defined as the mean of the three pre-dose measurements on D1 for each treatment period. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. All available data at the actual relative times were included in the derivation of the weighted mean with pre-dose measurements representing the time point zero, and all subsequent time points calculated relative to dosing in that period. Data for adjusted mean is presented as least square mean.

  • Part 2: Summary of AUC after a single dose [ Time Frame: Pre-dose (0.0 h) and 30 M, 1, 2, 4, 6, 8, 12 and 24 h post dose of each treatment period on D1 and D14; Pre-dose (0.0 h) and 30 M, 1, 2, 4 and 6 h post dose of each treatment period on D7. ]
    Plasma samples for PK analysis were drawn on D1, 7 and 14 at indicated time points of each treatment period. The AUC from time zero (0M) to 2h (AUC 0-2) was area under the plasma concentration-time curve over the 2h time period. AUC(0-6) was area under the plasma concentration-time curve from 0M to 6h. AUC(0-t) was area under the plasma concentration-time curve from 0M to last quantifiable concentration. The AUC extrapolated to inf (AUC[0-inf]) was calculated as the sum of AUC(0-t) and Ct/lambda z, where Ct is the observed GSK961081 concentration obtained from the log-linear regression analysis of the last quantifiable time-point and lambda z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. The number of time points used in the estimation of lambda z.

  • Part 2: Summary of Cmax of GSK961081 after a single dose [ Time Frame: Pre-dose (0.0 h) and 30 M, 1, 2, 4, 6, 8, 12 and 24 h post dose of each treatment period on D1 and D14; Pre-dose (0.0 h) and 30 M, 1, 2, 4 and 6 h post dose of each treatment period on D7. ]
    Plasma samples for PK analysis were drawn on D1, 7 and 14 at indicated time points of each treatment period. The first occurrence of the maximum observed GSK961081 concentration determined directly from the raw concentration-time data after each single dose. All participants were present at the time of measurement.

  • Part 2: Summary of t-last, t-max and t-half [ Time Frame: Pre-dose (0.0 h) and 30 M, 1, 2, 4, 6, 8, 12 and 24 h post dose of each treatment period on D1 and D14; Pre-dose (0.0 h) and 30 M, 1, 2, 4 and 6 h post dose of each treatment period on D7. ]
    PK population. Only those participants available at the specified time points were analyzed (represented by n=x,x in the category titles). Different participants may have been analyzed at different time points; thus, the overall number of participants analyzed reflects everyone in the PK population.

  • Part 2: Serial sGaw measurement over 24 hours post-dose on D1 and 14 [ Time Frame: Up to D14 of each treatment period (up to 16 weeks) ]
    sGaw was assessed by whole body plethysmography at 30 M, 1, 4, 12 and 24 h post dose of each treatment period on D1 and D14. Participants must be resting in the body box for at least 30 seconds prior to any assessments. Data for adjusted


Enrollment: 82
Study Start Date: June 2007
Study Completion Date: May 2008
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
GSK961081
GSK961081
Drug: GSK961081

Detailed Description:
A study to assess the pharmacokinetics of single escalating doses of inhaled GSK961081 DPI (a dual pharmacophore) in healthy subjects (Part 1) and a randomised, double-blind, double dummy, crossover (incomplete block) study to assess the safety, tolerability, pharmacodynamics (pulmonary and systemic) and pharmacokinetics of 14 days dosing with inhaled GSK961081 DPI compared with placebo and tiotropium plus salmeterol in patients with COPD (Part 2).
  Eligibility

Ages Eligible for Study:   40 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject is male or female (of non-child bearing potential) > 40 years of age and < 75 years of age.
  • Non- child bearing potential is defined as physiologically incapable of becoming pregnant, including females who are post menopausal ( more than 2 years without menses with appropriate clinical history ie age, history of vasomotor symptoms-estradiol and FSH levels may be checked if indicated) and females who are surgically sterile (hysterectomy, tubal ligation or bilateral oophorectomy.
  • Subject diagnosed with COPD (stage II) in accordance with ATS/ERS guidelines (see Appendix 2: COPD Guidelines).
  • Subject is a smoker or an ex smoker with a history of at least 10 pack years (1 pack year= 20 cigarettes smoked per day for 1 year or equivalent)
  • Subject has FEV1/FVC < 0.7 post - bronchodilator (salbutamol)
  • Subject has FEV1 < 80 % of predicted normal for height, age, gender after inhalation of salbutamol
  • Response to ipratropium bromide defined as:

Either an increase in FEV1 of > 12 % and > 150 mLwithin 2 hour following inhalation of 80 µcg ipratropium bromide at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hour following inhalation of 80 µcg ipratropium bromide within 6 months of screening and an increase in FEV1 of > 6 % and > 100 mL within 2 h following inhalation of 80 mg ipratropium bromide at the screening visit (in order to allow for potential fluctuations in the response to ipratropium bromide in patients known to be responders to ipratropium bromide)

  • Response to salbutamol defined as:

Either an increase in FEV1 of > 12 % and > 150 mL within 2 hour following inhalation of 400 mg salbutamol at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hour following inhalation of 400 mg salbutamol within 6 months of screening and an increase in FEV1 of > 6 % and >100 mL within 2 h following inhalation of 400 mg salbutamol at the screening visit (in order to allow for potential fluctuations in the response to salbutamol in patients known to be responders to salbutamol)

  • Body mass index within the range 18-35 kilograms/metre² (kg/m²).
  • Subject is able and willing to give written informed consent to take part in the study.
  • Subject is available to complete all study measurements

Exclusion Criteria:

  • Subjects who have a past or present disease, which as judged by the Investigator and medical monitor may affect the outcome of the study or the safety of the subject
  • Women who are pregnant or lactating
  • An unwillingness of subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as IUD, diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants or tubal ligation if the woman could become pregnant from the time of the first dose study medication until 90 days post-dose
  • The subject has a positive urine drug screen. A minimum list of drugs that will be screened for include Amphetamines, barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.
  • The subject has a positive alcohol test (breath or urine) predose.
  • A history, or suspected history, of alcohol abuse within the 6 months before the screening visit.
  • A positive test for hepatitis C antibody, hepatitis B surface antigen, or HIV.
  • The subject has participated in a clinical study with another New Chemical Entity within the past 2 months or a participated in a clinical study with any other drug during the previous month.
  • The subject has donated a unit of blood within the 56 days or intends to donate within 56 days after completing the study.
  • The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet.
  • Subject has an FEV1 < 50 % of predicted for age, height and gender after inhalation of salbutamol.
  • The subject has a diagnosis of active tuberculosis, lung cancer, sarcoidosis, bronchiectasis, lung fibrosis, pulmonary hypertension or with a primary diagnosis of asthma
  • The subject has a known allergy or hypersensitivity to ipratropium, salbutamol, tiotropium, salmeterol or lactose
  • A subject in whom ipratropium, salbutamol, tiotropium and/or salmeterol is contraindicated
  • Subjects with lung volume reduction surgery within 12 months of screening
  • Poorly controlled COPD defined as:

Either: acute worsening of COPD that is managed by the subject at home by treatment with increased corticosteroids or antibiotics in the 6 weeks before screening Or: more than 2 exacerbations in the previous 12 months before screening that required a course of oral steroids or antibiotics, and/or required hospitalisation

  • Subject has had a respiratory tract infection in the 4 weeks before screening
  • Subject requires treatment with inhaled cromolyn sodium, theophyline, oral beta agonists, nebulised anticholinergics or leukotriene antagonists
  • Subject is unable to abstain from long acting beta agonist from 72 hours before screening and throughout the dosing period
  • Subject is unable to abstain from tiotropium from 28 days before screening and throughout the dosing period
  • Subject is predicted to be unable to abstain from short acting inhaled beta agonists (to be used as rescue medication during the study) for 6 hours before screening and before study visits, when required, until all post dose lung function tests have been completed for a given study day.
  • Subject has received oral corticosteroids within the 6 weeks before screening
  • Subject is receiving > 1000 mg FP (or equivalent) a day of inhaled corticosteroid or has changed dose within the 6 weeks before screening or is predicted not to be able to maintain a constant dose during the study
  • Subject is receiving oxygen therapy or nocturnal positive pressure treatment
  • Subject has prostate hypertrophy or narrow angle glaucoma
  • The subject is unable to use the dosing devices correctly.
  • Subject with carcinoma that has not been in complete remission for at least 5 years (with the exception of carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma if the subject is considered cured)
  • A history of congestive heart failure, coronary insufficiency or cardiac arrhythmia
  • Abnormal 12- lead ECG abnormality which is either clinically significant or may interfere with QTc measurement
  • A supine mean heart rate outside the range 40-90 beats per minute (bpm) at screening.
  • Elevated supine blood pressure higher than 160/95 at screening.
  • Subject is receiving a diuretic and/ or beta adrenergic antagonist.
  • Subject has a serum potassium level below the reference range at screening.
  • Strict vegetarians;
  • Shift-worker unable to comply with the study;
  • Inability to understand the protocol requirements, instructions and study-related restrictions; the nature, scope and possible consequences of the study;
  • Unlikely to complete the study; e.g., uncooperative attitude, inability to return for Follow-up Visits;
  • Subject is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff, or relative thereof directly involved in the conduct of the study;
  • Vulnerable individuals (e.g., persons kept in detention).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00478738

Locations
Germany
GSK Investigational Site
Mainz, Rheinland-Pfalz, Germany, 55131
GSK Investigational Site
Berlin, Germany, 14050
South Africa
GSK Investigational Site
Bloemfontein, South Africa, 9301
GSK Investigational Site
George, South Africa, 6530
GSK Investigational Site
Mowbray, South Africa, 7700
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Publications:
Study Data/Documents: Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: MAB104958
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00478738     History of Changes
Other Study ID Numbers: MAB104958
Study First Received: May 24, 2007
Last Updated: February 1, 2017
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Keywords provided by GlaxoSmithKline:
b-agonist,
COPD.
pharmacodynamic,
pharmacokinetic,
anti muscarinic,

Additional relevant MeSH terms:
Lung Diseases
Chronic Disease
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Lung Diseases, Obstructive

ClinicalTrials.gov processed this record on June 23, 2017