A 24-week Study to Evaluate the Efficacy and Safety of GSK573719/GW642444 125/25 mcg and 62.5/25mcg Inhalation Powder Compared With Placebo in Subjects With COPD
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: GSK573719/VI 62.5/25; GSK573719/VI 125/25; Placebo
Intervention description: Inhalation via Novel Dry Powder Inhaler Once a day; Inhalation via Novel Dry Powder Inhaler Once a day; Inhalation via Novel Dry Powder Inhaler Once a day
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 581.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      This is a 24-week, phase III multicenter, randomized, double-blind, placebo-controlled,
      parallel-group study. The study will have 9 scheduled visits and a telephone contact
      Follow-up visit one week following the end of study treatment.

      The study primary endpoint is

      -Clinic visit trough (pre-bronchodilator and pre-dose) FEV1 on Treatment Day 169 Trough FEV1
      on Treatment Day 169 is defined as the mean of the FEV1 values obtained 23 and 24 hours after
      dosing on Treatment Day 168 (i.e. at the Week 24 visit).

      Secondary endpoints are;

        -  Mean TDI focal score at Week 24

        -  Weighted mean clinic visit FEV1 over 0 to 6 hours post-dose at Visit 2 (Day 1)

      Eligible subjects will be randomised to GSK573719/GW642444 125/25mcg, GSK573719/GW642444
      62.5/25mcg and placebo treatment groups in a 1:1:1 ratio such that of the planned 573 total
      number of randomised subjects, approximately 191 subjects will be randomised to each active
      treatment group and 191 subjects will be randomised to placebo. All treatments will be
      administered once daily in the morning by inhalation using a Novel Dry Powder Inhaler (NDPI).

      There will be a total of 9 study clinic visits conducted on an outpatient basis. Subjects who
      meet the eligibility criteria at Screening (Visit.1) will complete a 7 to 14 day Run-In
      period followed by a 24-week Treatment period. Clinic visits will be at screening,
      Randomisation (Day1), Day2, after 4, 8, 12, 16, and 24-weeks of treatment, and 1 day after
      the Week 24 Visit (also referred as Treatment Day 169). A Follow-Up contact for adverse event
      assessment will be conducted by telephone approximately 7 days after Visit 9 or the Early
      Withdrawal Visit. The total duration of subject participation, including Follow-up will be
      approximately 27 weeks. All subjects will be provided with albuterol/salbutamol for use on an
      "as-needed" basis throughout the Run-In and Study Treatment Periods.

      At screening, pre-bronchodilator spirometry will be performed followed by
      post-albuterol/salbutamol spirometry testing. Post-albuterol/salbutamol FEV1 and FEV1/FVC
      values will be used to determine subject eligibility. To further characterise bronchodilator
      responsiveness, post ipratropium testing will be conducted following completion of
      post-albuterol/salbutamol spirometry.

      Spirometry will be conducted at each post-randomisation clinic visit. Six hour post-dose
      serial spirometry will be conducted at Visit 2. Trough spirometry will be obtained 23 and 24
      hours after the previous day's dose of blinded study medication at Visits 3 to 9.

      Assessments of dyspnea will be obtained using the Baseline and Transition Dyspnoea Index
      (BDI/TDI) which is an interviewer based instrument. At Visit 2, the severity of dyspnoea at
      baseline will be assessed using the BDI. At subsequent visits (Visits 4, 6, and 8) change
      from baseline will be assessed using the TDI. Administration of the BDI and TDI should be
      done prior to spirometry and any other study-related procedures Disease specific health
      status will be evaluated using the St. George's Respiratory Questionnaire (SGRQ) and COPD
      Assessment Test (CAT), at baseline (Visit 2) and Visits 4, 6 and 8.

      The occurrence of adverse events will be evaluated throughout the study beginning at Visit 2.
      SAEs will be collected over the same time period as for AEs. However, any SAEs assessed as
      related to study participation (e.g., study treatment, protocol-mandated procedures, invasive
      tests, or change in existing therapy) or related to a GSK concomitant medication, will be
      recorded from the time a subject consents to participate in the study up to and including any
      follow up contact.

      Vital signs (blood pressure and pulse rate), 12-lead ECGs and standard clinical laboratory
      tests (hematology and blood biochemistry) will be obtained at selected clinic visits.

      For determination of subject disposition, subjects will be considered to have completed the
      study, upon completion of Visit 9. There is no plan to provide any of the active study
      treatments for compassionate use following study completion.

      The Intent-to-Treat (ITT) population will be the primary population of interest, and is
      defined as all randomised subjects who have received at least one dose of the randomised
      study medication during the Treatment Period.

      Supplementary study conduct information not mandated to be present in this protocol is
      provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site
      personnel with administrative and detailed technical information that does not impact subject
      safety.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Type of subject: outpatient.

          2. Informed Consent: A signed and dated written informed consent prior to study
             participation.

          3. Age: 40 years of age or older at Screening (Visit 1).

          4. Gender: Male or female subjects are eligible to participate in the study.

          5. COPD History: An established clinical history of COPD in accordance with the
             definition by the American Thoracic Society/European Respiratory Society [Celli, 2004]
             as follows:

          6. Tobacco Use and Smoking History: Current or former cigarette smokers with a history of
             cigarette smoking of more than or equal to 10 pack-years

          7. Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a
             post-albuterol/salbutamol FEV1 of less than or equal to 70% of predicted normal values
             calculated using NHANES III reference equations at Visit 1 [Hankinson1999,Hankinson,
             2010].

          8. Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnoea Scale (mMRC)
             at Screening (Visit 2)

        Exclusion Criteria:

          1. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant
             during the study.

          2. Asthma: A current diagnosis of asthma.

          3. Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung
             infections (such as tuberculosis) and lung cancer are absolute exclusionary
             conditions. A subject, who in the opinion of the investigator has any other
             significant respiratory conditions in addition to COPD should be excluded. Examples
             may include clinically significant, bronchiectasis, pulmonary hypertension,
             sarcoidosis or interstitial lung disease.

          4. Other Diseases/Abnormalities: Subjects with historical or current evidence of
             clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
             immunological, endocrine (including uncontrolled diabetes or thyroid disease) or
             haematological abnormalities that are uncontrolled and/or a previous history of cancer
             in remission for < 5 years prior to Visit 1 (localized carcinoma of the skin that has
             been resected for cure is not exclusionary).

          5. Chest X-Ray: A chest X-ray or computed tomography (CT) scan that reveals evidence of
             clinically significant abnormalities not believed to be due to the presence of COPD. A
             chest X-ray must be taken at Visit 1 if a chest X-ray or CT scan is not available
             within 6 months prior to Visit 1.

          6. Contraindications: A history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or
             magnesium stearate or a medical condition such as of narrow-angle glaucoma, prostatic
             hypertrophy or bladder neck obstruction that, in the opinion of the study physician
             contraindicates study participation or use of an inhaled anticholinergic.

          7. Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit
             1.

          8. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior
             to Screening (Visit 1).

          9. 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at
             Visit 1, including the presence of a paced rhythm on a 12-lead electrocardiogram (ECG)
             which causes the underlying rhythm and ECG to be obscured. Investigators will be
             provided with ECG reviews conducted by a centralized independent cardiologist to
             assist in evaluation of subject eligibility.

         10. Screening Labs: Significantly abnormal finding from clinical chemistry and haematology
             tests at Visit 1.

         11. Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour
             period required prior to spirometry testing at each study visit.

         12. Medications prior to Screening: List are provided in the protocol

         13. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed
             for greater than 12 hours a day. As-needed oxygen use (i.e., less than 12 hours per
             day) is not exclusionary.

         14. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use)
             of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy.

         15. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary
             rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the
             maintenance phase of a pulmonary rehabilitation program are not excluded.

         16. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2
             years prior to Visit 1.

         17. Affiliation with Investigator Site: Is an investigator, sub-investigator, study
             coordinator, employee of a participating investigator or study site, or immediate
             family member of the aforementioned that is involved in this study.