A 12-week Study to Evaluate the Efficacy and Safety of Umeclidinium Compared With Tiotropium in Subjects With Chronic Obstructive Pulmonary Disease

A Randomized, Blinded, Double-dummy, Parallel-group Study to Evaluate the Efficacy and Safety of Umeclidinium (UMEC) 62.5 mcg Compared With Tiotropium 18 mcg in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

This is a multicentre, randomized, blinded, double dummy, parallel group study to evaluate the efficacy and safety of UMEC inhalation powder[ (62.5 microgram (mcg) once daily (QD)] when administered via a novel Dry Powder Inhaler compared with tiotropium (18 mcg QD) administered via a HANDIHALER® inhaler over a treatment period of 12 weeks (24 weeks in Germany) in subjects with chronic obstructive pulmonary disease (COPD). At the end of the run-in period, subjects who meet the randomization criteria will be randomized to receive UMEC 62.5 mcg administered via novel dry powder inhaler(nDPI) + Placebo administered via HANDIHALER inhaler OR Tiotropium 18 mcg administered via HANDIHALER inhaler + Placebo administered via nDPI in a 1:1 ratio. There will be up to 8 clinic visits conducted on an outpatient basis at Pre-Screening (Visit 0), Screening (Visit 1), a 7 to 14 day run-in period, randomization at Day 1 (Visit 2), and after randomization at Day 2 (Visit 3), Day 28 (Visit 4), Day 56 (Visit 5), Day 84 (Visit 6) and Day 85 (Visit 7). For subjects enrolled in Germany, there will be an additional 3 visits at Day 112 (Visit 8), Day 140 (Visit 9) and Day 168 (Visit 10). The total duration of subject participation in the study will be approximately 15 weeks (27 weeks in Germany). The primary endpoint of the study is clinic visit trough forced expiratory volume in one second (FEV1) on treatment Day 85. All subjects will have spirometry performed at clinic Visits 1 though 7. Trough spirometry will be obtained 23 and 24 hours after the previous day's dose of blinded study medication at Visits 3 to 7.

HANDIHALER is a registered trademark of Boehringer Ingelheim Pharma GmbH & Co. KG.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Umeclidinium; Drug: Umeclidinium matching placebo; Drug: Tiotropium; Drug: Tiotropium matching placebo

• Study Type: Interventional
• Enrollment (Actual): 1017
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425BEN
    • GSK Investigational Site
  • Ciudad Autónoma de Buenos Aires, Argentina, C1426ABP
    • GSK Investigational Site
• Canada
  • Quebec, Canada, G1W 4R4
    • GSK Investigational Site
  • Quebec, Canada, G1V 4G5
    • GSK Investigational Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2K 3S8
      • GSK Investigational Site
  • Newfoundland and Labrador
    • Saint John's, Newfoundland and Labrador, Canada, A1A 3R5
      • GSK Investigational Site
  • Nova Scotia
    • Truro, Nova Scotia, Canada, B2N 1L2
      • GSK Investigational Site
  • Ontario
    • Sudbury, Ontario, Canada, P3E 1H5
      • GSK Investigational Site
    • Toronto, Ontario, Canada, M5G 1N8
      • GSK Investigational Site
    • Toronto, Ontario, Canada, M3J 2C5
      • GSK Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H2R 1V6
      • GSK Investigational Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • GSK Investigational Site
    • St-Charles-Borromée, Quebec, Canada, J6E 2B4
      • GSK Investigational Site
• Chile
  • Talcahuano, Chile, 4270918
    • GSK Investigational Site
  • Región Metro De Santiago
    • Santiago, Región Metro De Santiago, Chile, 7500692
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 7860406
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 8360160
      • GSK Investigational Site
  • Valparaíso
    • Valparaiso, Valparaíso, Chile, 2341131
      • GSK Investigational Site
• Denmark
  • Aarhus C, Denmark, 8000
    • GSK Investigational Site
  • Hvidovre, Denmark, 2650
    • GSK Investigational Site
  • Kobenhavn NV, Denmark, 2400
    • GSK Investigational Site
  • Odense, Denmark, DK-5000
    • GSK Investigational Site
• France
  • Bletterans, France, 39140
    • GSK Investigational Site
  • Nantes cedex 2, France, 44277
    • GSK Investigational Site
  • Toulon, France, 83000
    • GSK Investigational Site
  • Tours, France, 37100
    • GSK Investigational Site
  • Vieux Condé, France, 59690
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 10117
    • GSK Investigational Site
  • Berlin, Germany, 10717
    • GSK Investigational Site
  • Berlin, Germany, 13156
    • GSK Investigational Site
  • Bayern
    • Aschaffenburg, Bayern, Germany, 63739
      • GSK Investigational Site
  • Hessen
    • Frankfurt, Hessen, Germany, 60389
      • GSK Investigational Site
    • Neu-Isenburg, Hessen, Germany, 63263
      • GSK Investigational Site
    • Rodgau, Hessen, Germany, 63110
      • GSK Investigational Site
    • Wiesbaden, Hessen, Germany, 65187
      • GSK Investigational Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01069
      • GSK Investigational Site
  • Sachsen-Anhalt
    • Teuchern, Sachsen-Anhalt, Germany, 06682
      • GSK Investigational Site
  • Thueringen
    • Schmoelln, Thueringen, Germany, 04626
      • GSK Investigational Site
• Italy
  • Emilia-Romagna
    • Riccione (RN), Emilia-Romagna, Italy, 47838
      • GSK Investigational Site
  • Lombardia
    • Milano, Lombardia, Italy, 20138
      • GSK Investigational Site
  • Marche
    • Torrette (AN), Marche, Italy, 60020
      • GSK Investigational Site
  • Toscana
    • Pisa, Toscana, Italy, 56124
      • GSK Investigational Site
  • Veneto
    • Negrar, Veneto, Italy, 37024
      • GSK Investigational Site
• Korea, Republic of
  • Bucheon-Si, Gyeonggi-Do, Korea, Republic of, 420-767
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 136-705
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 130-709
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 156-707
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 134-814
    • GSK Investigational Site
  • Wonju-si, Gangwon-do, Korea, Republic of, 220-701
    • GSK Investigational Site
• Romania
  • Bacau, Romania, 600252
    • GSK Investigational Site
  • Braila, Romania, 810003
    • GSK Investigational Site
  • Bucharest, Romania, 030303
    • GSK Investigational Site
  • Codlea, Romania, 505100
    • GSK Investigational Site
  • Comuna Alexandru Cel Bun, Romania, 617507
    • GSK Investigational Site
  • Deva, Romania, 330084
    • GSK Investigational Site
  • Focsani, Romania, 620043
    • GSK Investigational Site
  • Galati, Romania, 800189
    • GSK Investigational Site
  • Ploiesti, Romania, 100379
    • GSK Investigational Site
  • Timisoara, Romania, 300310
    • GSK Investigational Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 153000
    • GSK Investigational Site
  • Arkhangelsk, Russian Federation, 163001
    • GSK Investigational Site
  • Barnaul, Russian Federation, 656 045
    • GSK Investigational Site
  • Irkutsk, Russian Federation, 664003
    • GSK Investigational Site
  • Izhevsk, Russian Federation, 426063
    • GSK Investigational Site
  • Kemerovo, Russian Federation, 650002
    • GSK Investigational Site
  • Moscow, Russian Federation, 117997
    • GSK Investigational Site
  • Moscow, Russian Federation, 115 280
    • GSK Investigational Site
  • Novosibirsk, Russian Federation, 630102
    • GSK Investigational Site
  • Saint-Petersburg, Russian Federation, 194354
    • GSK Investigational Site
  • Saint-Petersburg, Russian Federation, 194356
    • GSK Investigational Site
  • Saint-Petersburg, Russian Federation, 198260
    • GSK Investigational Site
  • Saint-Petersburg, Russian Federation, 196084
    • GSK Investigational Site
  • Sestroretsk, Russian Federation, 197706
    • GSK Investigational Site
  • Sochi, Russian Federation, 354057
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 194356
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 198216
    • GSK Investigational Site
  • St.Petersburg, Russian Federation
    • GSK Investigational Site
  • Stavropol, Russian Federation, 355017
    • GSK Investigational Site
  • Tomsk, Russian Federation, 634050
    • GSK Investigational Site
  • Ufa, Russian Federation, 450071
    • GSK Investigational Site
  • Vladimir, Russian Federation, 600023
    • GSK Investigational Site
• South Africa
  • Bellville, South Africa, 7530
    • GSK Investigational Site
  • Durban, South Africa, 4001
    • GSK Investigational Site
  • Korsten, South Africa, 6014
    • GSK Investigational Site
  • Lynnwood Ridge, Pretoria, South Africa, 0040
    • GSK Investigational Site
  • Mowbray, South Africa, 7700
    • GSK Investigational Site
  • Somerset West, South Africa, 7130
    • GSK Investigational Site
  • Sophiatown, South Africa, 2129
    • GSK Investigational Site
  • Welkom, South Africa, 9460
    • GSK Investigational Site
  • Eastern Cape
    • Port Elizabeth, Eastern Cape, South Africa, 6001
      • GSK Investigational Site
  • Gauteng
    • Boksburg, Gauteng, South Africa, 1459
      • GSK Investigational Site
• Ukraine
  • Dnipropetrovsk, Ukraine, 49074
    • GSK Investigational Site
  • Kharkiv, Ukraine, 61039
    • GSK Investigational Site
  • Kharkiv, Ukraine, 61002
    • GSK Investigational Site
  • Kiev, Ukraine, 03680
    • GSK Investigational Site
  • Kryvyi Rig, Ukraine, 50096
    • GSK Investigational Site
  • Kyiv, Ukraine, 03038
    • GSK Investigational Site
  • Poltava, Ukraine, 36038
    • GSK Investigational Site
  • Zaporizhzhia, Ukraine, 69050
    • GSK Investigational Site
• United States
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type of subject: outpatient.
• Informed Consent: A signed and dated written informed consent prior to study participation.
• Age: Subjects 40 years of age or older at Visit 1.
• Gender: Male and female subjects are eligible to participate in the study. A female is eligible to enter and participate in the study if she is of:

Non-child bearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement therapy. OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods used consistently and correctly (i.e., in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact). - Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society

• Smoking History: Current or former cigarette smokers with a history of cigarette smoking of >=10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years)]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack-year history.
• Severity of Disease: A pre and post-albuterol/salbutamol FEV1/ Forced Vital Capacity (FVC) ratio of <0.70 and a post-albuterol/salbutamol FEV1 of >=30% and <=70% of predicted normal values at Visit 1. Predicted values will be based upon the ERS Global Lung Function Initiative
• Dyspnea: A score of >=2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.
• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Asthma: A current diagnosis of asthma.
• 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.
• Other Diseases/Abnormalities: Any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any subject who has any condition (e.g. neurological condition) that is likely to affect respiratory function should not be included in the study.
• Severe Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class C) should be excluded unless, in the opinion of the investigator, the benefit is likely to outweigh the risk.
• Moderate to severe Renal Impairment: Patients with moderate to severe renal impairment (e.g., end-stage renal disease requiring dialysis) should be excluded, unless in the opinion of the investigator, the benefit is likely to outweigh the risk.
• Unstable or life threatening cardiac disease: Long-acting muscarinic antagonists (LAMAs) should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association Class IV heart failure
• Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
• Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.
• Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
• Lung Resection: Lung volume reduction surgery within the 12 months prior to Visit 1.
• 12-Lead electrocardiogram (ECG): Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study: Atrial fibrillation with rapid ventricular rate >120 beats per minute; Sustained or nonsustained ventricular tachycardia; Second degree heart block Mobitz type II or third degree heart block (unless pacemaker or defibrillator had been inserted)
• Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
• Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids-12 weeks; Systemic, oral or parenteral corticosteroids- 6 weeks; Antibiotics (for lower respiratory tract infection)- 6 weeks ; long-acting beta2-agonists/inhaled corticosteroids (LABA/ICS) combination products if LABA/ICS therapy is discontinued completely-30 days; LABA/ICS combination products only If discontinuing ICS/LABA therapy and switching to ICS monotherapy- 48 hours for the salmeterol or formoterol component, 14 days for the vilanterol component [The dose of ICS must be a dose of fluticasone propionate (FP) or equivalent but not to exceed 1000 mcg/day] ; Use of ICS at a dose >1000 mcg/day of FP or equivalent- 30 days; Initiation or discontinuation of ICS use-30 days (Use of ICS is permitted provided the dose does not exceed 1000mcg of FP or equivalent; ICS use not to be initiated or discontinued within 30 days prior to Visit 1, except for subjects on LABA/ICS therapy who may discontinue the ICS/LABA product as indicated in the table above and switch to ICS monotherapy); Phosphodiesterase 4 (PDE4) Inhibitor (roflumilast)- 14 days; Inhaled long acting beta2 agonists (LABAs): salmeterol, formoterol-48 hours, olodaterol, indacaterol, vilanterol- 14 days; LAMAs: tiotropium, aclidinium, glycopyrronium, umeclidinium- 7 days; LAMA/LABA combination products if LAMA/LABA therapy is discontinued completely- Apply whichever mono component has the longest washout; Theophyllines- 48 hours; Oral beta2-agonists: Long-acting- 48 hours, Short-acting 12 hours; Inhaled short acting beta2-agonists- 4 hours (Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing) ; Inhaled short-acting anticholinergics- 4 hours; Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products- 4 hours; Any other investigational medication - 30 days or within 5 drug half lives (whichever is longer).
• 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. <=12 hours per day) is not exclusionary.
• 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.
• 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.
• Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
• 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.
• Inability to read: In the opinion of the investigator, any subject who is unable to read and/or write would not be able to complete a questionnaire

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Umeclidinium 62.5 mcg + placebo; Subjects will receive UMEC Inhalation Powder 62.5 mcg once daily via nDPI plus placebo once daily via HANDIHALER inhaler for 12 weeks (24 weeks in Germany). Subjects will be instructed to take one inhalation each morning from both the nDPI and the HANDIHALER inhaler	Drug: Umeclidinium; Umeclidinium 62.5 mcg once daily in the morning via nDPI; Drug: Umeclidinium matching placebo; Umeclidinium matching placebo once daily in the morning via nDPI
Active Comparator: Tiotropium 18mcg + placebo; Subjects will receive Tiotropium 18 mcg once daily via HANDIHALER inhaler plus placebo once daily via nDPI for 12 weeks (24 weeks in Germany). Subjects will be instructed to take one inhalation each morning from both the nDPI and the HANDIHALER inhaler	Drug: Tiotropium; Tiotropium 18 mcg once daily in the morning via HANDIHALER inhaler; Drug: Tiotropium matching placebo; Tiotropium matching placebo once daily in the morning via HANDIHALER inhaler

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 85	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 84 (Week 12). Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Baseline trough FEV1 is the mean of the two assessments made -30 and -5 minutes (min) pre-dose on Day 1. Change from baseline was calculated as the trough FEV1 value on Day 85 minus the BL value. Analysis performed using a repeated measures model with covariates of treatment, baseline FEV1, centre group, 24 hour subset flag, Day, Day by baseline and Day by treatment interactions. The least squares mean changes are presented here.	Baseline (BL) and Day 85

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Shah D, Driessen M, Risebrough N, Baker T, Naya I, Briggs A, Ismaila AS. Cost-effectiveness of umeclidinium compared with tiotropium and glycopyrronium as monotherapy for chronic obstructive pulmonary disease: a UK perspective. Cost Eff Resour Alloc. 2018 May 10;16:17. doi: 10.1186/s12962-018-0101-3. eCollection 2018.
• Feldman G, Maltais F, Khindri S, Vahdati-Bolouri M, Church A, Fahy WA, Trivedi R. A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 mug compared with tiotropium 18 mug in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016 Apr 7;11:719-30. doi: 10.2147/COPD.S102494. eCollection 2016.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): May 25, 2015
• Study Completion (Actual): June 15, 2015

Study Registration Dates

• First Submitted: July 31, 2014
• First Submitted That Met QC Criteria: July 31, 2014
• First Posted (Estimate): August 4, 2014

Study Record Updates

• Last Update Posted (Actual): January 24, 2018
• Last Update Submitted That Met QC Criteria: January 18, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: COPD; tiotropium; double-dummy; umeclidinium; long-acting muscarinic antagonist; novel dry powder inhaler; inhaler preference; inhaler critical errors
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: 201316

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Clinical Study Report
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Statistical Analysis Plan
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Dataset Specification
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Informed Consent Form
   Information identifier: 201316
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register