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Comparative Study of Umeclidinium/Vilanterol (UMEC/VI) in a Fixed Dose Combination With Indacaterol Plus Tiotropium

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02257385
Recruitment Status : Completed
First Posted : October 6, 2014
Results First Posted : March 3, 2016
Last Update Posted : March 1, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
This is a Phase IIIb multicentre, randomised, blinded, triple dummy, parallel group study to evaluate the efficacy and safety of UMEC/VI inhalation powder (62.5/25 microgram [mcg] Once daily [QD]) when administered via ELLIPTA® Dry Powder Inhaler (DPI) compared to indacaterol plus tiotropium (150 mcg/18 mcg respectively QD) administered via individual inhalers over a treatment period of 12 weeks in participants with moderate to very severe Chronic Obstructive Pulmonary Disease (COPD). The purpose of this study is to demonstrate that UMEC/VI (delivered via ELLIPTA DPI), when used in symptomatic moderate to very severe COPD participants, is non-inferior to the combination of indacaterol (delivered via BREEZHALER® inhaler) plus tiotropium (delivered via HANDIHALER® inhaler) on measures of trough forced expiratory volume in one second (FEV1) after 12 weeks of treatment. Participants who met the eligibility criteria at screening (Visit 1) will complete a 5 to 7 day run in period prior to randomisation at Visit 2. Clinic visits will follow at day 2, week 2, week 4, week 8 and week 12 of treatment, plus week 12 + 1 day (Visits 3 to 8). The total duration of study participation will be approximately 14 weeks. ELLIPTA is a registered trademark of the GSK group of companies. HANDIHALER is a registered trademark of Boehringer Ingelheim Pharma GmbH & Co. KG. BREEZHALER is a registered trademark of Novartis AG.

Condition or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Drug: UMEC/VI Drug: UMEC/VI matching placebo Drug: Tiotropium Drug: Tiotropium matching placebo Drug: Indacaterol Drug: Indacaterol matching placebo Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI) Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 967 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Study DB2116961, A Multicentre, Randomised, Blinded, Parallel Group Study to Compare UMEC/VI (Umeclidinium/Vilanterol) in a Fixed Dose Combination With Indacaterol Plus Tiotropium in Symptomatic Subjects With Moderate to Very Severe COPD
Actual Study Start Date : October 15, 2014
Actual Primary Completion Date : May 4, 2015
Actual Study Completion Date : May 4, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD

Arm Intervention/treatment
Experimental: UMEC/VI arm
Participants will be instructed to self-administer one dose each morning of UMEC/VI Inhalation Powder 62.5/25 mcg once daily via ELLIPTA DPI, placebo once daily via HANDIHALER inhaler and placebo once daily via BREEZHALER inhaler
Drug: UMEC/VI
ELLIPTA DPI will be supplied with 30 doses (2 strips with 30 blisters per strip) where first strip contains Umeclidinium bromide (unit dose strengths 62.5 mcg per blister) blended with lactose monohydrate and magnesium stearate 0.6% weight/weight (w/w) of total drug product and second strip contains Vilanterol (unit dose strengths 25 mcg per blister) blended with lactose monohydrate and magnesium stearate 1.0% w/w of total drug product

Drug: UMEC/VI matching placebo
ELLIPTA DPI will be supplied with 30 doses (2 strips with 30 blisters per strip) where first strip contains lactose monohydrate and magnesium stearate 0.6% w/w of total drug product and second strip contains lactose monohydrate and magnesium stearate 1.0% w/w of total drug product

Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)
Albuterol/salbutamol MDI or nebules for as needed use will be issued throughout the study. Albuterol/salbutamol will be sourced from local commercial stock. If not available locally, GSK will source centrally

Placebo Comparator: Tiotropium + Indacaterol arm
Participants will be instructed to self-administer one dose each morning of Tiotropium bromide 18 mcg once daily via HANDIHALER inhaler, Indacaterol 150 mcg once daily via BREEZHALER inhaler and placebo once daily via ELLIPTA DPI
Drug: Tiotropium
Tiotropium (as bromide monohydrate) inhalation capsules 18 mcg per dose will be supplied along with HANDIHALER inhalers manufactured by Boehringer Ingelheim

Drug: Tiotropium matching placebo
Tiotropium matching placebo capsules manufactured by GSK, will contain lactose and will be supplied along with HANDIHALER inhalers

Drug: Indacaterol
Indacaterol inhalation capsules 150 mcg per dose will be supplied by GSK along with BREEZHALER inhalers manufactured by Novartis

Drug: Indacaterol matching placebo
Indacaterol matching placebo capsules manufactured by GSK, will contain lactose and will be supplied along with BREEZHALER inhalers manufactured by Novartis

Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)
Albuterol/salbutamol MDI or nebules for as needed use will be issued throughout the study. Albuterol/salbutamol will be sourced from local commercial stock. If not available locally, GSK will source centrally




Primary Outcome Measures :
  1. Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Treatment Day 85 (Visit 8) [ Time Frame: Baseline (BL) and Day 85 ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the 2 assessments made 30 and 5 minutes (min) pre-dose (PD) on Day 1. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after dosing on Day 84 (at Week 12 + 1 day). Analysis was performed using mixed model repeated measures (RM) with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1), center group, day, day by BL interaction and day by trt interaction, where day was nominal.


Secondary Outcome Measures :
  1. Change From Baseline in Weighted Mean (WM) FEV1 Over 0-6 Hour Post-dose at Day 84 [ Time Frame: Baseline and Day 84 ]
    BL FEV1 was the mean of the 2 assessments made 30 and 5 min PD on Day 1. WM FEV1 derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1 and 84 using the 0-6 hr post-dose FEV1 measurements collected on that day, which included PD FEV1 (taken 30 and 5 min prior to dosing on Day 1 and the 30 and 5 min reading prior to dosing on Day 84) and post-dose FEV1 measurements at 1, 3 and 6 hr post-dose.WM change from BL was the WM at at the visit minus the BL value. Analysis was performed using a RM model with covariates of trt, BL FEV1 (mean of values measured at 30 and 5 min PD on Day 1) center group, day, day by BL and day by trt interaction, where day was nominal. Only par with data available at the specified TP were analyzed but all par w/o missing covariate information and with >=1 post-BL measurement were included in the analysis.



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type of subject: Outpatient
  • Informed Consent: A signed and dated written informed consent prior to study participation.
  • Participants 40 years of age or older at Visit 1.
  • Gender: Male or female participants. 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. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
  • 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 a pre and post-albuterol/salbutamol FEV1 of <=70% predicted normal value at Visit 1, calculated using Quanjer reference equations.
  • Dyspnoea: A score of >= 2 on the Modified Medical Research Council Dyspnoea Scale (mMRC) at Visit 1.
  • QT interval corrected (QTc) Criteria: QTc <450 milliseconds (msec) or QTc <480 msec for patients with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The QTc should be based on single or averaged QTc values of triplicate Electrocardiogram (ECGs) obtained over a brief recording period.
  • French participants: 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. Allergy rhinitis is not exclusionary.
  • Other Diseases/Abnormalities: Participants with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
  • Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician, contraindicates study participation or use of an inhaled anticholinergic or beta 2 agonist.
  • Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit 1.
  • Lung Resection: Participants with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
  • 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Specific ECG findings that preclude subject eligibility will be listed in protocol The study investigator will determine the medical significance of any ECG abnormalities not listed.
  • Screening labs: Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1 as determined by the study investigator.
  • 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); Oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract infection) (6 weeks); Cytochrome P450 3A4 strong inhibitors ( 6 weeks); Long Acting Beta-Agonist (LABA)/ inhaled corticosteroids (ICS) combination products (e.g. fluticasone/salmeterol, mometasone, furoate/formoterol fumarate, budesonide/formoterol, fumarate), If LABA/ICS therapy is discontinued completely (30 days); If discontinuing LABA therapy and switching to ICS monotherapy (48 hours for salmeterol or formoterol, 14 days for Olodaterol, Indacaterol or, Vilanterol); Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent (30 days); Initiation or discontinuation of ICS use (30 days); Inhaled long acting beta2-agonists (LABA): Salmeterol, Formoterol (48 hours), Olodaterol, Indacaterol and Vilanterol (14 days); Long acting muscarinic antagonists (LAMA) (Tiotropium, Aclidinium, Glycopyrronium, Umeclidinium) (7 days); LABA/LAMA combination products (Whichever mono component has the longest washout); Roflumilast (14 days); Oral beta-agonists- Long-acting (48 hours), Short-acting(12 hours); Theophyllines (48 hours); Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Inhaled sodium cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4 hours); Inhaled short-acting anticholinergic (short acting muscarinic antagonist [SAMA]) products eg ipratropium (4 hours); Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products (SAMA/Short Acting beta2-agonists [SABA]) (4 hours); Any other investigational medication (30 days or within 5 drug half-lives)
  • Oxygen: Use of Long Term Oxygen Therapy (LTOT).This is defined as oxygen therapy prescribed for greater than 12 hours per 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 12 weeks prior to Visit 1. Participants 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 would not be able to complete a questionnaire.
  • Participants who are pre-screen or screen failures cannot be re-screened.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02257385


Locations
Show Show 85 study locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Layout table for investigator information
Study Director: GSK Clinical Trials GlaxoSmithKline

Additional Information:
Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 116961
For additional information about this study please refer to the GSK Clinical Study Register

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02257385    
Other Study ID Numbers: 116961
First Posted: October 6, 2014    Key Record Dates
Results First Posted: March 3, 2016
Last Update Posted: March 1, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Keywords provided by GlaxoSmithKline:
indacaterol
efficacy
FEV1
ELLIPTA
non inferiority
vilanterol
COPD
safety
tiotropium
umeclidinium bromide
GSK573719
Additional relevant MeSH terms:
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Pulmonary Disease, Chronic Obstructive
Lung Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Bromides
Albuterol
Tiotropium Bromide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Tocolytic Agents
Reproductive Control Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Anticonvulsants