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

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02207829
• Other study ID #: 201316
• Status: Completed
• Phase: Phase 3
• First received: July 31, 2014
• Last updated: January 18, 2018
• Start date: September 1, 2014
• Est. completion date: June 15, 2015

Study information

• Verified date: January 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1017
• Est. completion date: June 15, 2015
• Est. primary completion date: May 25, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Umeclidinium
Umeclidinium 62.5 mcg once daily in the morning via nDPI
• Umeclidinium matching placebo
Umeclidinium matching placebo once daily in the morning via nDPI
• Tiotropium
Tiotropium 18 mcg once daily in the morning via HANDIHALER inhaler
• Tiotropium matching placebo
Tiotropium matching placebo once daily in the morning via HANDIHALER inhaler

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Saint John's	Newfoundland and Labrador
Canada	GSK Investigational Site	Sherbrooke	Quebec
Canada	GSK Investigational Site	St-Charles-Borromée	Quebec
Canada	GSK Investigational Site	Sudbury	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Truro	Nova Scotia
Canada	GSK Investigational Site	Winnipeg	Manitoba
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Talcahuano
Chile	GSK Investigational Site	Valparaiso	Valparaíso
Denmark	GSK Investigational Site	Aarhus C
Denmark	GSK Investigational Site	Hvidovre
Denmark	GSK Investigational Site	Kobenhavn NV
Denmark	GSK Investigational Site	Odense
France	GSK Investigational Site	Bletterans
France	GSK Investigational Site	Nantes cedex 2
France	GSK Investigational Site	Toulon
France	GSK Investigational Site	Tours
France	GSK Investigational Site	Vieux Condé
Germany	GSK Investigational Site	Aschaffenburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Neu-Isenburg	Hessen
Germany	GSK Investigational Site	Rodgau	Hessen
Germany	GSK Investigational Site	Schmoelln	Thueringen
Germany	GSK Investigational Site	Teuchern	Sachsen-Anhalt
Germany	GSK Investigational Site	Wiesbaden	Hessen
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Negrar	Veneto
Italy	GSK Investigational Site	Pisa	Toscana
Italy	GSK Investigational Site	Riccione (RN)	Emilia-Romagna
Italy	GSK Investigational Site	Torrette (AN)	Marche
Korea, Republic of	GSK Investigational Site	Bucheon-Si, Gyeonggi-Do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Wonju-si, Gangwon-do
Romania	GSK Investigational Site	Bacau
Romania	GSK Investigational Site	Braila
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Codlea
Romania	GSK Investigational Site	Comuna Alexandru Cel Bun
Romania	GSK Investigational Site	Deva
Romania	GSK Investigational Site	Focsani
Romania	GSK Investigational Site	Galati
Romania	GSK Investigational Site	Ploiesti
Romania	GSK Investigational Site	Timisoara
Russian Federation	GSK Investigational Site	Arkhangelsk
Russian Federation	GSK Investigational Site	Arkhangelsk
Russian Federation	GSK Investigational Site	Barnaul
Russian Federation	GSK Investigational Site	Irkutsk
Russian Federation	GSK Investigational Site	Izhevsk
Russian Federation	GSK Investigational Site	Kemerovo
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Sestroretsk
Russian Federation	GSK Investigational Site	Sochi
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St.Petersburg
Russian Federation	GSK Investigational Site	Stavropol
Russian Federation	GSK Investigational Site	Tomsk
Russian Federation	GSK Investigational Site	Ufa
Russian Federation	GSK Investigational Site	Vladimir
South Africa	GSK Investigational Site	Bellville
South Africa	GSK Investigational Site	Boksburg	Gauteng
South Africa	GSK Investigational Site	Durban
South Africa	GSK Investigational Site	Korsten
South Africa	GSK Investigational Site	Lynnwood Ridge, Pretoria
South Africa	GSK Investigational Site	Mowbray
South Africa	GSK Investigational Site	Port Elizabeth	Eastern Cape
South Africa	GSK Investigational Site	Somerset West
South Africa	GSK Investigational Site	Sophiatown
South Africa	GSK Investigational Site	Welkom
Ukraine	GSK Investigational Site	Dnipropetrovsk
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kiev
Ukraine	GSK Investigational Site	Kryvyi Rig
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Poltava
Ukraine	GSK Investigational Site	Zaporizhzhia
United States	GSK Investigational Site	Spartanburg	South Carolina

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Chile,  Denmark,  France,  Germany,  Italy,  Korea, Republic of,  Romania,  Russian Federation,  South Africa,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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

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