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

NCT02257385 | Completed Phase 3 Results

• 1 other identifier: 116961
• Study Type: interventional
• Target: 967
• Locations: 12 countries
• Sites: 84

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

indacaterol; efficacy; FEV1; ELLIPTA; non inferiority; vilanterol; COPD; safety; tiotropium; umeclidinium bromide; GSK573719

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Treatment Day 85 (Visit 8)

  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.

  Baseline (BL) and Day 85

Secondary Outcomes (1)

• Change From Baseline in Weighted Mean (WM) FEV1 Over 0-6 Hour Post-dose at Day 84

  Baseline and Day 84

Study Arms (2)

UMEC/VI arm

EXPERIMENTAL

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; Drug: UMEC/VI matching placebo; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)

Tiotropium + Indacaterol arm

PLACEBO COMPARATOR

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; Drug: Tiotropium matching placebo; Drug: Indacaterol; Drug: Indacaterol matching placebo; Drug: Albuterol/salbutamol Metered Dose Inhaler (MDI)

Interventions

UMEC/VI DRUG

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

UMEC/VI arm

UMEC/VI matching placebo DRUG

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

UMEC/VI arm

Tiotropium DRUG

Tiotropium (as bromide monohydrate) inhalation capsules 18 mcg per dose will be supplied along with HANDIHALER inhalers manufactured by Boehringer Ingelheim

Tiotropium + Indacaterol arm

Tiotropium matching placebo DRUG

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

Tiotropium + Indacaterol arm

Indacaterol DRUG

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

Tiotropium + Indacaterol arm

Indacaterol matching placebo DRUG

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

Tiotropium + Indacaterol arm

Albuterol/salbutamol Metered Dose Inhaler (MDI) DRUG

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

Tiotropium + Indacaterol arm; UMEC/VI arm

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.
• 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.

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.
• 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).
• 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)
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (84)

GSK Investigational Site

Mar del Plata, Buenos Aires, 7600, Argentina

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GSK Investigational Site

San Miguel de Tucumán, Tucumán Province, 4000, Argentina

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GSK Investigational Site

Buenos Aires, C1424BSF, Argentina

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GSK Investigational Site

Buenos Aires, C1425BEN, Argentina

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GSK Investigational Site

Buenos Aires, C1426ABP, Argentina

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GSK Investigational Site

Mendoza, 5500, Argentina

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GSK Investigational Site

Mendoza, M5500CCG, Argentina

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GSK Investigational Site

San Miguel de Tucumán, 4000, Argentina

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GSK Investigational Site

Puente Alto - Santiago, Región Metro de Santiago, 8207257, Chile

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GSK Investigational Site

Santiago, Región Metro de Santiago, 7500692, Chile

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GSK Investigational Site

Santiago, Región Metro de Santiago, 7510186, Chile

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GSK Investigational Site

Santiago, 7500698, Chile

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GSK Investigational Site

Haapsalu, 90502, Estonia

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GSK Investigational Site

Tallinn, 10117, Estonia

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GSK Investigational Site

Tallinn, 10138, Estonia

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GSK Investigational Site

Gières, 38610, France

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GSK Investigational Site

Nantes, 44277, France

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GSK Investigational Site

Perpignan, 66000, France

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GSK Investigational Site

Reims, 51092, France

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GSK Investigational Site

Strasbourg, 67091, France

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GSK Investigational Site

Tarbes, 65013, France

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GSK Investigational Site

Rüdersdorf, Brandenburg, 15562, Germany

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GSK Investigational Site

Frankfurt am Main, Hesse, 60389, Germany

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GSK Investigational Site

Frankfurt am Main, Hesse, 60596, Germany

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GSK Investigational Site

Schwerin, Mecklenburg-Vorpommern, 19055, Germany

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GSK Investigational Site

Magdeburg, Saxony-Anhalt, 39112, Germany

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GSK Investigational Site

Berlin, 10367, Germany

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GSK Investigational Site

Berlin, 10787, Germany

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GSK Investigational Site

Berlin, 12203, Germany

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GSK Investigational Site

Hamburg, 20253, Germany

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Hamburg, 20354, Germany

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GSK Investigational Site

Hamburg, 22299, Germany

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GSK Investigational Site

Balassagyarmat, 2660, Hungary

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GSK Investigational Site

Budaörs, 2040, Hungary

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GSK Investigational Site

Debrecen, 4032, Hungary

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GSK Investigational Site

Gödöllő, 2100, Hungary

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GSK Investigational Site

Nyíregyháza, 4400, Hungary

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GSK Investigational Site

Pécs, 7635, Hungary

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Szeged, 6722, Hungary

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GSK Investigational Site

Szikszó, 3800, Hungary

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GSK Investigational Site

Piacenza, Emilia-Romagna, 29121, Italy

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GSK Investigational Site

Pordenone, Friuli Venezia Giulia, 33170, Italy

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GSK Investigational Site

Mantova, Lombardy, 46100, Italy

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GSK Investigational Site

Tradate (VA), Lombardy, 21049, Italy

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Novara, Piedmont, 28100, Italy

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GSK Investigational Site

Lima, Lima Province, Lima 27, Peru

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GSK Investigational Site

Lima, Lima 14, Peru

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GSK Investigational Site

Lima, Lima 18, Peru

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GSK Investigational Site

Lima, Lima 1, Peru

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GSK Investigational Site

Lima, Lima 32, Peru

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GSK Investigational Site

Elblag, 82-300, Poland

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GSK Investigational Site

Krakow, 31-024, Poland

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GSK Investigational Site

Ostrów Wielkopolski, 63-400, Poland

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GSK Investigational Site

Piekary Śląskie, 41-940, Poland

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GSK Investigational Site

Sopot, 81-741, Poland

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GSK Investigational Site

Słupsk, 76-200, Poland

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GSK Investigational Site

Bucharest, 020125, Romania

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GSK Investigational Site

Bucharest, 050159, Romania

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GSK Investigational Site

Cluj-Napoca, 400371, Romania

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GSK Investigational Site

Constanța, 900002, Romania

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GSK Investigational Site

Râmnicu Vâlcea, 240564, Romania

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GSK Investigational Site

Timișoara, 300310, Romania

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GSK Investigational Site

Timișoara, 300465, Romania

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GSK Investigational Site

Arkhangelsk, 153000, Russia

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GSK Investigational Site

Irkutsk, 664079, Russia

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GSK Investigational Site

Kazan', 420015, Russia

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GSK Investigational Site

Moscow, 115 478, Russia

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GSK Investigational Site

Moscow, 125284, Russia

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GSK Investigational Site

Omsk, 644112, Russia

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GSK Investigational Site

Orenburg, 460040, Russia

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GSK Investigational Site

Perm, 614068, Russia

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GSK Investigational Site

Saint Petersburg, 194356, Russia

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GSK Investigational Site

Saint Petersburg, 198216, Russia

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GSK Investigational Site

Saint Petesburg, 195030, Russia

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GSK Investigational Site

Stavropol, 355017, Russia

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GSK Investigational Site

Tomsk, 634063, Russia

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GSK Investigational Site

Ulyanovsk, 432063, Russia

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GSK Investigational Site

Yekaterinburg, 620039, Russia

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GSK Investigational Site

Yekaterinburg, 620149, Russia

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GSK Investigational Site

Bojnice, 972 01, Slovakia

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GSK Investigational Site

Humenné, 066 01, Slovakia

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GSK Investigational Site

Poprad, 058 01, Slovakia

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GSK Investigational Site

Spišská Nová Ves, 052 01, Slovakia

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GSK Investigational Site

Vráble, 952 01, Slovakia

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Related Publications (1)

• Kalberg C, O'Dell D, Galkin D, Newlands A, Fahy WA. Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial. Drugs R D. 2016 Jun;16(2):217-27. doi: 10.1007/s40268-016-0131-2.

  PMID: 27028749 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

Tiotropium Bromide; indacaterol; 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)

Scopolamine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Organic Chemicals; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring; Ethanolamines; Amino Alcohols; Alcohols; 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 3
• 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: October 15, 2014
• Primary Completion: May 4, 2015
• Study Completion: May 4, 2015
• Last Updated: March 1, 2018
• Results First Posted: March 3, 2016

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will share

Locations

RO (7); CL (4); IT (5); PL (6); PE (5); ES (3); FR (6); HU (8); SL (5); AR (8); DE (11); RU (16)