Safety Study Using GSK573719 And Tiotropium In Patients With Chronic Obstructive Pulmonary Disease

NCT ID: NCT00515502

Last Updated: 2017-08-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-06-21
• Study Completion Date: 2007-11-06

Brief Summary

GSK573719 is a high-affinity specific muscarinic receptor (mAChR) antagonist which is being developed for once daily treatment of chronic obstructive pulmonary disease (COPD). The long duration of action of GSK573719 when administered via inhalation in animal models supports the potential for use as a once-daily bronchodilator for COPD.

Detailed Description

A randomised, double blind, placebo-controlled, double dummy, 4-way cross-over, dose ascending study to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of single inhaled doses of GSK573719 (3 escalating mcg doses will be used) and tiotropium bromide (18µg) via DPI in COPD patients

Conditions

Pulmonary Disease, Chronic Obstructive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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 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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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 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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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 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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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 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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

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.

Group Type: ACTIVE_COMPARATOR

GSK573719

Intervention Type: 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

Tiotropium

Intervention Type: DRUG

strips of five capsules, each containing 18 μg administered via dry powder inhaler

Interventions

GSK573719

250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg

Intervention Type: DRUG

Tiotropium

strips of five capsules, each containing 18 μg administered via dry powder inhaler

Intervention Type: DRUG

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).

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Hanover, Lower Saxony, Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Hamburg, , Germany

Countries

Germany

References

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.

Reference Type: BACKGROUND

PMID: 23276660 (View on PubMed)

Study Documents

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

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Related Links

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Other Identifiers

AC4108123

Identifier Type: -

Identifier Source: org_study_id