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Study to Evaluate the Safety and Efficacy of Formoterol in a Daily Dose of 18 µg (9 µg Twice Daily) in Japanese Chronic Obstructive Pulmonary Disease (COPD) Patients

Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT01047553
Collaborator
(none)
251
Enrollment
27
Locations
1
Arm
19
Duration (Months)
9.3
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a multicentre, open, randomised, parallel-group study with formoterol 9 μg one inhalation b.i.d, or standard COPD therapy. Standard (reference) COPD treatment arm should be the group to refer to when safety results of formoterol arm will be evaluated. 240 patients with moderate-to-severe COPD will be randomised (120 patients in the formoterol-arm and 120 patients on standard COPD therapy).

Condition or Disease Intervention/Treatment Phase
  • Drug: Formoterol (OT)
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
251 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open Phase III, Multi-centre 52-week, Parallel-group Study Evaluating the Safety and Efficacy of Formoterol 18 μg Daily Dose Compared With Standard COPD Treatment, in Japanese Patients With Chronic Obstructive Pulmonary Disease (COPD)
Study Start Date :
Dec 1, 2009
Actual Primary Completion Date :
Jan 1, 2011
Actual Study Completion Date :
Jul 1, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

Formoterol 9 μg/dose

Drug: Formoterol (OT)
9 μg/dose, Inhaled, twice daily for 52 weeks
Other Names:
  • Oxis Turbuhaler®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Clinical Laboratory Test: Haematology -Erythrocytes [Baseline and week 52]

      Mean change from Baseline

    2. Clinical Laboratory Test: Haematology -Haemoglobin [Baseline and week 52]

      Change from baseline

    3. Clinical Laboratory Test: Haematology-Leucocytes [Baseline and week 52]

      Change from baseline

    4. Clinical Laboratory Test: Haematology-Platelet Count [Baseline and week 52]

      Change from baseline

    5. Clinical Laboratory Test: Haematology Eosinophils [baseline and week 52]

      Change from baseline

    6. Clinical Laboratory Test: Haematology Basophil [Baseline and week 52]

      Change from baseline

    7. Clinical Laboratory Test: Haematology-Lymphocytes [Baseline and week 52]

      Change from baseline

    8. Clinical Laboratory Test: Haematology-Monocytes [Baseline and week 52]

      Change from baseline

    9. Clinical Laboratory Test: Haematology -Neutrophils [Baseline and week 52]

      Change from baseline

    10. Clinical Laboratory Test: Clinical Chemistry- S-Alanine Aminotransferase [Baseline and week 52]

      Change from baseline

    11. Clinical Laboratory Test: Clinical Chemistry-S-Aspartate Aminotransferase [Baseline and week 52]

      Change from baseline

    12. Clinical Laboratory Test: Clinical Chemistry-S-Alkaline Phosphatase (ALP) [Baseline and week 52]

      Change from baseline

    13. Clinical Laboratory Test: Clinical Chemistry-S-Creatinine [Baseline and week 52]

      Change from Baseline

    14. Clinical Laboratory Test: Clinical Chemistry-S-Total Bilirubin [Baseline and week 52]

      Change from baseline

    15. Clinical Laboratory Test: Clinical Chemistry-S-Sodium [Baseline and week 52]

      Change from baseline

    16. Clinical Laboratory Test: Clinical Chemistry-S-Potassium [Baseline and week 52]

      Change from baseline

    17. Clinical Laboratory Test: Clinical Chemistry-S- Calcium [Baseline and week 52]

      Change from baseline

    18. Clinical Laboratory Test: Clinical Chemistry-S-Albumin [Baseline and week 52]

      Change from baseline

    19. Clinical Laboratory Test: Clinical Chemistry-S-Total Protein [Baseline and week 52]

      Change from baseline

    20. Clinical Laboratory Test: Clinical Chemistry - S-Blood Urea Nitrogen (BUN) [Baseline and week 52]

      Change from baseline

    21. Vital Signs- Sitting SBP [Baseline and week 52]

      Change from baseline

    22. Vital Signs- Sitting DBP [Baseline and week 52]

      Change from baseline

    23. Vital Signs - Pulse Rate [Baseline and week 52]

      Change from baseline

    24. ECG Variables - Heart Rate [Baseline and week 52]

      Change from baseline

    25. ECG Variables - QT Interval [Baseline and week 52]

      Change from baseline

    26. ECG Variables - QTcB Interval [Baseline and week 52]

      Change from baseline

    27. ECG Variables QTcF Interval [Baseline and week 52]

      Change from baseline

    28. ECG Variables RR Interval [Baseline and week 52]

      Change from baseline

    Secondary Outcome Measures

    1. Forced Expiratory Volume in One Second (FEV1) [Before randomization, 0, 4, 8, 17, 26, 34, 43 and 52 weeks after randomization]

      The ratio of the average value of available data for mean from Weeks 0, 4, 8, 17, 26, 34, 43 and 52 to the baseline for each treatment group

    2. Forced Vital Capacity (FVC) [Before randomization, 0, 4, 8, 17, 26, 34, 43 and 52 weeks after randomization]

      The ratio of the average value of available data for Weeks 0, 4, 8, 17, 26, 34, 43 and 52 to the baseline for each treatment group

    3. Morning Peak Expiratory Flow(PEF) [Daily during run-in period (14 - 18 days before Randomisation visit)and daily during 52-week randomization treatment]

      The change from Run-in period average to Treatment period average for each treatment group

    4. Evening Peak Expiratory Flow (PEF) [Daily during run-in period (14 - 18 days before Randomisation visit) and daily during 52-week randomization treatment]

      The change from Run-in period average to Treatment period average for each treatment group

    5. Night-time Awakening Due to Chronic Obstructive Pulmonary Disease (COPD) Symptoms [Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment]

      There are 5 alternatives (scored 0 to 4, with 4 being the most severe condition). The change from Run-in period average to Treatment period average for each treatment group

    6. Daytime Breathlessness Due to Chronic Obstructive Pulmonary Disease (COPD) Symptoms [Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment]

      There are 5 alternatives (scored 0 to 4, with 4 being the most severe condition). The change from Run-in period average to Treatment period average for each treatment group

    7. Daytime Cough Due to Chronic Obstructive Pulmonary Disease (COPD) Symptoms [Daily during run-in period (14 - 18 days before Randomisation visit) and daily during 52-week randomization treatment]

      There are 5 alternatives (scored 0 to 4, with 4 being the most severe condition). The change from Run-in period average to Treatment period average for each treatment group

    8. Total Chronic Obstructive Pulmonary Disease (COPD) Symptom Score [Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment]

      The Total COPD Symptom score is the sum of the measures night-time awakening, breathlessness and cough, ranges from 0 to 12 with 12 being the most severe. The change from Run-in period average to Treatment period average for each treatment group.

    9. Number of COPD Exacerbations Over the Treatment Period [Daily during 52-week randomization treatment]

      A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as worsening in COPD symptoms requiring treatment with either a course of systemic steroid or hospitalisation. Number of COPD exacerbation during 52-week randomization treatment was presented here.

    10. Use of SABA (Salbutamol) as Reliever Medication [Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment]

      The change from Run-in period average to Treatment period average for each treatment group.

    11. St George's Respiratory Questionnaire (SGRQ) Total Score [Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment]

      SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health). The change from Run-in period average to Treatment period average for each treatment group

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    40 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Outpatients, men or women ≥ 40 years

    • A clinical diagnosis of COPD according to guidelines, and current COPD symptoms.

    • Post-bronchodilator FEV1 < 80% of predicted normal value and FEV1/FVC < 70%, post-bronchodilator

    Exclusion Criteria:

    • A history and/or current clinical diagnosis of asthma and atopic diseases such as Allergic rhinitis

    • Patients who have experienced COPD exacerbation requiring at least one of the following treatment, hospitalisation and/or a course of systemic steroid within 4 weeks prior to the study start.

    • Significant or unstable ischaemic heart disease, arrhythmia, cardiomyopathy, heart failure, uncontrolled hypertension as defined by the investigator, or any other relevant cardiovascular disorder as judged by the investigator

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Nagoya Aichi Japan
    2 Research Site Akita-shi Akita Japan
    3 Research Site Chitose Hokkaido Japan
    4 Research Site Obihiro Hokkaido Japan
    5 Research Site Sapporo Hokkaido Japan
    6 Research Site AKO Hyogo Japan
    7 Research Site Kobe-shi Hyogo Japan
    8 Research Site Hitachi Ibaraki Japan
    9 Research Site Tsukuba Ibaraki Japan
    10 Research Site Kanazawa Ishikawa Japan
    11 Research Site Sakaide Kagawa Japan
    12 Research Site Fujisawa Kanagawa Japan
    13 Research Site Kawasaki-shi Kanagawa Japan
    14 Research Site Yokohama Kanagawa Japan
    15 Research Site Koshi Kumamoto Japan
    16 Research Site Nagaoka Niigata Japan
    17 Research Site Saiki-shi Oita Japan
    18 Research Site Moriguchi Osaka Japan
    19 Research Site Matsue Shimane Japan
    20 Research Site Bunkyo Tokyo Japan
    21 Research Site Chuo Tokyo Japan
    22 Research Site Katsushika-ku Tokyo Japan
    23 Research Site Kodaira Tokyo Japan
    24 Research Site Setagaya Tokyo Japan
    25 Research Site Tosima-ku Tokyo Japan
    26 Research Site Fukuoka Japan
    27 Research Site Kyoto Japan

    Sponsors and Collaborators

    • AstraZeneca

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT01047553
    Other Study ID Numbers:
    • D5122C00002
    First Posted:
    Jan 13, 2010
    Last Update Posted:
    Jan 4, 2013
    Last Verified:
    Dec 1, 2012
    Keywords provided by AstraZeneca
    Chronic Obstructive Pulmonary Disease
    COPD
    Japanese
    Phase 3
    Safety
    OT
    Oxis
    Additional relevant MeSH terms:
    Lung Diseases
    Lung Diseases, Obstructive
    Pulmonary Disease, Chronic Obstructive
    Formoterol Fumarate

    Study Results

    Participant Flow

    Recruitment Details The first participant entered the study on 18 December 2009, and the last participant completed the study on 20 July 2011. A total of 320 participants were enrolled at 30 centers in Japan, and 251 participants who fulfilled the randomization criteria were randomized.
    Pre-assignment Detail The study started with an enrolment visit, Visit 1, 1 week prior to Visit 2, and 1 week run-in period before randomization. At Visit 2 participants had to have pre-bronchodilatory forced expiratory volume in one second (FEV1) less than 80 percent of the predicted normal value.
    Arm/Group Title Formoterol Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Period Title: Overall Study
    STARTED 125 126
    COMPLETED 108 117
    NOT COMPLETED 17 9

    Baseline Characteristics

    Arm/Group Title Formoterol Standard Treatment Total
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment Total of all reporting groups
    Overall Participants 125 126 251
    Age (Years) [Mean (Full Range) ]
    Mean (Full Range) [Years]
    70.8
    70.3
    70.6
    Sex: Female, Male (Count of Participants)
    Female
    6
    4.8%
    9
    7.1%
    15
    6%
    Male
    119
    95.2%
    117
    92.9%
    236
    94%

    Outcome Measures

    1. Primary Outcome
    Title Clinical Laboratory Test: Haematology -Erythrocytes
    Description Mean change from Baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [erythrocytes counts x10000/μl]
    -6.25
    (23.8)
    -5.2
    (27.5)
    2. Primary Outcome
    Title Clinical Laboratory Test: Haematology -Haemoglobin
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [g/dL]
    -0.29
    (0.73)
    -0.20
    (1.14)
    3. Primary Outcome
    Title Clinical Laboratory Test: Haematology-Leucocytes
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [leukocyte count/µL]
    -132.1
    (1535.3)
    -289.5
    (1284.6)
    4. Primary Outcome
    Title Clinical Laboratory Test: Haematology-Platelet Count
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [Platelet Count x10000/μl]
    0.17
    (3.29)
    -0.40
    (4.06)
    5. Primary Outcome
    Title Clinical Laboratory Test: Haematology Eosinophils
    Description Change from baseline
    Time Frame baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [percentage of Eosinophil]
    0.49
    (2.21)
    0.45
    (2.45)
    6. Primary Outcome
    Title Clinical Laboratory Test: Haematology Basophil
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [percentage of Basophil]
    0.05
    (0.37)
    0.01
    (0.35)
    7. Primary Outcome
    Title Clinical Laboratory Test: Haematology-Lymphocytes
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [percentage of Lymphocyte]
    -1.31
    (7.86)
    -0.43
    (7.06)
    8. Primary Outcome
    Title Clinical Laboratory Test: Haematology-Monocytes
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [percentage of Monocyte]
    -0.01
    (1.55)
    -0.03
    (1.49)
    9. Primary Outcome
    Title Clinical Laboratory Test: Haematology -Neutrophils
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [percentage of Neutrophil]
    1.92
    (8.32)
    -0.28
    (7.64)
    10. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry- S-Alanine Aminotransferase
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [U/l]
    -0.3
    (10.0)
    4.9
    (65.9)
    11. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Aspartate Aminotransferase
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [U/l]
    0.4
    (12.0)
    2.6
    (39.3)
    12. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Alkaline Phosphatase (ALP)
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [U/l]
    3.8
    (44.7)
    -4.4
    (52.9)
    13. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Creatinine
    Description Change from Baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mg/dL]
    0.009
    (0.089)
    0.021
    (0.117)
    14. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Total Bilirubin
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mg/dL]
    0.05
    (0.22)
    0.02
    (0.19)
    15. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Sodium
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mEq/l]
    -0.3
    (1.9)
    -0.2
    (2.0)
    16. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Potassium
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mEq/L]
    -0.15
    (0.34)
    -0.07
    (0.37)
    17. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S- Calcium
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mg/dl]
    -0.02
    (0.42)
    -0.03
    (0.35)
    18. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Albumin
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [g/dl]
    0.00
    (0.28)
    0.00
    (0.23)
    19. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry-S-Total Protein
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [g/dl]
    -0.05
    (0.40)
    -0.09
    (0.37)
    20. Primary Outcome
    Title Clinical Laboratory Test: Clinical Chemistry - S-Blood Urea Nitrogen (BUN)
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mg/dl]
    -0.48
    (4.00)
    0.07
    (3.99)
    21. Primary Outcome
    Title Vital Signs- Sitting SBP
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mmHg]
    -2.1
    (14.8)
    -2.1
    (16.4)
    22. Primary Outcome
    Title Vital Signs- Sitting DBP
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [mmHg]
    -2.7
    (8.9)
    -3.5
    (10.1)
    23. Primary Outcome
    Title Vital Signs - Pulse Rate
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [beats/minute]
    1.5
    (10.7)
    -0.1
    (10.2)
    24. Primary Outcome
    Title ECG Variables - Heart Rate
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 121 119
    Mean (Standard Deviation) [beats/min]
    2.0
    (11.4)
    0.6
    (12.0)
    25. Primary Outcome
    Title ECG Variables - QT Interval
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 121 119
    Mean (Standard Deviation) [milisecond]
    -2.0
    (22.8)
    2.6
    (26.7)
    26. Primary Outcome
    Title ECG Variables - QTcB Interval
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 121 119
    Mean (Standard Deviation) [milisecond]
    2.1
    (20.6)
    1.2
    (22.2)
    27. Primary Outcome
    Title ECG Variables QTcF Interval
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 121 119
    Mean (Standard Deviation) [milisecond]
    0.5
    (15.1)
    1.7
    (19.1)
    28. Primary Outcome
    Title ECG Variables RR Interval
    Description Change from baseline
    Time Frame Baseline and week 52

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any safety data after randomisation were available were included in the safety population.
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 121 119
    Mean (Standard Deviation) [milisecond]
    -12.1
    (7.2)
    131.7
    (124.1)
    29. Secondary Outcome
    Title Forced Expiratory Volume in One Second (FEV1)
    Description The ratio of the average value of available data for mean from Weeks 0, 4, 8, 17, 26, 34, 43 and 52 to the baseline for each treatment group
    Time Frame Before randomization, 0, 4, 8, 17, 26, 34, 43 and 52 weeks after randomization

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Geometric Mean (Full Range) [percentage of baseline]
    101.46
    99.42
    30. Secondary Outcome
    Title Forced Vital Capacity (FVC)
    Description The ratio of the average value of available data for Weeks 0, 4, 8, 17, 26, 34, 43 and 52 to the baseline for each treatment group
    Time Frame Before randomization, 0, 4, 8, 17, 26, 34, 43 and 52 weeks after randomization

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Geometric Mean (Full Range) [Percentage of baseline]
    101.62
    99.13
    31. Secondary Outcome
    Title Morning Peak Expiratory Flow(PEF)
    Description The change from Run-in period average to Treatment period average for each treatment group
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit)and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [Liter/minute (L/min)]
    12.2
    (34.9)
    7.3
    (26.2)
    32. Secondary Outcome
    Title Evening Peak Expiratory Flow (PEF)
    Description The change from Run-in period average to Treatment period average for each treatment group
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [Liter/minute (L/min)]
    9.6
    (34.0)
    7.9
    (28.2)
    33. Secondary Outcome
    Title Night-time Awakening Due to Chronic Obstructive Pulmonary Disease (COPD) Symptoms
    Description There are 5 alternatives (scored 0 to 4, with 4 being the most severe condition). The change from Run-in period average to Treatment period average for each treatment group
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Median (Standard Deviation) [units on a scale]
    0.0
    (0.4)
    -0.1
    (0.6)
    34. Secondary Outcome
    Title Daytime Breathlessness Due to Chronic Obstructive Pulmonary Disease (COPD) Symptoms
    Description There are 5 alternatives (scored 0 to 4, with 4 being the most severe condition). The change from Run-in period average to Treatment period average for each treatment group
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [units on a scale]
    -0.2
    (0.7)
    -0.2
    (0.8)
    35. Secondary Outcome
    Title Daytime Cough Due to Chronic Obstructive Pulmonary Disease (COPD) Symptoms
    Description There are 5 alternatives (scored 0 to 4, with 4 being the most severe condition). The change from Run-in period average to Treatment period average for each treatment group
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [units on a scale]
    -0.2
    (0.8)
    -0.1
    (0.7)
    36. Secondary Outcome
    Title Total Chronic Obstructive Pulmonary Disease (COPD) Symptom Score
    Description The Total COPD Symptom score is the sum of the measures night-time awakening, breathlessness and cough, ranges from 0 to 12 with 12 being the most severe. The change from Run-in period average to Treatment period average for each treatment group.
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [units on a scale]
    -0.5
    (1.2)
    -0.4
    (1.4)
    37. Secondary Outcome
    Title Number of COPD Exacerbations Over the Treatment Period
    Description A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as worsening in COPD symptoms requiring treatment with either a course of systemic steroid or hospitalisation. Number of COPD exacerbation during 52-week randomization treatment was presented here.
    Time Frame Daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Number [number of exacerbations]
    27
    19
    38. Secondary Outcome
    Title Use of SABA (Salbutamol) as Reliever Medication
    Description The change from Run-in period average to Treatment period average for each treatment group.
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [Times/Day]
    -0.2
    (0.7)
    0.0
    (1.1)
    39. Secondary Outcome
    Title St George's Respiratory Questionnaire (SGRQ) Total Score
    Description SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health). The change from Run-in period average to Treatment period average for each treatment group
    Time Frame Daily during run-in period (14 - 18 days before Randomisation visit ) and daily during 52-week randomization treatment

    Outcome Measure Data

    Analysis Population Description
    All randomised subjects who received at least one dose of formoterol or standard COPD treatment for each treatment group respectively and for whom any efficacy data after randomisation were available were included in the efficacy population (Full Analysis Set: FAS).
    Arm/Group Title Arm 1 - Formoterol Arm 2 - Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    Measure Participants 125 126
    Mean (Standard Deviation) [units on a scale]
    -1.34
    (8.48)
    -0.57
    (7.78)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Formoterol Standard Treatment
    Arm/Group Description Formoterol 9 μg twice daily Standard COPD (JRS guideline and GOLD) treatment
    All Cause Mortality
    Formoterol Standard Treatment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Formoterol Standard Treatment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 20/125 (16%) 18/126 (14.3%)
    Cardiac disorders
    Palpitations 1/125 (0.8%) 0/126 (0%)
    Myocardial Ischaemia 1/125 (0.8%) 0/126 (0%)
    Cardiac Failure Congestive 1/125 (0.8%) 0/126 (0%)
    Angina Pectoris 1/125 (0.8%) 0/126 (0%)
    Eye disorders
    Visual Acuity Reduced 0/125 (0%) 1/126 (0.8%)
    Cataract 1/125 (0.8%) 1/126 (0.8%)
    Gastrointestinal disorders
    Stomach Mass 0/125 (0%) 1/126 (0.8%)
    Inguinal Hernia 1/125 (0.8%) 1/126 (0.8%)
    General disorders
    Device Failure 1/125 (0.8%) 0/126 (0%)
    Infections and infestations
    Pharyngitis 1/125 (0.8%) 0/126 (0%)
    Pneumonia 4/125 (3.2%) 1/126 (0.8%)
    Injury, poisoning and procedural complications
    Venom Poisoning 1/125 (0.8%) 0/126 (0%)
    Thoracic Vertebral Fracture 0/125 (0%) 1/126 (0.8%)
    Tibia Fracture 1/125 (0.8%) 0/126 (0%)
    Spinal Cord Injury Cervical 0/125 (0%) 1/126 (0.8%)
    Investigations
    Chest X-Ray Abnormal 1/125 (0.8%) 0/126 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung Neoplasm Malignant 1/125 (0.8%) 0/126 (0%)
    Oesophageal Squamous Cell Carcinoma Stage 0 0/125 (0%) 1/126 (0.8%)
    Bone Neoplasm 0/125 (0%) 1/126 (0.8%)
    Prostate Cancer 0/125 (0%) 2/126 (1.6%)
    Gastric Cancer 1/125 (0.8%) 1/126 (0.8%)
    Nervous system disorders
    Lacunar Infarction 0/125 (0%) 1/126 (0.8%)
    Loss Of Consciousness 0/125 (0%) 1/126 (0.8%)
    Epilepsy 0/125 (0%) 1/126 (0.8%)
    Cerebral Infarction 0/125 (0%) 1/126 (0.8%)
    Brain Stem Infarction 0/125 (0%) 1/126 (0.8%)
    Psychiatric disorders
    Depression 1/125 (0.8%) 0/126 (0%)
    Bipolar Disorder 0/125 (0%) 1/126 (0.8%)
    Reproductive system and breast disorders
    Spermatic Cord Disorder 1/125 (0.8%) 0/126 (0%)
    SPERMATIC CORD DISORDER 1/125 (0.8%) 0/126 (0%)
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis 1/125 (0.8%) 0/126 (0%)
    Dyspnoea Exertional 0/125 (0%) 1/126 (0.8%)
    Dyspnoea 1/125 (0.8%) 0/126 (0%)
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE 5/125 (4%) 4/126 (3.2%)
    Vascular disorders
    Aortic Dissection 1/125 (0.8%) 0/126 (0%)
    Other (Not Including Serious) Adverse Events
    Formoterol Standard Treatment
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 54/125 (43.2%) 60/126 (47.6%)
    Cardiac disorders
    Palpitations 3/125 (2.4%) 2/126 (1.6%)
    Eye disorders
    Conjunctivitis 5/125 (4%) 5/126 (4%)
    Gastrointestinal disorders
    Stomatitis 3/125 (2.4%) 0/126 (0%)
    Nausea 3/125 (2.4%) 2/126 (1.6%)
    Gastritis 3/125 (2.4%) 5/126 (4%)
    Constipation 5/125 (4%) 4/126 (3.2%)
    Hepatobiliary disorders
    Hepatic Function Abnormal 1/125 (0.8%) 3/126 (2.4%)
    Infections and infestations
    Influenza 1/125 (0.8%) 3/126 (2.4%)
    Upper Respiratory Tract Infection 4/125 (3.2%) 2/126 (1.6%)
    Rhinitis 5/125 (4%) 2/126 (1.6%)
    Pneumonia 8/125 (6.4%) 3/126 (2.4%)
    Pharyngitis 7/125 (5.6%) 4/126 (3.2%)
    Bronchitis 5/125 (4%) 9/126 (7.1%)
    NASOPHARYNGITIS 42/125 (33.6%) 53/126 (42.1%)
    Injury, poisoning and procedural complications
    Contusion 4/125 (3.2%) 3/126 (2.4%)
    Musculoskeletal and connective tissue disorders
    Periarthritis 3/125 (2.4%) 0/126 (0%)
    Back Pain 13/125 (10.4%) 2/126 (1.6%)
    Nervous system disorders
    Headache 2/125 (1.6%) 4/126 (3.2%)
    Dizziness 6/125 (4.8%) 2/126 (1.6%)
    Psychiatric disorders
    Insomnia 3/125 (2.4%) 4/126 (3.2%)
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease 9/125 (7.2%) 5/126 (4%)
    Skin and subcutaneous tissue disorders
    Urticaria 3/125 (2.4%) 0/126 (0%)
    Dermatitis Contact 3/125 (2.4%) 0/126 (0%)
    Eczema 4/125 (3.2%) 1/126 (0.8%)
    Vascular disorders
    Hypertension 3/125 (2.4%) 5/126 (4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Results Point of Contact

    Name/Title Gerard Lynch
    Organization AstraZeneca
    Phone
    Email aztrial_results_posting@astrazeneca.com
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT01047553
    Other Study ID Numbers:
    • D5122C00002
    First Posted:
    Jan 13, 2010
    Last Update Posted:
    Jan 4, 2013
    Last Verified:
    Dec 1, 2012