A Randomized Study, Comparing Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Single Inhaler Triple Therapy, Versus Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

NCT03478683 | Completed Phase 4 Results FDA Drug FDA Device

• 2 other identifiers: 2076082017-001149-28
• Study Type: interventional
• Target: 729
• Locations: 4 countries
• Sites: 57

Brief Summary

The primary purpose of this study is to evaluate lung function and health related quality of life (HRQoL) after 84 days of treatment with a single inhaler triple therapy combination of FF/UMEC/VI \[100/62.5/25 microgram (mcg)\] once daily via the ELLIPTA™ compared with a multiple inhaler combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The study will inform healthcare providers that subjects can be effectively and safely switched to FF/UMEC/VI single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort MDI and Spiriva Handihaler. Eligible subjects will enter a 4-week run-in period during which they will be administered budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA. Following the run-in period, subjects will be randomized to receive one of the following study treatments for 84 days: 1) FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning plus two inhalations of placebo to match budesonide/formoterol via MDI, twice daily plus placebo to match tiotropium via HandiHaler once daily in the morning or 2) Budesonide/formoterol 320/9 mcg via MDI, twice daily plus tiotropium 18 mcg via HandiHaler once daily in the morning plus placebo via ELLIPTA once daily in the morning. Subjects will then enter a one week follow-up period. The total duration for a subject in the study will be approximately 17 weeks. ELLIPTA is a registered trademark of the GlaxoSmithKline group of companies.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

long-acting muscarinic receptor antagonists; tiotropium; HRQoL; Budesonide/formoterol; chronic obstructive pulmonary disease; COPD

Outcome Measures

Primary Outcomes (2)

• Weighted Mean Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 0-24 Hours at Week 12 for Modified Per Protocol (mPP) Population

  FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated.

  Baseline and Week 12

• Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours at Week 12 for ITT Population

  FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average of the two FEV1 measurements made at 30 minutes and 5 minutes pre-dose on Day 1. The weighted mean was derived by calculating the area under the FEV1 time curve (AUC) over the actual time of assessment relative to the time of dosing (over 24-hour period) using the trapezoidal rule, and then dividing the value by the time interval (24-hour) over which the AUC was calculated.

  Baseline and Week 12

Secondary Outcomes (2)

• Change From Baseline in Trough FEV1 on Day 2, Day 28, Day 84 and Day 85

  Baseline, Days 2, 28, 84 and 85

• Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours on Day 1

  Baseline and Day 1

Study Arms (2)

FF/UMEC/VI 100/62.5/25 mcg

EXPERIMENTAL

Subjects will receive budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA during the 4-week run-in period. Subjects will be administered FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning plus placebo to match budesonide/formoterol via MDI, two inhalations twice daily plus placebo to match tiotropium via HandiHaler once daily in the morning for 84 days in the treatment period.

Drug: budesonide/formoterol; Drug: albuterol/salbutamol; Drug: FF/UMEC/VI; Drug: Placebo to match budesonide/formoterol; Drug: tiotropium; Drug: placebo to match tiotropium; Device: ELLIPTA; Device: MDI; Device: HandiHaler

Budesonide/formoterol plus tiotropium

ACTIVE COMPARATOR

Subjects will receive budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA during the 4-week run-in period. Subjects will be administered budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily plus tiotropium 18 mcg via HandiHaler once daily in the morning plus placebo via ELLIPTA once daily in the morning for 84 days in the treatment period.

Drug: budesonide/formoterol; Drug: albuterol/salbutamol; Drug: tiotropium; Drug: Placebo to match FF/UMEC/VI; Device: ELLIPTA; Device: MDI; Device: HandiHaler

Interventions

budesonide/formoterol DRUG

Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily

Budesonide/formoterol plus tiotropium; FF/UMEC/VI 100/62.5/25 mcg

albuterol/salbutamol DRUG

Subjects will be provided short-acting albuterol/salbutamol as-rescue medication to be used on an as-needed basis throughout the study.

Budesonide/formoterol plus tiotropium; FF/UMEC/VI 100/62.5/25 mcg

FF/UMEC/VI DRUG

Subjects will receive FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning

FF/UMEC/VI 100/62.5/25 mcg

Placebo to match budesonide/formoterol DRUG

Subjects will be administered two inhalations of matching placebo twice daily via MDI

FF/UMEC/VI 100/62.5/25 mcg

tiotropium DRUG

Subjects will receive tiotropium (18 mcg) once daily in the morning via HandiHaler device

Budesonide/formoterol plus tiotropium; FF/UMEC/VI 100/62.5/25 mcg

Placebo to match FF/UMEC/VI DRUG

Matching placebo to FF/UMEC/VI will be administered via ELLIPTA once daily in the morning.

Budesonide/formoterol plus tiotropium

placebo to match tiotropium DRUG

Subjects will receive tiotropium matching placebo via Handihaler once daily in the morning

FF/UMEC/VI 100/62.5/25 mcg

ELLIPTA DEVICE

Subjects will receive FF/UMEC/VI 100/62.5/25 mcg and matching placebo via ELLIPTA in the treatment period. Budesonide/formoterol plus tiotropium once daily plus placebo will be administered via ELLIPTA during the run-in period.

Budesonide/formoterol plus tiotropium; FF/UMEC/VI 100/62.5/25 mcg

MDI DEVICE

Subjects will receive budesonide/formoterol and placebo to match budesonide/formoterol via MDI in the treatment period.

Budesonide/formoterol plus tiotropium; FF/UMEC/VI 100/62.5/25 mcg

HandiHaler DEVICE

Subjects will be administered tiotropium (18 mcg) or placebo to match tiotropium via HandiHaler during the treatment period.

Budesonide/formoterol plus tiotropium; FF/UMEC/VI 100/62.5/25 mcg

Eligibility Criteria

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

You may qualify if:

• Subjects must be capable of giving signed informed consent prior to study start.
• Only outpatient subjects will be included
• Subjects (male or female) must be 40 years of age or older at Screening (Visit 1). A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and until safety follow-up contact after the last dose of study treatment
• An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society
• Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years at Screening (Visit 1) \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
• Subjects with a score of \>=10 on the COPD Assessment Test (CAT) at Screening (Visit 1)
• Subjects must demonstrate a post-bronchodilator FEV1 \<50 % predicted normal or a post-bronchodilator FEV1 \<80 % predicted normal and a documented history of \>=2 moderate exacerbations or one severe (hospitalized) exacerbation in the previous 12 months. Subjects must also have a measured post albuterol/salbutamol FEV1/forced vital capacity (FVC) ratio of \<0.70 at screening
• Subjects must have been receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening

You may not qualify if:

• Women who are pregnant or lactating or are planning on becoming pregnant during the study
• Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD).
• Subjects with alpha 1-antitrypsin deficiency as the underlying cause of COPD
• Subjects with active tuberculosis, lung cancer, and clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary diseases
• Subjects who have undergone lung volume reduction surgery within the 12 months prior to Screening
• Immune suppression (e.g. advanced human immunodeficiency virus \[HIV\] with high viral load and low cluster of differentiation 4 \[CD4\] count, lupus on immunosuppressants) that in the opinion of the investigator would increase risk of pneumonia or other risk factors for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis).
• Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening and at least 30 days following the last dose of oral or systemic corticosteroids (if applicable)
• Respiratory tract infection that has not resolved at least 7 days prior to Screening
• Chest x-ray (posteroanterior and lateral) reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on chest X-ray (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest X-ray at Screening Visit 1 (or historical radiograph or computerized tomography \[CT\] scan obtained within 3 months prior to screening). For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office for Radiation Protection (BfS).
• Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. 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.
• Unstable liver disease: alanine transaminase (ALT) \>2 times Upper Limit of Normal (ULN); and bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 %). Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
• Subjects with any of the following at Screening (Visit 1) would be excluded: 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.
• Abnormal and clinically significant 12-lead electrocardiogram (ECG) finding at Visit 1. 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. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead ECG tracing that is interpreted at, but not limited to, any of the following: i) Atrial Fibrillation (AF) with rapid ventricular rate \>120 beats per minute (BPM); ii) Sustained and non-sustained Ventricular tachycardia (VT); iii). Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); iv) QT interval corrected for heart rate by Fridericia's formula (QTcF) \>=500 milliseconds (msec) in subjects with QRS \<120 msec and QTcF \>=530 msec in subjects with QRS \>=120 msec.
• A history of allergy or hypersensitivity to any corticosteroid, 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 Investigator, contraindicates study participation.
• Subjects with carcinoma that has not been in complete remission for at least 3 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 3 year waiting period if the subject has been considered cured by treatment.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (57)

GSK Investigational Site

Gold River, California, 95670, United States

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GSK Investigational Site

Clearwater, Florida, 33756, United States

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GSK Investigational Site

Clearwater, Florida, 33765, United States

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GSK Investigational Site

DeBary, Florida, 32713, United States

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GSK Investigational Site

Edgewater, Florida, 32132, United States

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GSK Investigational Site

Miami, Florida, 33135, United States

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GSK Investigational Site

Miami, Florida, 33144, United States

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GSK Investigational Site

Miami, Florida, 33165, United States

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GSK Investigational Site

Miami, Florida, 33186, United States

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GSK Investigational Site

Ocala, Florida, 34470, United States

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GSK Investigational Site

Ocala, Florida, 34474, United States

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GSK Investigational Site

Port Charlotte, Florida, 33952, United States

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GSK Investigational Site

Port Orange, Florida, 32127, United States

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GSK Investigational Site

Peachtree Corners, Georgia, 30071, United States

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GSK Investigational Site

Flint, Michigan, 48503, United States

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GSK Investigational Site

Fridley, Minnesota, 55432, United States

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GSK Investigational Site

Woodbury, Minnesota, 55125, United States

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GSK Investigational Site

Albuquerque, New Mexico, 87108, United States

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GSK Investigational Site

The Bronx, New York, 10455, United States

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GSK Investigational Site

Asheville, North Carolina, 28801, United States

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GSK Investigational Site

Raleigh, North Carolina, 27607, United States

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GSK Investigational Site

Shelby, North Carolina, 28150, United States

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GSK Investigational Site

Columbus, Ohio, 43213, United States

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GSK Investigational Site

Columbus, Ohio, 43215, United States

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GSK Investigational Site

Dayton, Ohio, 45417, United States

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GSK Investigational Site

Tulsa, Oklahoma, 74136, United States

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GSK Investigational Site

Portland, Oregon, 97202, United States

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GSK Investigational Site

Anderson, South Carolina, 29621, United States

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GSK Investigational Site

Columbia, South Carolina, 29204, United States

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GSK Investigational Site

Easley, South Carolina, 29640, United States

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GSK Investigational Site

Fort Mill, South Carolina, 29707, United States

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GSK Investigational Site

Greenville, South Carolina, 29615, United States

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GSK Investigational Site

Lancaster, South Carolina, 29720, United States

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GSK Investigational Site

Mt. Pleasant, South Carolina, 29464, United States

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GSK Investigational Site

Rock Hill, South Carolina, 29732, United States

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GSK Investigational Site

Spartanburg, South Carolina, 29303, United States

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GSK Investigational Site

Baytown, Texas, 77521, United States

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GSK Investigational Site

Cypress, Texas, 77429, United States

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GSK Investigational Site

Houston, Texas, 77058, United States

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GSK Investigational Site

Tomball, Texas, 77375, United States

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GSK Investigational Site

Jindřichův Hradec, 377 01, Czechia

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GSK Investigational Site

Kralupy nad Vltavou, 278 01, Czechia

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GSK Investigational Site

Lovosice, 410 02, Czechia

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GSK Investigational Site

Rokycany, 337 01, Czechia

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GSK Investigational Site

Teplice, 415 01, Czechia

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GSK Investigational Site

Rüdersdorf, Brandenburg, 15562, Germany

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GSK Investigational Site

Frankfurt am Main, Hesse, 60596, Germany

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GSK Investigational Site

Hanover, Lower Saxony, 30159, Germany

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GSK Investigational Site

Hanover, Lower Saxony, 30173, Germany

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GSK Investigational Site

Großhansdorf, Schleswig-Holstein, 22927, Germany

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GSK Investigational Site

Berlin, 12157, Germany

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GSK Investigational Site

Hamburg, 20354, Germany

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GSK Investigational Site

Breda, 4818 CK, Netherlands

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GSK Investigational Site

Heerlen, 6419 PC, Netherlands

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GSK Investigational Site

Hengelo, 7555 DL, Netherlands

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GSK Investigational Site

Hoorn, 1624 NP, Netherlands

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GSK Investigational Site

Zutphen, 7207 AE, Netherlands

Location

Related Publications (1)

• Ferguson GT, Brown N, Compton C, Corbridge TC, Dorais K, Fogarty C, Harvey C, Kaisermann MC, Lipson DA, Martin N, Sciurba F, Stiegler M, Zhu CQ, Bernstein D. Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials. Respir Res. 2020 May 29;21(1):131. doi: 10.1186/s12931-020-01360-w.

  PMID: 32471423 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Budesonide, Formoterol Fumarate Drug Combination; Albuterol; Formoterol Fumarate; Tiotropium Bromide

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; Budesonide; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Phenethylamines; Ethylamines; Scopolamine Derivatives; Tropanes; Azabicyclo Compounds; Aza Compounds; Alkaloids; Heterocyclic Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heterocyclic Compounds, Bridged-Ring

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

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
• Masking Details: This is a phase 4 double blind study, which will use a triple dummy design for dosing.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a parallel group study. Eligible subjects will be randomized in a ratio of 1:1 to receive either FF/UMEC/VI single inhaler triple therapy or multiple inhaler triple combination therapy (budesonide/formoterol plus tiotropium) during the treatment period.

Study Record Dates

• First Submitted: March 23, 2018
• First Posted: March 27, 2018
• Study Start: June 25, 2018
• Primary Completion: March 14, 2019
• Study Completion: March 14, 2019
• Last Updated: October 28, 2020
• Results First Posted: February 12, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

NL (5); CZ (5); US (40); DE (7)