A Study to Evaluate the Effect of Umeclidinium (UMEC) as Combination Therapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

NCT02257372 | Completed Phase 4 Results

• 1 other identifier: 201314
• Study Type: interventional
• Target: 236
• Locations: 4 countries
• Sites: 28

Brief Summary

This is a multicenter, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of the addition of UMEC (62.5 microgram\[mcg\]) when administered once-daily via dry powder inhaler (DPI) to Inhaled corticosteroid/ Long-acting beta2-agonist (ICS/LABA) twice-daily compared with placebo via DPI added to the ICS/LABA therapy over a treatment period of 12 weeks in subjects with COPD. This study is designed to investigate the addition of UMEC to ICS/LABA combinations at approved doses and frequencies for the treatment of COPD including SERETIDE™ 500/50 mcg twice daily, Fluticasone Propionate/Salmeterol Combination (FSC) 500/50 twice daily generic products such as AIRFLUSAL FORSPIRO inhaler 500/50 mcg twice daily or ROLENIUM ELPENHALER inhaler 500/50 mcg twice daily and SYMBICORT TURBUHALER inhaler at doses of 200/6 mcg twice daily and 400/12 mcg twice daily, over 12 weeks in subjects with COPD. Albuterol/salbutamol metered-dose-inhaler (MDI) or nebules will be issued throughout the study for use as-needed (prn). Subjects who meet the eligibility criteria will be randomly assigned to one of the following blinded study treatment regimens in equal proportion (1:1): UMEC 62.5 mcg once-daily and Placebo once-daily. Approximately 230 subjects (115 subjects per treatment) will be randomized in order to complete at least 206 evaluable subjects. The total duration of the study will be approximately 14 weeks for each subject. UMEC is a Long-acting Muscarinic Antagonist (LAMA) currently under development as a monotherapy, as a combination product with a LABA, vilanterol (VI), for the treatment of COPD, and as a combination product with an ICS, fluticasone furoate (FF), for the treatment of asthma. The UMEC/VI combination 62.5/25 .mcg once-daily has been approved in the United States (U.S.) and Canada for COPD under the trade name ANORO™ ELLIPTA™ and is under regulatory review in other countries. SERETIDE, ANORO, and ELLIPTA are trade marks of the GlaxoSmithKline Group of Companies. Other company or product names mentioned herein may be the property of their respective owners.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

FEV1; DPI; ICS/LABA; UMEC; COPD

Outcome Measures

Primary Outcomes (1)

• 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 was measured using spirometry. BL FEV1 is the mean of the two assessments made 30 and 5 minutes (min) pre-dose on Day 1.Change from BL was calculated as the trough FEV1 value on Day 85 minus the BL value. Analysis was performed using mixed model repeated measures with covariates of treatment, BL FEV1 (mean of the values measured at 30 min and 5 min pre-dose on Day 1), type of ICS/LABA, smoking status, Day, Day by BL interaction and Day by treatment interaction, where Day is nominal.

  Baseline (BL) and Day 85

Secondary Outcomes (1)

• Change From Baseline in Weighted Mean 0-6 Hour FEV1 Obtained Post-dose on Day 84

  Baseline and Day 84

Study Arms (2)

UMEC (62.5 mcg)

EXPERIMENTAL

Participants will self-administer blinded UMEC (62.5 mcg) each morning (once daily) as one inhalation from the double-blind DPI over a treatment period of 12 weeks. Participants will receive open labeled ICS/LABA medication through out duration of the treatment period as background treatment.

Drug: UMEC DPI; Drug: ICS/LABA medication; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)

Placebo

EXPERIMENTAL

Participants will self-administer blinded placebo each morning (once daily) as one inhalation from the double-blind DPI over a treatment period of 12 weeks. Participants will receive open labeled ICS/LABA medication through out duration of the treatment period as background treatment

Drug: Placebo DPI; Drug: ICS/LABA medication; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)

Interventions

UMEC DPI DRUG

The UMEC DPI will contain one blister strip which will have 30 blisters of UMEC as dry powder blended with lactose and magnesium stearate, with no companion strip. Each actuation of the DPI will deliver the contents of one blister from each strip simultaneously.

UMEC (62.5 mcg)

Placebo DPI DRUG

The matching placebo DPI, identical in appearance to the inhaler containing active study medication, will have two blister strips, each containing 30 blisters of lactose and magnesium stearate.

Placebo

ICS/LABA medication DRUG

Participants will use ICS/LABA combinations that are approved for the treatment of COPD at approved doses and frequency including SERETIDE 500/50mcg twice daily, FSC 500/50 mcg twice daily generic products such as AIRFLUSAL FORSPIRO inhaler 500/50mcg twice daily or ROLENIUM ELPENHALER inhaler 500/50mcg twice daily and SYMBICORT TURBUHALER inhaler at doses of 200/6mcg twice daily and 400/12mcg twice daily. The ICS/LABA will be sourced from local commercial stock while on the study

Placebo; UMEC (62.5 mcg)

Albuterol/salbutamol Metered Dose Inhaler (MDI) DRUG

Albuterol/salbutamol MDI or nebules will be issued throughout the study as rescue medication, for use as-needed. Albuterol/salbutamol will be sourced from local commercial stock or provided centrally from GlaxoSmithKline.

Placebo; UMEC (62.5 mcg)

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 following 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): Abstinence; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Implants of levonorgestrel; Estrogenic vaginal ring; Percutaneous contraceptive patches; Intrauterine device (IUD) or intrauterine system (IUS) that meets the Standard Operating Procedure (SOP) effectiveness criteria as stated in the product label; Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
• 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 \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. 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 Forced Expiratory Volume in One Second /Forced Vital Capacity (FEV1/FVC) ratio of \<0.70 and post-albuterol/salbutamol FEV1 of \<=70% of predicted normal values at Visit 1 (Screening) calculated using reference values provided by Quanjer.
• Current clinically prescribed medication: The subject must be on the dose and frequency of one of the following ICS/LABA combinations approved for COPD at least 30 days prior screening : FSC at a dose of 500/50 mcg twice-daily (i.e. SERETIDE DISKUS™ inhaler or approved generic product such as AIRFLUSAL FORSPIRO inhaler 500/50 mcg twice daily or ROLENIUM ELPENHALER inhaler 500/50 mcg twice daily) ; The combination of budesonide/formoterol (i.e., SYMBICORT TURBUHALER inhaler) at doses of 200/6 mcg twice-daily or 400/12 mcg twice-daily .
• Dyspnea: A score of \>=2 on the Modified Medical Research Council (mMRC) Dyspnea Scale at Visit 1.

You may not qualify if:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Asthma: A current diagnosis of asthma.
• Other Diseases/Abnormalities: The subject is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediately life-threatening illness e.g. cancer.
• Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic, corticosteroid (intranasal, inhaled or systemic) lactose/milk protein or magnesium stearate.
• Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.
• Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1.
• Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit 1.
• Unstable or life threatening cardiac disease: UMEC 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 (NYHA) Class IV heart failure
• Lead Electrocardiogram (ECG): Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Principle 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 (bpm); Sustained or nonsustained ventricular tachycardia; Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted)
• Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.
• Interactions: Concomitant administration with beta-blockers and strong Cytochrome P450 3A4 (CYP3A4) inhibitors is only permitted if, in the Investigator's opinion, the likely benefit outweighs the potential risk.
• 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.
• 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); CYP3A4 strong inhibitors (6 weeks) ; ICS /LABA combination products except SERETIDE and approved FSC 500/50 generic products and SYMBICORT at approved doses and frequencies for COPD (30 days) ; SERETIDE, approved FSC 500/50 generic products, and SYMBICORT at approved doses and frequencies for COPD (12 hours prior to screening); Phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) (14 days); Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium, UMEC) (7 days); Inhaled long acting beta2 agonists (LABA) (salmeterol, formoterol: 48 hrs) olodaterol, indacaterol (14 days); LAMA/LABA combination products (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); 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). Note: Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing. Intra-articular and epidural corticosteroid injections are permitted. Corticosteroids for short term treatment of COPD exacerbations is allowed
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (28)

GSK Investigational Site

Kuřim, 66434, Czechia

Location

GSK Investigational Site

Olomouc, 772 00, Czechia

Location

GSK Investigational Site

Rokycany, 337 01, Czechia

Location

GSK Investigational Site

Teplice, 415 10, Czechia

Location

GSK Investigational Site

Žatec, 438 01, Czechia

Location

GSK Investigational Site

Dillingen an der Donau, Bavaria, 89407, Germany

Location

GSK Investigational Site

Munich, Bavaria, 80339, Germany

Location

GSK Investigational Site

Potsdam, Brandenburg, 14467, Germany

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60596, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 51069, Germany

Location

GSK Investigational Site

Essen, North Rhine-Westphalia, 45355, Germany

Location

GSK Investigational Site

Goch, North Rhine-Westphalia, 47574, Germany

Location

GSK Investigational Site

Berlin, 10629, Germany

Location

GSK Investigational Site

Berlin, 13125, Germany

Location

GSK Investigational Site

Berlin, 14059, Germany

Location

GSK Investigational Site

Athens, 115 27, Greece

Location

GSK Investigational Site

Heraklion, Crete, 71110, Greece

Location

GSK Investigational Site

Kavala, 65500, Greece

Location

GSK Investigational Site

N. Efkarpia, Thessaloniki, 564 29, Greece

Location

GSK Investigational Site

Rethymnon, Crete, 74100, Greece

Location

GSK Investigational Site

Thessaloniki, 56403, Greece

Location

GSK Investigational Site

Thessaloniki, 57010, Greece

Location

GSK Investigational Site

Almelo, 7609 PP, Netherlands

Location

GSK Investigational Site

Breda, 4818 CK, Netherlands

Location

GSK Investigational Site

Eindhoven, 5623 EJ, Netherlands

Location

GSK Investigational Site

Harderwijk, 3844 DG, Netherlands

Location

GSK Investigational Site

Hoorn, 1624 NP, Netherlands

Location

GSK Investigational Site

Kloosterhaar, 7694 AC, Netherlands

Location

Related Publications (1)

• Sousa AR, Riley JH, Church A, Zhu CQ, Punekar YS, Fahy WA. The effect of umeclidinium added to inhaled corticosteroid/long-acting beta2-agonist in patients with symptomatic COPD: a randomised, double-blind, parallel-group study. NPJ Prim Care Respir Med. 2016 Jun 23;26:16031. doi: 10.1038/npjpcrm.2016.31.

  PMID: 27334739 DERIVED

Related 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.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Albuterol

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Phenethylamines; Ethylamines

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2014
• First Posted: October 6, 2014
• Study Start: September 30, 2014
• Primary Completion: March 24, 2015
• Study Completion: March 24, 2015
• Last Updated: August 17, 2017
• Results First Posted: November 24, 2015

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

NL (6); GR (7); DE (10); CZ (5)