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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)

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ClinicalTrials.gov Identifier: NCT03478696
Recruitment Status : Completed
First Posted : March 27, 2018
Last Update Posted : June 4, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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 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.

Condition or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Drug: budesonide/formoterol Drug: albuterol/salbutamol Drug: FF/UMEC/VI Drug: Placebo to match budesonide/formoterol Drug: tiotropium Drug: Placebo to match FF/UMEC/VI Drug: placebo to match tiotropium Device: ELLIPTA Device: MDI Device: HandiHaler Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 732 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Double (Participant, Investigator)
Masking Description: This is a phase 4 double blind study, which will use a triple dummy design for dosing.
Primary Purpose: Treatment
Official Title: A Phase IV, 12-week, Randomised, Double-blind, Triple Dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) With Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) Based on Lung Function and Symptoms in Participants With Chronic Obstructive Pulmonary Disease
Actual Study Start Date : June 25, 2018
Actual Primary Completion Date : March 18, 2019
Actual Study Completion Date : March 18, 2019


Arm Intervention/treatment
Experimental: FF/UMEC/VI 100/62.5/25 mcg
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
Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily

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

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

Drug: Placebo to match budesonide/formoterol
Subjects will be administered two inhalations of matching placebo twice daily via MDI

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

Drug: placebo to match tiotropium
Subjects will receive tiotropium matching placebo via Handihaler once daily in the morning

Device: ELLIPTA
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.

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

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

Active Comparator: Budesonide/formoterol plus tiotropium
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
Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily

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

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

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

Device: ELLIPTA
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.

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

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




Primary Outcome Measures :
  1. Weighted mean change from Baseline in forced expiratory volume in 1 second (FEV1) over 0-24 hours at Week 12 [ Time Frame: Baseline and Week 12 ]
    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 will be measured using spirometry. All subjects will have a 24-hour serial spirometry performed at randomization and Day 84. Weighted mean change from Baseline in FEV1 over 0-24 hours at Week 12 will be reported.


Secondary Outcome Measures :
  1. Change from Baseline in trough FEV1 on Day 2, Day 28, Day 84 and Day 85 [ Time Frame: Baseline and Days 2, 28, 84, 85 ]
    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 will be measured using spirometry. All subjects will have a 24-hour serial spirometry performed at randomization and Day 84. In addition, trough FEV1 data will be collected pre-dose on Day 28. Change from Baseline in trough FEV1 on Day 2, Day 28, Day 84 and Day 85 will be reported.

  2. Weighted mean change from Baseline in FEV1 over 0-24 hours on Day 1 [ Time Frame: Baseline and Day 1 ]
    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 will be measured using spirometry. All subjects will have a 24-hour serial spirometry performed at randomization and Day 84. Weighted mean change from Baseline in FEV1 over 0-24 hours on Day1 will be reported.



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:

  • 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

Exclusion Criteria:

  • 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.
  • Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3 liters per minute (L/min) at screening (Oxygen use <=3 L/min flow is not exclusionary)
  • Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit
  • Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Programme within 4 weeks prior to screening or subjects who plan to enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded.
  • Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years
  • Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits
  • Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study
  • Study Investigators, sub-Investigators, coordinators, employees of a participating Investigator or study site, or immediate family members of the aforementioned that is involved with this study
  • In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials
  • Use of various medication prior to screening.

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): NCT03478696


  Show 55 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03478696     History of Changes
Other Study ID Numbers: 207609
2017-001150-33 ( EudraCT Number )
First Posted: March 27, 2018    Key Record Dates
Last Update Posted: June 4, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request Site
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study
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.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No

Keywords provided by GlaxoSmithKline:
fluticasone furoate/umeclidinium/vilanterol
HRQoL
COPD
long-acting muscarinic receptor antagonists
Tiotropium
Budesonide/formoterol

Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Chronic Disease
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Fluticasone
Budesonide
Formoterol Fumarate
Tiotropium Bromide
Albuterol
Budesonide, Formoterol Fumarate Drug Combination
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Parasympatholytics
Cholinergic Antagonists