A Study to Assess the Safety and Tolerability of Once Daily Inhaled Doses of GSK573719 Made With Magnesium Stearate in Subjects With Chronic Obstructive Pulmonary Disease(COPD)for 7 Days
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: GSK573719
Intervention description: 7 day repeat dose
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 37.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Chronic Obstructive Pulmonary Disease (COPD); Magnesium stearate; GSK573719

Summary:

      The study drug which is an inhaled bronchodilator (lung airway relaxant)has been given to
      both healthy volunteers and to COPD patients before. This study will assess a new formulation
      of GSK573719. Many drugs are known to deteriorate over time. To make the study medicine less
      likely to deteriorate in its container, it is mixed with an inactive substance that helps to
      to maintain the quality of the study medicine. Previous studies have looked at GSK573719 with
      another inactive substance called Cellobiose Octaacetate (COA). This study will be looking at
      a new formulation of GSK573719 using Magnesium Stearate (MgSt) as the inactive substance.
      MgSt itself is not a medicine but is approved as a food ingredient and has also has been
      approved to be used in a number of marketed medical inhalers. The purpose of this study is to
      assess the safety and tolerability of compound GSK573719 with Magnesium Stearate for
      once-daily treatment of COPD(Chronic Obstructive Pulmonary Disease). This drug will be given
      to 2 groups of 12 people for 7 days. Group 1 will receive 250mcg or placebo and group 2 will
      receive 1000mcg or placebo. Group 2 will not be dosed until at least 6 people have completed
      dosing in group 1 without any significant safety concerns. The following safety measures will
      be assessed including: ECGs, heart rate, blood pressure, blood samples for safety labs, lung
      function and 24 hour monitoring of the heart. We will also take blood and urine samples to
      measure medication levels in the body.

      GlaxoSmithKline will be funding the research and it will be recruiting at Synexus in 7 of
      their centres in the UK.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female between 40 and 75 years of age

          -  A female subject is eligible to participate if she is of:

               -  Non childbearing potential including pre-menopausal females with documented
                  (medical report verification) hysterectomy, bilateral salpingectomy or bilateral
                  oophorectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or
                  6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and
                  estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy
                  with or without hysterectomy.

          -  Male subjects must agree to use one of the listed contraception methods. This
             criterion must be followed from the time of the first dose of study medication until
             90 days post-last dose.

          -  Subject diagnosed with COPD, as defined by the GOLD guidelines.

          -  BMI within the range 18 - 34 kg/m2 (inclusive).

          -  Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years
             (Pack years = (cigarettes per day smoked/20) x number of years smoked)).

          -  Average QTcB or QTcF ≤ 450 msec taken from triplicate assessments at screening; or QTc
             ≤ 480 msec in subjects with Bundle Branch Block.

          -  Subject has a post-bronchodilator (400 μg salbutamol) FEV1 of ≥ 35% to ≤ 80% of
             predicted normal.

          -  Subject has FEV1/FVC < 0.7 post-bronchodilator (400 μg salbutamol).

          -  Subjects have a 24hour holter recording that is within normal limits for the
             individual 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.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  Subject is available to complete all study measurements and procedures.

        Exclusion Criteria:

          -  Subjects who have a past or present disease, which as judged by the Investigator, may
             affect subject safety or influence the outcome of the study.

          -  The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that
             will be screened for include amphetamines, barbiturates, cocaine and opiates.

        The detection of drugs taken for a legitimate medical purpose would not necessarily be an
        exclusion to study participation. The detection of alcohol would not be an exclusion at
        screening but would need to be negative pre-dose and during the study.

          -  Female subject has a positive pregnancy test.

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening.

          -  A positive test for HIV antibody (if tested, according to local SOP's).

          -  History of high alcohol consumption within 1 month of the study defined as:

               -  an average weekly intake of greater than 21 units or an average daily intake of
                  greater than 3 units (males), or defined as an average weekly intake of greater
                  than 14 units or an average daily intake of greater than 2 units (females). One
                  unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits
                  or 1 glass (125ml) of wine.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.

          -  History of sensitivity to any of the study medications, or components thereof
             (including allergy to milk protein/lactose) or a history of drug or other allergy
             that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their
             participation.

          -  Subject has donated a unit (400 mL) of blood within 60 days of screening or, intends
             to donate during the study.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  The subject is unable to use the novel dry powder inhaler correctly.

          -  The subject requires treatment for prostate hypertrophy.

          -  The subject has a history of narrow angle glaucoma.

        Respiratory criteria

          -  Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt
             bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that
             might, in the opinion of the Investigator, compromise the safety of the subject or
             affect the interpretation of the results.

          -  Subject has poorly controlled COPD, defined as the occurrence of any of the following:

               -  Either: acute worsening of COPD that is managed by the subject at home requiring
                  treatment with corticosteroids in the 2 weeks prior to the screening visit.

               -  Or: more than two exacerbations in the previous 4 months prior to the screening
                  visit that required a course of oral corticosteroids or, for which the subject
                  was hospitalised.

          -  Subject has had a respiratory tract infection in the 2 weeks prior to first dose.

        Cardiovascular criteria

          -  Current congestive heart failure (greater than NYHA II) and myocardial infarction
             (within 9 months of the screening date).

          -  A history of clinically significant arrhythmia or clinically important 24 h 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, or an ECG that is not suitable for QT
             measurements (e.g. LBBB or poorly defined termination of the T wave).

          -  Third degree heart block or pacemaker.

          -  Risk factors for torsades des pointes (heart failure NYHA II-IV, familial long QT
             syndrome).

          -  Elevated resting blood pressure or a mean blood pressure equal to or higher than
             150/90 mmHg at screening. A history of and treatment for hypertension is acceptable
             provided control has been achieved for > 2 months prior to screening.

          -  A mean heart rate outside the range 50-100 bpm at screening.

        Concurrent medication criteria

          -  Subject requires treatment with nebulised beta-2 agonist or nebulised
             anticholinergics.

          -  Subject has received oral or parenteral corticosteroids within 2 weeks of screening.

          -  Subject is unable to abstain from long-acting bronchodilators from 48 hours prior to
             the screening and treatment periods (i.e. the last assessment in the dosing period).

        (Note, subjects may resume use of their usual medication in between screening and the
        treatment period if the restrictions in Section 9 Concomitant Medications and Non-Drug
        Therapies are followed and provided the long acting bronchodilator component is stopped
        again 48h or more prior to dosing).

          -  Subject is receiving co-medication with drugs which are commonly recognised to prolong
             the QTc interval (e.g. quinolones, amiodorane, disopyramide, quinidine, sotalol,
             chlorpromazine, haloperidol, ketoconazole, terfenadine, cisapride and terodiline).

          -  Subject requires regular treatment with oral corticosteroids (prednisolone or
             equivalent).

          -  Subject is receiving treatment with beta-blockers, except eye drops.

          -  Subject is receiving treatment with long-term or short-term oxygen therapy, NIPPV or
             requires nocturnal positive pressure for sleep apnea.