An Investigation Of The Interaction Of GSK961081 With Inhaled Beta-Agonist And Anti-Muscarinic Drugs.

Study Overview
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Brief Summary
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GSK961081 is a potent dual pharmacophore that demonstrates both antimuscarinic and beta-agonist pharmacology in preclinical studies, both pharmacologies being of long duration. If reproduced in man, GSK961081 has the potential to deliver a medicine that can be given once daily. The bronchodilatation after inhalation of single doses of GSK961081 alone and in the presence of the short acting beta agonist salbutamol and the short acting muscarinic antagonist, ipratropium bromide will be measured in this study. Any residual bronchodilatation post-inhalation of GSK961081 and demonstrated by addition of salbutamol or ipratropium bromide may provide an indirect assessment of the beta-agonist and antimuscarinic components of GSK961081

Detailed Description
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GSK961081 is a potent dual pharmacophore that demonstrates both antimuscarinic and beta-agonist pharmacology in preclinical studies, both pharmacologies being of long duration. If reproduced in man, GSK961081 has the potential to deliver a medicine that can be given once daily. The bronchodilatation after inhalation of single doses of GSK961081 alone and in the presence of the short acting beta agonist salbutamol and the short acting muscarinic antagonist, ipratropium bromide will be measured in this study. Any residual bronchodilatation post-inhalation of GSK961081 and demonstrated by addition of salbutamol or ipratropium bromide may provide an indirect assessment of the beta-agonist and antimuscarinic components of GSK961081

Official Title
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A Randomized, Double-blind, Crossover Study to Investigate the Bronchodilatation Post-inhalation of GSK961081 Alone and With the Addition of Cumulative Doses of Short Acting Bronchodilators (Salbutamol and Ipratropium Bromide) in Patients With COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: 400 microgrammes GSK961081
* Drug: 1200 microgrammes GSK961081


Participation Criteria
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Eligibility Criteria
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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 i.e. 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 in accordance with ATS/ERS guidelines (as per protocol). 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 ipatropium bromide defined as: Either an increase in FEV1 of > 12 % and > 150 mL within 2 hours following inhalation of 80 µg ipratopium bromide (Atrovent MDI via spacer) at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following inhalation of 80 µg ipratopium bromide within 6 months of screening and an increase in FEV1 of > 6 % and > 100 mL within 2h following inhalation of 80 µg ipratopium bromide (Atrovent MDI via spacer) 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 hours following inhalation of 400 µg salbutamol MDI (via spacer) at the screening visit Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following inhalation of 400 µg salbutamol MDI within 6 months of screening and an increase in FEV1 of > 6 % and >100 mL within 2h following inhalation of 400 µg salbutamol MDI (via spacer) 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 (BMI) within the range 18-35 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 assessments 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 Subjects with clinically relevant findings on laboratory safety tests. Subjects with laboratory values outside the reference range may be include in the study if the Investigator and medical monitor agree that these findings would not put the subject at risk or interfere with the objectives of the study 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 drugs of abuse screen. A minimum list of drugs that will be screened for include amphetamines, barbituates, cocaine, opiates, cannabinoids and benzodiazepines. 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 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 of dosing or intends to donate within 56 days after completing the study. Subject has an FEV1 < 40 % 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 bromide, salbutamol, or lactose A subject in whom ipratropium bromide or salbutamol 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 ß2- agonists, nebulised anticholinergics or leukotriene antagonists Subject is unable to abstain from long acting ß2-agonist from 72 hours before screening and throughout the dosing period Subject is unable to abstain from tiotropium bromide from 28 days before screening and throughout the dosing period Subject is predicted to be unable to abstain from short acting inhaled ß2-agonists or short acting antimuscarinics for 6 hours before screening and for 6 hours before dosing with GSK961081 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 µg 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 Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study investigator would prevent use of an inhaled anticholinergic The subject is unable to use the dosing devices (MDPI/ MDI/ spacer) 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 or a finding on screening 24h Holter monitor that would contraindicate the subject's participation in the study 12- lead ECG abnormality which is either clinically significant or may interfere with QTc measurement or QTc > 450 msec or PR interval outside the range 120 to 220 msec. A supine mean heart rate outside the range 40-90 bpm at screening. Persistently elevated supine blood pressure higher than 160/95 at screening. Subject is receiving a high-dose diuretic and/ or ß2-adrenergic antagonist Subject has a serum potassium level below the reference range at screening. 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 400 microgrammes GSK961081 and salbutamol<br>400 microgrammes of GSK961081 single-dose (via DISKUS Metered Dry Powder Inhaler/ MDPI) followed by cumulative doses (3x 200 microgrammes at 20 min intervals, administered via spacer) of salbutamol at 1h, 12h and 24h of dosing. | Drug: 400 microgrammes GSK961081<br>* Inhaled GSK961081 administered via Dry Powder Inhaler.<br>|
| Experimental: 1200 microgrammes GSK961081 and salbutamol<br>1200 microgrammes of GSK961081 single-dose (via DISKUS MDPI) followed by cumulative doses (3x 200 microgrammes at 20 min intervals, administered via spacer) of salbutamol at 1h, 12h and 24h of dosing. | Drug: 400 microgrammes GSK961081<br>* Inhaled GSK961081 administered via Dry Powder Inhaler.<br>Drug: 1200 microgrammes GSK961081<br>* Inhaled GSK961081 adminisntered via dry powder inhaler.<br>|
| Experimental: 400 microgrammes GSK961081 and ipratropium bromide<br>400 microgrammes of GSK961081 single-dose (via DISKUS MDPI) followed by cumulative doses (20 microgrammes, 20 microgrammes and 40 microgrammes at 20 min intervals, administered via spacer) of ipratropium bromide at 1h, 12h and 24h of dosing. | Drug: 1200 microgrammes GSK961081<br>* Inhaled GSK961081 adminisntered via dry powder inhaler.<br>|
| Experimental: 1200 microgrammes of GSK961081 and ipratropium bromide<br>1200 microgrammes of GSK961081 single-dose (via DISKUS MDPI) followed by cumulative doses (20 microgrammes, 20 microgrammes and 40 microgrammes at 20 min intervals, administered via spacer) of ipratropium bromide at 1h, 12h and 24h of dosing. | Drug: 400 microgrammes GSK961081<br>* Inhaled GSK961081 administered via Dry Powder Inhaler.<br>Drug: 1200 microgrammes GSK961081<br>* Inhaled GSK961081 adminisntered via dry powder inhaler.<br>|
| Placebo Comparator: 400 microgrammes of GSK961081 and placebo<br>400 microgrammes of GSK961081 single-dose (via DISKUS Metered Dry Powder Inhaler/ MDPI) followed by cumulative doses (3 doses at 20 min intervals, administered via spacer) of placebo at 1h, 12h and 24h of dosing. | Drug: 1200 microgrammes GSK961081<br>* Inhaled GSK961081 adminisntered via dry powder inhaler.<br>|
| Placebo Comparator: 1200 microgrammes of GSK961081 and placebo<br>1200 microgrammes of GSK961081 single-dose (via DISKUS Metered Dry Powder Inhaler/ MDPI) followed by cumulative doses (3 doses at 20 min intervals, administered via spacer) of placebo at 1h, 12h and 24h of dosing. | Drug: 400 microgrammes GSK961081<br>* Inhaled GSK961081 administered via Dry Powder Inhaler.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Change in Forced Expiratory Volume in One Second (FEV1) From Baseline (Pre-dose on Day 1) in Combination With Short Acting Bronchodialator (Salbutamol or Ipratropium Bromide) at 1h,12h and 24h. | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second as measured by spirometry. Adjusted mean has been presented as least square (LS) mean. | Baseline (pre-dose on Day 1), 1h, 12h, and 24h on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Change in Forced Vital Capacity (FVC) in One Second From Pre-dose in Combination With Short Acting Bronchodialator (Salbutamol or Ipratropium Bromide) at 1h, 12h and 24h. | FVC is defined as the amount of air that can be forcibly exhaled from the lungs after a maximum inspiration as measured by spirometry. Adjusted mean has been presented as least square (LS) mean. | Baseline (Pre-dose on Day 1), 1h, 12h, and 24h on Day 1 | 
| Number of Participants With Adverse Events and Serious Adverse Events | An adverse event (AE) is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious AE (SAE) is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. | Upto 82 days | 
| Number of Participants With Laboratory Abnormalities of Potential Clinical Concern (PCC) | The normal ranges of laboratory parameters were hemoglobin: 130-167 grams per deciliter (g/dL), platelets: 173-383 Giga per liter (GI/L), lymphocytes: 20.1-44.5 %, glucose: 3.8857-6.106 millimoles per liter (mmol/L), creatinine: 44.2-132.6 micromoles per liter (uM/L) , aspartate transaminases (AST): 12-32 international units per liter (IU/L), total bilirubin (TB): 4.275-25.65 uM/L and potassium: 3.4-4.7 mmol/L, respectively. Laboratory values recorded outside the normal range were considered of potential clinical concern (PCC). | Up to 42 days | 
| Change From Baseline (Pre-dose on Day 1) in Systolic and Diastolic Blood Pressure up to 27 Hours | Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was analyzed. Change from baseline is the difference in the blood pressure at the indicated time point minus the Baseline value. | Up to 27 hours post Day 1 dosing | 
| Mean Change From Baseline (Pre-dose on Day 1) in Heart Rate Over 27 Hours | Heart rate was considered as a measure of vital sign. Change from baseline is the difference in the blood pressure at the indicated time point minus the Baseline value. | Up to 27 hours post Day 1 dosing | 
| Number of Participants With Maximum Change From Baseline 12-LED Electrocardiogram (ECG) Findings | Analysis QTc interval of ECG was performed by Bazett's formula (QTc B) and Fridericia's correction (QTc F). Number of participants with abnormal ECG findings were recorded. Any participant with QTc(B) or QTc(F) >500 milliseconds (msec) or uncorrected QT >600 msec (machine or manual over read) was withdrawn from the study. Participants that had right bundle branch block with QTc(B) or QTc(F) >530 msec were also withdrawn from the study. | From dosing until 24h post-dose. | 
| Maximum Change From Baseline (Pre-dose on Day 1) in QTc (F) in Supine Position From 0 to 4 Hours After Dosing | Analysis of QT (F) interval during ECG (taken in supine position) was performed using Fridericia's method. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted means are considered as least square (LS) mean values while presenting the data. | From dosing until 4 hours (0-4h) | 
| Maximum Change From Baseline (Pre-dose on Day 1) in QTc (F) in Supine Position From 0 to 27 Hours After Dosing | Analysis of Q T (F) interval during ECG (taken in supine position) was performed using Fridericia's method. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted means are considered as LS mean values while presenting the data . | From dosing until 27 hours (0-27h) | 
| Weighted Mean Change From Baseline (Pre-dose on Day 1) in QTc(F) in Supine Position From 0 to 4 Hours | Analysis of QT(F) interval during ECG (taken in supine position) was performed using Fridericia's method. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. | From dosing until 4 hours (0-4h) | 
| Maximum Change From Baseline (Pre-dose on Day 1) in QTc(B) in Supine Position From 0 to 4 Hours and 0 to 27 Hours | Analysis of QT (B) interval during ECG (taken in supine position) was performed using Bazett's method. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data . | From dosing until 4 hours (0-4h) and 27 hours (0-27h) | 
| Weighted Mean Change From Baseline (Pre-dose on Day 1) in QTc(B) in Supine Position From 0 to 4 Hours | Analysis of QT (B) interval during ECG (taken in supine position) was performed using Bazett's method. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. | From dosing until 4 hours (0-4h) | 
| Maximum Change From Baseline (Pre-dose on Day 1) in Supine Heart Rate From 0 to 4 Hours and From 0 to 27 Hours. | Heart rate was measured in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted means are considered as LS mean values while presenting the data. | From dosing until 4 hours (0-4h) and until 27 hours (0-27 h) | 
| Weighted Mean Change From Baseline (Pre-dose on Day 1) in Heart Rate in Supine Position From 0 to 4 Hours | Heart rate was recorded in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. | From dosing until 4 hours (0-4h) | 
| Maximum Change From Baseline (Pre-dose on Day 1) in Supine Systolic Blood Pressure (SBP) Over 4 and 27 Hours and Weighted Mean Change From Baseline in Supine SBP Over 4 Hours | Systolic blood pressure (SBP) values were recorded in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted or maximum change/ (MC) and weighted mean change (WMC) are considered as LS mean change values while presenting the data. | 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change | 
| Minimum Change From Baseline (Pre-dose on Day 1) in Supine Diastolic Blood Pressure (DBP) Over 4 and 27 Hours and Weighted Mean Change From Baseline in Supine DBP Over 4 Hours | Diastolic blood pressure (DBP) values were recorded in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted or maximum change/(MC) and weighted mean change (WMC) are considered as LS mean change values while presenting the data . | 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change | 
| Maximum Change From Baseline (Pre-dose on Day 1) in Glucose Over 4 and 27 Hours and Weighted Mean Change From Baseline in Glucose Over 4 Hours | Maximum change (MC) from Baseline (BL) and weighted mean change (WMC) from baseline in glucose (GLU) were analyzed. Change from Baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. | 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change | 
| Minimum Change From Baseline (Pre-dose on Day 1) in Potassium Over 4 and 27 Hours and Weighted Mean Change From Baseline in Potassium Over 4 Hours | Maximum change (MC) from Baseline (BL) and weighted mean change (WMC) from baseline in potassium (K) were analyzed. Change from Baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. | 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change | 
| Time to Maximum Change From Baseline (Pre-dose on Day 1) for QTc(B), QTc(F), Heart Rate, Systolic BP, Glucose in Supine Position and Time to Minimum Change From Baseline for Potassium and Diastolic BP in Supine Position | Analysis of QT (B) or QTc (F) interval during ECG (taken in supine position) was performed using Bazett's method and Fridericia's method, respectively. Heart rate, BP, potassium, and glucose were measured in supine body position. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. | From dosing until 4 hours (0-4h) | 
| Area Under Plasma Concentration Time Curve (AUC) of GSK961081 to the Last Quantifiable Concentration | AUC(0-t) is the area under plasma concentration time curve of GSK961081 to the last quantifiable concentration. This parameter was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. A large proportion of AUC(0-t) and Cmax values were reported as not countable (NC) at the GSK961081 400 micrograms (ug) dose level, therefore only limited summaries were calculated. Logarithmic transformed values are presented. AUC(0-t) imputed with 1/2 lowest observed AUC(0-t), where lowest AUC(0-t) was 56.46 hour picograms per milliliter (h*pg/mL). | Up to 82 days | 
| Maximum Plasma Concentration (Cmax) of GSK961081 Over Period Determined Directly From the Concentration-time Data | Cmax is the Maximum observed concentration of GSK961081 determined directly from the concentration-time data. A large proportion of Cmax values were reported as not countable (NC ) at the GSK961081 400 micrograms (ug) dose level, therefore only limited summaries were calculated. Logarithmic transformed values are presented. Cmax was imputed with 1/2 lowest limit of quantification (LLQ), where LLQ was 25 picograms per milliliter (pg/mL). | Up to 82 days | 
| Time to Maximum Plasma Concentration (Tmax) of GSK961081 Over Period Determined Directly From the Concentration-time Data | Tmax is the time to maximum plasma concentration of GSK961081 over period determined directly from the concentration-time data | Up to 82 days | 
| Time to Last Quantifiable Plasma Concentration (Tlast) of GSK961081 Over Period Determined Directly From the Concentration-time Data | Tlast is the time to last quantifiable plasma concentration of GSK961081 over period determined directly from the concentration-time data | Up to 82 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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salbutamol,, Chronic Obstructive Pulmonary Disease (COPD), GSK961081 muscarinic receptor antagonist,, COPD, ipratropium bromide,, Asthma, ß2-adrenergic agonist,