Clinical trial NCT02207829: A 12-week Study to Evaluate the Efficacy and Safety of Umeclidinium Compared With Tiotropium in Subjects With Chronic Obstructive Pulmonary Disease
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: COPD
inhaler critical errors
double-dummy
novel dry powder inhaler
inhaler preference
tiotropium
umeclidinium
long-acting muscarinic antagonist
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-08-04
Enrollment: 1017
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 85
timeFrame: Baseline (BL) and Day 85
Secondary outcomes:
Other outcomes:
Locations:
city: Spartanburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Winnipeg
country: Canada
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state: Manitoba
city: Saint John's
country: Canada
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state: Newfoundland and Labrador
city: Truro
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Sudbury
country: Canada
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state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
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facility: GSK Investigational Site
state: Ontario
city: Montreal
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facility: GSK Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: St-Charles-Borromée
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Valparaiso
country: Chile
facility: GSK Investigational Site
state: Valparaíso
city: Talcahuano
country: Chile
facility: GSK Investigational Site
city: Aarhus C
country: Denmark
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city: Hvidovre
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city: Kobenhavn NV
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facility: GSK Investigational Site
city: Odense
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facility: GSK Investigational Site
city: Bletterans
country: France
facility: GSK Investigational Site
city: Nantes cedex 2
country: France
facility: GSK Investigational Site
city: Toulon
country: France
facility: GSK Investigational Site
city: Tours
country: France
facility: GSK Investigational Site
city: Vieux Condé
country: France
facility: GSK Investigational Site
city: Aschaffenburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Neu-Isenburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Rodgau
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Wiesbaden
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Teuchern
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Schmoelln
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Riccione (RN)
country: Italy
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state: Emilia-Romagna
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Torrette (AN)
country: Italy
facility: GSK Investigational Site
state: Marche
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Negrar
country: Italy
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state: Veneto
city: Bucheon-Si, Gyeonggi-Do
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Wonju-si, Gangwon-do
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city: Bacau
country: Romania
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city: Braila
country: Romania
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city: Bucharest
country: Romania
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city: Codlea
country: Romania
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city: Comuna Alexandru Cel Bun
country: Romania
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city: Deva
country: Romania
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city: Focsani
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city: Galati
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city: Ploiesti
country: Romania
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city: Timisoara
country: Romania
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city: Arkhangelsk
country: Russian Federation
facility: GSK Investigational Site
city: Arkhangelsk
country: Russian Federation
facility: GSK Investigational Site
city: Barnaul
country: Russian Federation
facility: GSK Investigational Site
city: Irkutsk
country: Russian Federation
facility: GSK Investigational Site
city: Izhevsk
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Sestroretsk
country: Russian Federation
facility: GSK Investigational Site
city: Sochi
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St.Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Stavropol
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Ufa
country: Russian Federation
facility: GSK Investigational Site
city: Vladimir
country: Russian Federation
facility: GSK Investigational Site
city: Port Elizabeth
country: South Africa
facility: GSK Investigational Site
state: Eastern Cape
city: Boksburg
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Bellville
country: South Africa
facility: GSK Investigational Site
city: Durban
country: South Africa
facility: GSK Investigational Site
city: Korsten
country: South Africa
facility: GSK Investigational Site
city: Lynnwood Ridge, Pretoria
country: South Africa
facility: GSK Investigational Site
city: Mowbray
country: South Africa
facility: GSK Investigational Site
city: Somerset West
country: South Africa
facility: GSK Investigational Site
city: Sophiatown
country: South Africa
facility: GSK Investigational Site
city: Welkom
country: South Africa
facility: GSK Investigational Site
city: Dnipropetrovsk
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kiev
country: Ukraine
facility: GSK Investigational Site
city: Kryvyi Rig
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Poltava
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhia
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.