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A Comparative Study Between Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Single Inhaler Triple Therapy Versus Tiotropium Monotherapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT03474081
Recruitment Status : Recruiting
First Posted : March 22, 2018
Last Update Posted : March 27, 2019
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE March 15, 2018
First Posted Date  ICMJE March 22, 2018
Last Update Posted Date March 27, 2019
Actual Study Start Date  ICMJE March 29, 2018
Estimated Primary Completion Date June 25, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2018)
Change from Baseline in trough forced expiratory volume in 1 second (FEV1) at Day 85 [ Time Frame: Baseline and Day 85 ]
Lung function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is the mean volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. FEV1 will be measured using a standardized calibrated spirometer.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03474081 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Change from Baseline in trough FEV1 at Day 28 [ Time Frame: Baseline and Day 28 ]
    Lung function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is the mean volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. FEV1 will be measured using a standardized calibrated spirometer.
  • Change from Baseline in trough FEV1 at Day 84 [ Time Frame: Baseline and Day 84 ]
    Lung function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is the mean volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. FEV1 will be measured using a standardized calibrated spirometer.
  • Number of subjects with adverse events (AEs) and serious AEs (SAEs) [ Time Frame: Up to 95 days ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
  • Number of subjects with abnormal values for blood pressure [ Time Frame: Up to 84 days ]
    Systolic and diastolic blood pressure will be measured in a sitting position after approximately 5 minutes rest.
  • Number of subjects with abnormal pulse rate [ Time Frame: Up to 84 days ]
    Pulse rate will be measured in a sitting position after approximately 5 minutes rest.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2018)
  • Change from Baseline in trough FEV1 [ Time Frame: Baseline, Day 28 and Day 84 ]
    Lung function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is the mean volume of air that can be forced out in one second after taking a deep breath approximately 24 hours after the last administration of study drug. FEV1 will be measured using a standardized calibrated spirometer.
  • Number of subjects with adverse events (AEs) and serious AEs (SAEs) [ Time Frame: Up to 95 days ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
  • Number of subjects with abnormal values for blood pressure [ Time Frame: Up to 84 days ]
    Systolic and diastolic blood pressure will be measured in a sitting position after approximately 5 minutes rest.
  • Number of subjects with abnormal pulse rate [ Time Frame: Up to 84 days ]
    Pulse rate will be measured in a sitting position after approximately 5 minutes rest.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Comparative Study Between Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Single Inhaler Triple Therapy Versus Tiotropium Monotherapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Official Title  ICMJE A Phase IV, 12 Week, Randomised, Double-blind, Double-dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI), With Tiotropium Monotherapy Based on Lung Function and Symptoms in Participants With Chronic Obstructive Pulmonary Disease
Brief Summary COPD is a progressive disease characterized by increasing obstruction to airflow and the progressive development of respiratory symptoms including chronic cough, increased sputum production, dyspnea and wheezing. Once-daily triple therapy of an Inhaled Corticosteroid/ Long-acting Muscarinic Receptor Antagonists/ Long Acting Beta-Agonist (ICS/LAMA/LABA) that is combination of FF/UMEC/VI in a single device is being developed with the aim of providing a new treatment option for the management of advanced COPD. 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 once daily via the ELLIPTA® dry powder inhaler (DPI) compared with tiotropium once daily via HANDIHALER®, in subjects with COPD. Subjects will be randomized 1:1 to receive FF/UMEC/VI or tiotropium in the morning for 84 days. Subjects will also receive albuterol/salbutamol as a rescue therapy throughout the study. Approximately 848 subjects with advanced COPD will be enrolled in the study. The total study duration will be approximately 17 weeks including, 4-week run-in period, 12-week treatment period and a 1-week follow-up period. ELLIPTA is a registered trademark of GlaxoSmithKline (GSK) group of companies. HANDIHALER and RESPIMAT are registered trademarks of Boeringher Ingelheim.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Subjects will be randomized 1:1 to receive either FF/UMEC/VI via ELLIPTA DPI along with placebo to match tiotropium or tiotropium via HANDIHALER along with placebo to match FF/UMEC/VI in the morning for 84 days.
Masking: Double (Participant, Investigator)
Masking Description:
This will be a double blind study. Subjects and investigator will be masked.
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Disease, Chronic Obstructive
Intervention  ICMJE
  • Drug: FF/UMEC/VI
    A single inhaler triple therapy of FF/UMEC/VI will be provided via ELLIPTA DPI. FF/UMEC/VI will be available as dry white powder with dosing strengths of 100/25/62.5 mcg per blister.
  • Drug: Tiotropium
    Tiotropium will be provided as a hard gelatin capsule for oral inhalation containing 18 mcg tiotropium bromide blended with lactose, administered via HANDIHALER DPI.
  • Drug: Albuterol/salbutamol
    Albuterol/salbutamol will be provided as an inhalation via MDI with a spacer or nebules and will be given as a rescue medication throughout the study.
  • Drug: Placebo to match FF/UMEC/VI
    Placebo matching FF/UMEC/VI will be available as a dry white powder of lactose or magnesium stearate, administered via ELLIPTA DPI.
  • Drug: Placebo to match tiotropium
    Placebo will be given as hard gelatin capsule for oral inhalation containing lactose, administered via HANDIHALER DPI.
  • Device: ELLIPTA inhaler
    ELLIPTA DPI will contain two individual blister strips with 30 blisters per strip. FF/UMEC/VI and placebo to match FF/UMEC/VI will be administered to the subjects using ELLIPTA DPI.
  • Device: HANDIHALER
    Tiotropium and placebo to match tiotropium will be administered to the subjects using HANDIHALER DPI.
  • Device: MDI
    Albuterol/salbutamol will be provided as a rescue medication throughout the study using MDI.
Study Arms  ICMJE
  • Experimental: Subjects receiving FF/UMEC/VI + Placebo to match tiotropium
    Eligible subjects will receive FF/UMEC/VI at a dose of 100/62.5/25 microgram (mcg) administered once daily in the morning via ELLIPTA along with placebo to match tiotropium administered once daily in the morning via HANDIHALER. Subjects will self-administer 4 puffs of rescue medication (Albuterol/salbutamol) via metered dose inhaler (MDI).
    Interventions:
    • Drug: FF/UMEC/VI
    • Drug: Albuterol/salbutamol
    • Drug: Placebo to match tiotropium
    • Device: ELLIPTA inhaler
    • Device: HANDIHALER
    • Device: MDI
  • Experimental: Subjects receiving Tiotropium + Placebo to match FF/UMEC/VI
    Eligible subjects will receive Tiotropium at a dose of 18 mcg administered once daily in the morning via HANDIHALER along with placebo to match FF/UMEC/VI administered once daily in the morning via ELLIPTA. Subjects will self-administer 4 puffs of rescue medication (Albuterol/salbutamol) via MDI.
    Interventions:
    • Drug: Tiotropium
    • Drug: Albuterol/salbutamol
    • Drug: Placebo to match FF/UMEC/VI
    • Device: ELLIPTA inhaler
    • Device: HANDIHALER
    • Device: MDI
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 16, 2018)
1041
Original Estimated Enrollment  ICMJE
 (submitted: March 15, 2018)
848
Estimated Study Completion Date  ICMJE June 25, 2019
Estimated Primary Completion Date June 25, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects capable of giving signed informed consent.
  • Outpatients will be included in the study.
  • Subjects 40 years of age or older at Screening (Visit 1).
  • Male or female subjects will be included; 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 the 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 [example given {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.
  • A score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
  • Subjects must demonstrate at Screening: A post-bronchodilator FEV1 <50 percent predicted normal or a post-bronchodilator FEV1 <80 percent 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 with tiotropium alone (via the HANDIHALER or RESPIMAT®) 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 alpha1-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 immunosuppressant's) 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). Subjects at potentially high risk for pneumonia (e.g. very low body mass index [BMI], severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator.
  • 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/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.
  • Alanine Transaminase (ALT) >2x Upper Limit of Normal (ULN); and bilirubin >1.5x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent). 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). Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.
  • Subjects with any of the following at Screening (Visit 1): 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: atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM); sustained and non-sustained ventricular tachycardia (VT); second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate (QTc) >=500 millisecond (msec) in subjects with QRS <120 msec and QTc >=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/minute) (Oxygen use <=3 L/minute 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 Programme during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Programme 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, study 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.
  • Subjects taking following drug therapies will be excluded; subjects taking inhaled short-acting anticholinergics alone or along with short-acting beta agonist combination within 6 hours prior to screening; subjects taking inhaled short-acting beta2 agonists within >=4 hours prior to screening; subjects taking ICS, ICS/inhaled LABA combinations (e.g., FF/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate; FF/VI), Phosphodiesterase 4 (PDE4) inhibitors (roflumilast), LABA (e.g., indacaterol, olodaterol), LAMA (e.g., LAMA/LABA combinations UMEC, aclidinium, glycopyrronium), LAMA/LABA combinations, theophyllines, sodium cromoglycate and nedocromil sodium, anti-leukotrienes as maintenance treatment within 3 months prior to Visit 1 will be excluded. Maintenance treatment is defined as use for >=14 consecutive days (at any time in the 3 months prior to Visit 1). Subjects taking long term antibiotic therapy. (Antibiotics are allowed for the short term treatment (<=14 days) of an exacerbation or for short term treatment (<=14 days) of other acute infections during the study); subjects taking systemic, oral, parenteral corticosteroids 30 days prior to screening; (During the study oral/systemic corticosteroids may be used for <=14 days to treat COPD exacerbations/pneumonia) will be excluded. Intra-articular injections are allowed; subjects taking any other investigational drug within 30 days or 5 half-lives whichever is longer prior to screening will be excluded.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Listed Location Countries  ICMJE Poland,   Russian Federation,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03474081
Other Study ID Numbers  ICMJE 207626
2017-001190-16 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
Pediatric Postmarket Surveillance of a Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: 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
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Parexel
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
PRS Account GlaxoSmithKline
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP