An Investigation Of The Interaction Of GSK961081 With Inhaled Beta-Agonist And Anti-Muscarinic Drugs.
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: 400 microgrammes GSK961081; 1200 microgrammes GSK961081
Intervention description: Inhaled GSK961081 administered via Dry Powder Inhaler.; Inhaled GSK961081 adminisntered via dry powder inhaler.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 45.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: salbutamol,; Chronic Obstructive Pulmonary Disease (COPD); GSK961081 muscarinic receptor antagonist,; COPD; ipratropium bromide,; Asthma; ß2-adrenergic agonist,

Summary:

      GSK961081 is a potent dual pharmacophore that demonstrates both antimuscarinic and
      beta-agonist pharmacology in preclinical studies, both pharmacologies being of long duration.
      If reproduced in man, GSK961081 has the potential to deliver a medicine that can be given
      once daily. The bronchodilatation after inhalation of single doses of GSK961081 alone and in
      the presence of the short acting beta agonist salbutamol and the short acting muscarinic
      antagonist, ipratropium bromide will be measured in this study. Any residual
      bronchodilatation post-inhalation of GSK961081 and demonstrated by addition of salbutamol or
      ipratropium bromide may provide an indirect assessment of the beta-agonist and antimuscarinic
      components of GSK961081
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject is male or female (of non-child bearing potential) ≥ 40 years of age and ≤ 75
             years of age.

          -  Non- child bearing potential is defined as physiologically incapable of becoming
             pregnant, including females who are post-menopausal (more than 2 years without menses
             with appropriate clinical history i.e. age, history of vasomotor symptoms-estradiol
             and FSH levels may be checked if indicated) and females who are surgically sterile
             (hysterectomy, tubal ligation or bilateral oophorectomy).

          -  Subject diagnosed with COPD in accordance with ATS/ERS guidelines (as per protocol).

          -  Subject is a smoker or an ex-smoker with a 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)

          -  Subject has FEV1 < 80 % of predicted normal for height, age, gender after inhalation
             of salbutamol

          -  Response to ipatropium bromide defined as:

          -  Either an increase in FEV1 of > 12 % and > 150 mL within 2 hours following inhalation
             of 80 µg ipratopium bromide (Atrovent MDI via spacer) at the screening visit

          -  Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following
             inhalation of 80 µg ipratopium bromide within 6 months of screening and an increase in
             FEV1 of > 6 % and > 100 mL within 2h following inhalation of 80 µg ipratopium bromide
             (Atrovent MDI via spacer) at the screening visit (in order to allow for potential
             fluctuations in the response to ipratropium bromide in patients known to be responders
             to ipratropium bromide)

          -  Response to salbutamol defined as:

          -  Either an increase in FEV1 of > 12 % and > 150 mL within 2 hours following inhalation
             of 400 µg salbutamol MDI (via spacer) at the screening visit

          -  Or: a documented increase in FEV1 of >12 % and > 150 mL within 2 hours following
             inhalation of 400 µg salbutamol MDI within 6 months of screening and an increase in
             FEV1 of > 6 % and >100 mL within 2h following inhalation of 400 µg salbutamol MDI (via
             spacer) at the screening visit (in order to allow for potential fluctuations in the
             response to salbutamol in patients known to be responders to salbutamol)

          -  Body mass index (BMI) within the range 18-35 kg/m2

          -  Subject is able and willing to give written informed consent to take part in the
             study.

          -  Subject is available to complete all study assessments

        Exclusion Criteria:

          -  Subjects who have a past or present disease, which as judged by the Investigator and
             medical monitor may affect the outcome of the study or the safety of the subject

          -  Subjects with clinically relevant findings on laboratory safety tests. Subjects with
             laboratory values outside the reference range may be include in the study if the
             Investigator and medical monitor agree that these findings would not put the subject
             at risk or interfere with the objectives of the study

          -  Women who are pregnant or lactating

          -  An unwillingness of subjects to abstain from sexual intercourse with pregnant or
             lactating women; or an unwillingness of the subject to use a condom/spermicide in
             addition to having their female partner use another form of contraception such as IUD,
             diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal
             implants or tubal ligation if the woman could become pregnant from the time of the
             first dose study medication until 90 days post-dose

          -  The subject has a positive urine drugs of abuse screen. A minimum list of drugs that
             will be screened for include amphetamines, barbituates, cocaine, opiates, cannabinoids
             and benzodiazepines.

          -  A history, or suspected history, of alcohol abuse within the 6 months before the
             screening visit.

          -  A positive test for hepatitis C antibody, hepatitis B surface antigen, or HIV.

          -  The subject has participated in a clinical study with another New Chemical Entity
             within the past 2 months or participated in a clinical study with any other drug
             during the previous month.

          -  The subject has donated a unit of blood within the 56 days of dosing or intends to
             donate within 56 days after completing the study.

          -  Subject has an FEV1 < 40 % of predicted for age, height and gender after inhalation of
             salbutamol.

          -  The subject has a diagnosis of active tuberculosis, lung cancer, sarcoidosis,
             bronchiectasis, lung fibrosis, pulmonary hypertension or with a primary diagnosis of
             asthma

          -  The subject has a known allergy or hypersensitivity to ipratropium bromide,
             salbutamol, or lactose

          -  A subject in whom ipratropium bromide or salbutamol is contraindicated

          -  Subjects with lung volume reduction surgery within 12 months of screening

          -  Poorly controlled COPD defined as:

          -  Either: acute worsening of COPD that is managed by the subject at home by treatment
             with increased corticosteroids or antibiotics in the 6 weeks before screening

          -  Or: more than 2 exacerbations in the previous 12 months before screening that required
             a course of oral steroids or antibiotics, and/or required hospitalisation

          -  Subject has had a respiratory tract infection in the 4 weeks before screening

          -  Subject requires treatment with inhaled cromolyn sodium, theophyline, oral ß2-
             agonists, nebulised anticholinergics or leukotriene antagonists

          -  Subject is unable to abstain from long acting ß2-agonist from 72 hours before
             screening and throughout the dosing period

          -  Subject is unable to abstain from tiotropium bromide from 28 days before screening and
             throughout the dosing period

          -  Subject is predicted to be unable to abstain from short acting inhaled ß2-agonists or
             short acting antimuscarinics for 6 hours before screening and for 6 hours before
             dosing with GSK961081 until all post-dose lung function tests have been completed for
             a given study day.

          -  Subject has received oral corticosteroids within the 6 weeks before screening

          -  Subject is receiving > 1000 µg FP (or equivalent) a day of inhaled corticosteroid or
             has changed dose within the 6 weeks before screening or is predicted not to be able to
             maintain a constant dose during the study

          -  Subject is receiving oxygen therapy or nocturnal positive pressure treatment

          -  Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck
             obstruction that in the opinion of the study investigator would prevent use of an
             inhaled anticholinergic

          -  The subject is unable to use the dosing devices (MDPI/ MDI/ spacer) correctly.

          -  Subject with carcinoma that has not been in complete remission for at least 5 years
             (with the exception of carcinoma in situ of the cervix, squamous cell carcinoma and
             basal cell carcinoma if the subject is considered cured)

          -  A history of congestive heart failure, coronary insufficiency or cardiac arrhythmia or
             a finding on screening 24h Holter monitor that would contraindicate the subject's
             participation in the study

          -  12- lead ECG abnormality which is either clinically significant or may interfere with
             QTc measurement or QTc > 450 msec or PR interval outside the range 120 to 220 msec.

          -  A supine mean heart rate outside the range 40-90 bpm at screening.

          -  Persistently elevated supine blood pressure higher than 160/95 at screening.

          -  Subject is receiving a high-dose diuretic and/ or ß2-adrenergic antagonist

          -  Subject has a serum potassium level below the reference range at screening.

          -  Inability to understand the protocol requirements, instructions and study-related
             restrictions; the nature, scope and possible consequences of the study.

          -  Unlikely to complete the study; e.g., uncooperative attitude, inability to return for
             follow-up visits.