Safety Study Using GSK573719 And Tiotropium In Patients W... | NCT00515502

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Seq 1: UMEC 250 µg, UMEC 500 µg, Tiotropium 18 µg, placebo	Active Comparator	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: umeclidinium bromide (UMEC) 250 micrograms (µg), UMEC 500 µg, Tiotropium 18 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days.	Drug: GSK573719 Drug: Tiotropium
Seq 2: UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg, placebo	Active Comparator	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days.	Drug: GSK573719
Seq 3: UMEC 250 µg, placebo, UMEC 500 µg, UMEC 1000 µg	Active Comparator	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, UMEC 500 µg and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days.	Drug: GSK573719
Seq 4: UMEC 250 µg, UMEC 500 µg, placebo, UMEC 1000 µg	Active Comparator	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, UMEC 500 µg, placebo and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
GSK573719	Drug	250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg	Seq 10: Tiotropium 18 µg, UMEC 250 µg, placebo, UMEC 500 µg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)	An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as 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, is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, or is an event of possible drug-induced liver injury. Refer to the general AE/SAE module for a list of AEs and SAEs.	From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks)
Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period	Resting heart rate was measured at pre-dose and 15 minutes (min), 45min, 1.5 hour (h) 4 h, 8 h, and 24 h post-dose of each treatment period and the maximum value for heart rate (0-4hours) was derived at rest. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.	Day 1 of each treatment period (up to Study Day 46)
Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period	Resting heart rate was measured at pre-dose and 15 minutes (min), 45 min, 1.5 hours (h), 4 h, 8 h and 24 h post-dose of each treatment period and the weighted mean value for heart rate (0-4 hours) was derived. Baseline is the mean of the 3 pre-dose measurements for each period. Participant level Baseline is the mean of the Baselines for each participant and period level Baseline is the difference between the Baseline and the participant level Baseline in each treatment period for each participant. Analysis was performed using a mixed model with participant level Baseline, period level Baseline, period and treatment group were fitted as fixed effects and participant as a random effect.

Secondary Outcomes

Measure	Description	Time Frame
Area Under Concentration-time Curve From Time 0 to 2 Hours [AUC(0-2)] and Area Under Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration [AUC(0-t)] of UMEC	Blood samples were collected to determine the plasma concentrations of UMEC from pre-dose up to 24 hour post-dose of each treatment period to derive the AUC(0-2) and AUC(0-t). Blood samples for PK analysis of UMEC were obtained on Day 1at pre-dose and 5 minutes (min), 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, and 24 h post UMEC dose administration.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Caucasian male or female subjects aged 40-75 years inclusive. The need to recruit only Caucasian subjects is related to the need to rigorously exclude 2D6 poor metabolisers based on genotype.
Female subjects must be of non-childbearing potential.
An established clinical history of COPD (ATS/ERS definition).
'Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.'
Subject is a smoker or an ex-smoker with a smoking 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) dose.
Subject has 40 ≥ FEV1 ≤ 80% of predicted normal for height, age and gender after inhalation of salbutamol dose.
Response to ipratropium bromide.
Subject is able and has given written informed consent to take part in the study.
Subject is available to complete all study measurements and procedures.
Subject's BMI is 18.0 - 32.0 kg/m2.
Subjects have a 24hr Holter recording that is within normal limits and does not demonstrate any clinically important abnormality that, in the opinion of the investigator, would make the subject unsuitable for participation in the study

Exclusion Criteria:

Subjects who have a past or present disease of any organ system, which as judged by the Investigator, may affect the outcome of this study.
The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cannabis, Cocaine and Opiates. The detection of drugs with a legitimate medical use would not be an exclusion to study participation.
The subject has a positive pre-study alcohol screen. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
A suspected history of alcohol abuse within the six months previous to the screening visit.
The subject has tested positive for hepatitis C antibody, hepatitis B surface antigen or HIV (if determined by local SOP's).
Subject has received an investigational drug within 30 days of screening.
The subject is currently taking medication which is known to be a CYP 2D6 inhibitor/substrate.
The subject has donated a unit (400ml) of blood within 60 days of screening, or, intends to donate during the study.
The subject has a known allergy or hypersensitivity to ipratropium bromide, tiotropium bromide, atropine and any of its derivatives or lactose/milk protein.
Subject is unable to use the DISKUS™/HandiHaler devices correctly.
Subject has prostatic hypertrophy, bladder outlet obstruction, or narrow angle glaucoma.
Subjects with a 2D6 poor metaboliser genotype (Caucasian).
The subject has claustrophobia that may be aggravated by entering the plethysmography cabinet (American Association of Respiratory Care 2001 guidelines for body plethysmography)
Received antibiotic therapy for either a lower respiratory tract infection or for COPD exacerbation within the 4 weeks prior to Screening.

Respiratory criteria

Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, allergic rhinitis, or asthma.
Subject has poorly controlled COPD, defined as either: acute worsening of COPD that is managed by the subject at home by treatment with corticosteroids in the 6 weeks prior to screening visit Or more than two exacerbations in the previous 6 months prior to screening that required a course of oral corticosteroids or antibiotics, or, for which the subject was hospitalised.
Subject has participated in a Pulmonary Rehabilitation Program within 4 weeks prior to screening visit or will enter a program during the study.
Subject has had a respiratory tract infection in the 4 weeks prior to the screening visit.

Cardiovascular criteria

Current congestive heart failure (greater than NYHA I), myocardial infarction (within 3-years of the screening date) or ischaemic heart disease requiring regular therapy (such as β blockers, long-acting nitrates, calcium antagonists or nicorandil). Aspirin, Clopidogrel and statins are allowed.
A history of clinically significant arrhythmia or clinically important 24hr Holter findings that, in the opinion of the investigator, would cause a safety concern for entry into the study.
A mean QTc(B) value at screening >450msec, the QTc(B) of all 3 screening ECGs are not within 10% of the mean, or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T wave)
Mobitz type II or third degree heart block.
Risk factors for torsades de pointes (heart failure NYHA II-IV, chronic hypokalaemia, familial long QT syndrome).
Elevated resting blood pressure or a mean blood pressure equal to or higher than 150/95 mmHg at screening. A history of hypertension is acceptable provided control has been achieved for > 3 months prior to screening with diuretic only.
A mean heart rate outside the range 50-100 bpm at screening (from vital signs measurement).

Concurrent medication criteria

Subject requires treatment with inhaled cromolyn sodium or nedocromil, oral β2-agonists, nebulised β2-agonists, nebulised anticholinergics or leukotriene modifiers.
Subject is unable to abstain from xanthines (other than caffeine) 13-15 days prior to the first dose of study medication until completion of the study (last study-related procedure at the follow-up visit).
Subject is unable to abstain from short-acting inhaled bronchodilators from 6hrs prior to screening until after completion of screening, or, from 6hrs prior to the administration of study medication until after completion of any given treatment period (i.e. the last assessment in a dosing period).
Subject is unable to abstain from long-acting inhaled bronchodilators from 72hrs prior to the screening until after completion of all treatment periods (i.e. the last assessment in the final dosing period).
Subject has changed dose of inhaled corticosteroids within the last 4 weeks, or, will be unable to maintain a constant dose of inhaled corticosteroids during the study.
Subject is receiving treatment with long term or short-term oxygen therapy or requires nocturnal positive pressure ventilation (CPAP or NIPPV).
Subject is receiving treatment with beta-blockers, except eye drops, Diltiazem or Verapamil.
Subject is receiving co-medication with drugs which are commonly recognised to prolong the QTc interval (e.g. quinolones, amiodarone, disopyramide, quinidine, sotalol, chlorpromazine, haloperidol, ketoconazole, terfenadine, cisapride and terodiline).

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Hanover	Lower Saxony	30625	Germany
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
23276660	Background	Tal-Singer R, Cahn A, Mehta R, Preece A, Crater G, Kelleher D, Pouliquen IJ. Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies. Eur J Pharmacol. 2013 Feb 15;701(1-3):40-8. doi: 10.1016/j.ejphar.2012.12.019. Epub 2012 Dec 28.

Label	URL
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.	View source

ID	Type	URL	Comment
AC4108123	Statistical Analysis Plan	View IPD

Arm/Group Information

ID	Title	Description
FG000	Seq 1: UMEC 250 µg, UMEC 500 µg, Tiotropium 18 µg, Placebo	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: umeclidinium bromide (UMEC) 250 micrograms (µg), UMEC 500 µg, Tiotropium 18 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days.
FG001	Seq 2: UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg, Placebo	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days.
FG002	Seq 3: UMEC 250 µg, Placebo, UMEC 500 µg, UMEC 1000 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, UMEC 500 µg and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG003	Seq 4: UMEC 250 µg, UMEC 500 µg, Placebo, UMEC 1000 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, UMEC 500 µg, placebo and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG004	Seq 5: Placebo, UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Placebo, UMEC 250 µg, UMEC 500 µg and UMEC 1000 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG005	Seq 6: UMEC 250 µg, Placebo, Tiotropium 18 µg, UMEC 500 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, Tiotropium 18 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG006	Seq 7: Placebo, Tiotropium 18 µg, UMEC 250 µg, UMEC 500 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Placebo, Tiotropium 18 µg, UMEC 250 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG007	Seq 8: Tiotropium 18 µg, Placebo, UMEC 250 µg, UMEC 500 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Tiotropium 18 µg, placebo, UMEC 250 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG008	Seq 9: Tiotropium 18 µg, UMEC 250 µg, UMEC 500 µg, Placebo	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Tiotropium 18 µg, UMEC 250 µg, UMEC 500 µg and placebo. Treatment periods were seperated by a washout period of at least 14 days.
FG009	Seq 10: Tiotropium 18 µg, UMEC 250 µg, Placebo, UMEC 500 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Tiotropium 18 µg, UMEC 250 µg, placebo and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG010	Seq 11: Placebo, UMEC 250 µg, Tiotropium 18 µg, UMEC 500 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: Placebo, UMEC 250 µg, Tiotropium 18 µg and UMEC 500 µg. Treatment periods were seperated by a washout period of at least 14 days.
FG011	Seq 12: UMEC 250 µg, Placebo, UMEC 500 µg, Tiotropium 18 µg	Participants received single doses of 4 treatments, over 4 treatment periods, in the following sequence: UMEC 250 µg, placebo, UMEC 500 µg and Tiotropium 18 µg. Treatment periods were seperated by a washout period of at least 14 days.

ID	Title	Description
BG000	All Study Treatments	Participants received a sequence containing 4 of the following 5 possible treatments: placebo, UMEC 250 µg, UMEC 500 µg, UMEC 1000 µg and Tiotropium 18 µg. Participants received each of the treatments in 1 of 4 single dose treatment periods, each of which was followed by a washout period. Treatment periods 1, 2, and 3 were followed by at least a 14-day washout period; Treatment period 4 was followed by a Follow-up visit within 10 days.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)

An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as 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, is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, or is an event of possible drug-induced liver injury. Refer to the general AE/SAE module for a list of AEs and SAEs.

All Subjects Population: all participants who received at least one dose of study medication.

Posted

Number

Participants

From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks)

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

ID	Term
C573971	GSK573719
D000069447	Tiotropium Bromide

ID	Term
D012602	Scopolamine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds

OG000	Placebo	Participants received a single inhaled dose of matching placebo via a dry powder inhaler (DPI) in one of the 4 treatment periods, separated by a washout period of at least 14 days.
OG001	UMEC 250 µg	Participants received a single inhaled dose of a dry powder formulation of UMEC 250 micrograms (µg) via a DPI in one of the 4 treatment periods, separated by a washout period of at least 14 days.
OG002	UMEC 500 µg	Participants received a single inhaled dose of a dry powder formulation of UMEC 500 µg via a DPI in one of the 4 treatment periods, separated by a washout period of at least 14 days.
OG003	UMEC 1000 µg	Participants received a single inhaled dose of a dry powder formulation of UMEC 1000 µg via a DPI in one of the 4 treatment periods, separated by a washout period of at least 14 days.
OG004	Tiotropium 18 µg	Participants received a single inhaled dose of a dry powder formulation of tiotropium 18 µg via a DPI in one of the 4 treatment periods, separated by a washout period of at least 14 days.