A 2 Part Study Examining Doses Of GSK961081 In Healthy Vo... | NCT00478738

Label	Type	Description	Intervention Names
GSK961081	Other	GSK961081	Drug: GSK961081

Name	Type	Description	Arm Group Labels	Other Names
GSK961081	Drug		GSK961081

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Part 1: Summary of area under the GSK961081 concentration-time curve (AUC) after a single dose	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.	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
Part 1: Summary of maximum observed concentration (Cmax) of GSK961081 after a single dose	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.	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
Part 1: Summary of last observed plasma concentration (t-last), time of maximum observed concentration (t-max) and terminal elimination half-life (t-half)	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.

Secondary Outcomes

Measure	Description	Time Frame
Part 1: 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. Refer to the general AE/SAE module for a list of AEs and SAEs.

Eligibility Module

Eligibility 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).

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Mainz	Rhineland-Palatinate	55131	Germany
GSK Investigational Site

Type	Date	Date Unknown
Release	Feb 6, 2017
Reset	Mar 24, 2017
Release	Apr 6, 2017
Unrelease		Yes
Release	May 1, 2017
Unrelease		Yes
Release	Aug 8, 2017
Reset	Feb 16, 2018
Release	Feb 20, 2018
Unrelease	Aug 15, 2018

Release Date	Unrelease Date	Unrelease Date Unknown	Reset Date	MCP Release Number
Feb 6, 2017			Mar 24, 2017
Apr 6, 2017

ID	Term
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002908	Chronic Disease