Clinical trial NCT00642148 (phase 2, status: completed)
Conditions: pulmonary disease, chronic obstructive
ICD codes: J44.9, J44.1, J44.0
Drugs: gw856553, placebo, seretide
SMILES: CC1=C(C=C(C=C1F)C(=O)NC1CC1)C1=CC=C(C=N1)C(=O)NCC(C)(C)C, CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O, OCC1=C(O)C=CC(=C1)C(O)CNCCCCCCOCCCCC1=CC=CC=C1
Eligibility criteria:

        Inclusion Criteria:

        Subjects eligible for enrolment in the study must meet all of the following criteria:

          -  Male adults or female adults of non-childbearing potential who are between 40 and 75
             years of age (inclusive). Note: a female is eligible to enter and participate in the
             study if she is of non-childbearing potential (i.e. physiologically incapable of
             becoming pregnant). This includes any female who is post-menopausal. For the purposes
             of this study, post menopausal is defined as being amenorrhoeic for greater than 1
             year with an appropriate clinical profile, e.g. age appropriate, history of vasomotor
             symptoms. Postmenopausal status may be confirmed by serum FSH and oestradiol
             concentrations at screening if deemed necessary by the PI. Surgical sterility will be
             defined as females who have had a hysterectomy and/or bilateral oophorectomy or tubal
             ligation.

          -  Chronic obstructive pulmonary disease diagnosis: an established clinical history of
             COPD in accordance with the following description by the American Thoracic
             Society/European Respiratory Society [American Thoracic Society / European Respiratory
             Society, 2004] Chronic obstructive pulmonary disease 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.

          -  Subjects with a cigarette smoking history of ≥10 pack years (1 pack year = 20
             cigarettes smoked per day for 1 year or the equivalent). Both current and former
             smokers are eligible to be enrolled. A former smoker is defined as a subject who has
             not smoked for ≥6 months at Visit 1.

          -  Subjects with a post-bronchodilator FEV1 to FVC ratio (FEV1:FVC) < 0.7 at Visit 1.
             Subjects will be assessed 30 (± 5) minutes after receiving salbutamol 400 μg.

          -  Subjects with a post-bronchodilator FEV1 ≥ 50% and < 80% of predicted normal for
             height, age and sex at Visit 1. Subjects will be assessed 30 (± 5) minutes after
             receiving salbutamol 400 μg.

          -  Subjects capable of providing signed written informed consent to participate.

          -  Subjects must have a QTc <450 msec on baseline ECG or triplicate ECG averaged over a
             brief recording interval. For subjects with baseline bundle branch block the QTc will
             be <480msec on baseline ECG or triplicate ECG averaged over a brief recording
             interval.

          -  A subject will be eligible for randomisation at the end of the run-in period only if
             the following additional criterion applies: Subjects with no evidence of an ongoing
             acute infection or sinus symptoms Specific information regarding warnings,
             precautions, contraindications, AEs, and other pertinent information on the
             investigational product that may impact subject eligibility is provided in the
             Investigator Brochure/Investigator Brochure supplement(s), product label, and other
             pertinent documents.

        Exclusion Criteria:

        A subject will not be eligible for inclusion in this study if any of the following criteria
        apply:

          -  Women who are pre-menopausal and of child-bearing potential, or pregnant.

          -  Subjects with a primary diagnosis of asthma or α-1 antitrypsin deficiency.

          -  Subjects who have required hospitalisation or treatment with oral corticosteroids
             and/or antibiotic therapy for acute worsening of COPD or lower respiratory tract
             infection in the 6 weeks prior to Visit 1

          -  Subjects with active tuberculosis or being treated for active tuberculosis,
             sarcoidosis or clinically overt bronchiectasis.

          -  Subjects with a history of any type of malignancy with the exception of successfully
             treated squamous cell cancer of the skin.

          -  Subjects with rheumatoid arthritis, connective tissue disorders and other conditions
             known to be associated with chronic inflammation (e.g. inflammatory bowel disease).

          -  Subjects with chronic infections such as gingivitis, periodontitis, prostatitis,
             gastritis, and urinary tract infections.

          -  Subjects with any acute infection, sinus symptoms, or significant trauma (burns,
             fractures).

          -  Subjects with clinically significant renal disease, diabetes mellitus/metabolic
             syndrome, hypertension or any other clinically significant cardiovascular,
             neurological, endocrine, or haematological abnormalities that are uncontrolled on
             permitted therapy (see Section 6.6.1).

          -  Subjects with clinically significant gastrointestinal or hepatic abnormalities.

          -  Subjects with hypoxaemia. (All subjects must have an O2 saturation of ≥ 88% on room
             air).

          -  History of Gilbert's syndrome. Subjects with a total bilirubin concentration above the
             upper limit of normal at Visit 1 will be excluded.

          -  Liver function tests (bilirubin, ALT, or AST) above upper limit of normal at Visit 1.
             The subject has a positive Hepatitis B surface antigen or Hepatitis C antibody result
             within 3 months of the start of the study.The subject has a history of HIV or other
             immunosuppressive disease.

          -  Subjects who have undergone recent surgery including lung volume reduction surgery or
             have conditions that prevent them from performing spirometry.

          -  Subjects with a history (or suspected history) of alcohol misuse or any other
             substance abuse.

          -  The subject has a three month prior history of regular alcohol consumption exceeding
             an average weekly intake of > 21 units (or an average daily intake of greater than 3
             units) for males, or an average weekly intake of > 14 units (or an average daily
             intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint
             (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine; or a positive alcohol
             breath test at the screening visit

          -  Subjects who will commence or who are likely to commence statin therapy
             (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) or treatment with
             intranasal or topical corticosteroids, acetylsalicyclic acid, non-steroidal
             anti-inflammatory drugs, gemfibrozil, clopidogrel, abciximab, peroxidase
             proliferator-activated receptor γ agonists (e.g, rosiglitazone), fibrates, or niacin
             from Visit 1 until study completion. (Subjects who are receiving these medications at
             a stable dose at Visit 1 may be entered in the study.)

          -  Subjects who require treatment with any of the following from the Visit 1 until study
             completion:

               -  Inhaled corticosteroids

               -  Inhaled cromolyn sodium or nedocromil

               -  Xanthines (theophylline preparations)

               -  Leukotriene modifiers

               -  Tiotropium

               -  Long-acting inhaled β2-agonists (salmeterol, formoterol)

               -  Oral β2-agonists

               -  Macrolide antibiotics for more than five days

          -  Subjects who have received treatment with oral, intravenous or intra-articular
             corticosteroids within 6 weeks of Visit 1 or thereafter.

          -  Subjects with any known hypersensitivity to salbutamol or ipratropium bromide.

          -  Subjects who are participating or plan to participate in the active phase of a
             pulmonary rehabilitation programme during the study. Maintenance rehabilitation is
             permitted.

          -  Subjects who have received an investigational drug within 30 days or within five drug
             half-lives of the investigational drug (whichever is longer).

          -  Subjects with any clinically relevant abnormality detected by the assessments at Visit
             1

          -  An unwillingness of male subjects to abstain from sexual intercourse with pregnant or
             lactating women; or unwillingness of the male subject to use a condom/spermicide in
             addition to having their female partner use another form of contraception such as an
             intra-uterine devices, diaphragm with spermicide, oral contraceptives, injectable
             progesterone, subdermal implants or a tubal ligation if the woman could become
             pregnant from the time of the first dose of investigational product for the duration
             of the study (i.e., through the follow-up phase).

          -  Subjects who have had a close household contact treated for active tuberculosis within
             the past 12 months, or who in the judgement of the investigator are at high risk for
             developing active tuberculosis, shall be excluded from the study.

          -  A subject will not be eligible for randomisation at the end of the run-in period if
             either of the following criteria applies:

               -  Subjects who have experienced an exacerbation during the run-in period requiring
                  treatment with oral corticosteroids and/or antibiotics and/or hospitalisation.

               -  Subjects who are unable to produce an induced sputum sample.