Clinical trial NCT00515502: Safety Study Using GSK573719 And Tiotropium In Patients With Chronic Obstructive Pulmonary Disease
Official title: 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 (250, 500 and 1000 μg) and Tiotropium Bromide (18 μg) Via DPI in COPD Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: chronic obstructive pulmonary disease,
GSK573719,
muscarinic receptor antagonist
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-08-13
Enrollment: 24
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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

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).

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)
timeFrame: From Day 1 of Treatment Period 1until Follow-up (up to 10 weeks)
measure: Maximum (0-4 Hours) Heart Rate on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Weighted Mean (0-4 Hours) Heart Rate at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Maximum (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Weighted Mean (0-4 Hours) Systolic Blood Pressure at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Maximum (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Weighted Mean (0-4 Hours) Diastolic Blood Pressure at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Maximum (0-4 Hours) QTcB at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Weighted Mean (0-4 Hours) QTcB at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Maximum (0-4 Hours) QTcF at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Weighted Mean (0-4 Hours) QTcF at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Maximum (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Mean (0-24 Hours) Heart Rate as Measured From Holter Monitoring at Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Hematocrit Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Mean Corpuscle Hemoglobin Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Mean Corpuscle Volume Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Red Blood Cells Count Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Platelets Count and White Blood Cells (WBC) Count Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Calcium, Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea Values at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
Secondary outcomes:
measure: 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
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Maximum Observed Plasma Concentration (Cmax) of UMEC
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Time of Maximum Observed Plasma Concentration (Tmax), Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast), and Plasma Half-life (t1/2) of UMEC
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Amount of Drug Excreted Unchanged in Urine From Time Zero to: 2h [Ae(0-2)] , 8h [Ae(0-8)], 12h [Ae(0-12)], 24h [Ae(0-24)], and 48h [Ae(0-48)]; and Area Under the Excretion Rate Curve From Time Zero to: 18h [AUER(0-18)] and 36h [AUER(0-36)] for UMEC
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Renal Clearance (CLr) of UMEC Following Dose Administration on Day 1
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Half-life for Renal Excretion of UMEC on Day 1
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Fraction of Dose Excreted Unchanged in Urine From Time Zero to: 24 Hours [Fe(0-24)] and 48 Hours [Fe(0-48)] for UMEC
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Mean Serial FEV1over 24 Hours After Dosing on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
measure: Mean Serial Specific Airway Resistance (sGaw) Over 24 Hours After Dosing on Day 1 of Each Treatment Period
timeFrame: Day 1 of each treatment period (up to Study Day 46)
Other outcomes:
Locations:
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.