Safety Study Using GSK573719 And Tiotropium In Patients With Chronic Obstructive Pulmonary Disease
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: GSK573719; Tiotropium
Intervention description: 250 micrograms (μg) per blister, administered via dry powder inhaler, dose-ascending study doses began at 250 ug, then 500 ug, and 1000 μg; strips of five capsules, each containing 18 μg administered via dry powder inhaler
Intervention MeSH terms: Tiotropium Bromide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 24.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: chronic obstructive pulmonary disease,; GSK573719,; muscarinic receptor antagonist

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.
    

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).