A Study Comparing the Efficacy, Safety and Tolerability of Fixed Dose Combination (FDC) of FF/UMEC/VI With the FDC of FF/VI and UMEC/VI; Administered Once-daily Via a Dry Powder Inhaler (DPI) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Not Recruiting

Trial ID: NCT02164513


The study evaluates the efficacy of fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) to reduce the annual rate of moderate and severe exacerbations compared with dual therapy of FF/VI or UMEC/VI in subjects with COPD. Published studies which assessed the use of an 'open' triple therapy (use of Inhaled Corticosteroid [ICS]/ Long-acting Muscarinic Receptor Antagonists [LAMA])/ Long Acting Beta-Agonist [LABA] delivered via multiple inhalers) in moderate-severe COPD patients, reported improvements in lung function, Health Related Quality of Life (HRQoL), hospitalization rates and rescue medication use, compared to dual therapy (ICS/LABA) or LAMA alone. These studies have also shown similar safety profile with dual or monotherapy doses for periods of up to one year. Given the clinical experience with FF, UMEC and VI, and that the associated risks with these compounds are anticipated from their known pharmacology, the potential benefit of a new therapy option in patients with moderate to severe COPD supports the further development of the closed triple combination (delivered via one inhaler). In the current study subjects meeting all inclusion/exclusion criteria will complete 2-week run-in period; 52 week treatment period and a 1-week safety follow-up period. Eligible subjects will be randomized to one of the following double-blind treatment groups FF/UMEC/VI 100 micrograms (mcg)/62.5 mcg/25 mcg once daily (QD), FF/VI 100 mcg/25 mcg QD, or UMEC/VI 62.5 mcg/25 mcg QD

Official Title

A Phase III, 52 Week, Randomized, Double-blind, 3-arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination FF/UMEC/VI With the Fixed Dose Dual Combinations of FF/VI and UMEC/VI, All Administered Once-daily in the Morning Via a Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease

Stanford Investigator(s)


Inclusion Criteria:

   - Informed Consent: A signed and dated written informed consent prior to study

   - Type of subject: Outpatient

   - Age: Subjects 40 years of age or older at Visit 1

   - Gender: Male or female subjects. 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 safety 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); 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)

   - COPD 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 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. Note: Pipe and/or
   cigar use cannot be used to calculate pack-year history

   - Severity of COPD symptoms: A score of >=10 on the COPD Assessment Test (CAT) at

   - Severity of COPD Disease: A post-albuterol/salbutamol FEV1/ Forced Vital Capacity
   (FVC) ratio of <0.70 at Screening

   - Existing COPD maintenance treatment: Subject must be receiving daily maintenance
   treatment for their COPD for at least 3 months prior to Screening. Note: Subjects
   receiving only Pro re nata (PRN) COPD medications are not eligible

   - History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 <50%
   predicted normal and a documented history of >= 1 moderate or severe COPD exacerbation
   in the previous 12 months OR a post-bronchodilator 50% <=FEV1 < 80% predicted normal
   and a documented history of >= 2 moderate exacerbations or a documented history of >=1
   severe COPD exacerbation (hospitalized) in the previous 12 months. Note: Percent
   predicted will be calculated using the European Respiratory Society Global Lung
   Function Initiative reference equations. Note: A documented history of a COPD
   exacerbation (e.g., medical record verification) is a medical record of worsening COPD
   symptoms that required systemic/oral corticosteroids and/or antibiotics (for a
   moderate exacerbation) or hospitalization (for a severe exacerbation). Prior use of
   antibiotics alone does not qualify as an exacerbation history unless the use was
   associated with treatment of worsening symptoms of COPD, such as increased dyspnea,
   sputum volume, or sputum purulence (color). Subject verbal reports are not acceptable

   - Liver function tests: alanine aminotransferase (ALT) <2x upper limit of normal (ULN);
   alkaline phosphatase <=1.5xULN; bilirubin <=1.5xULN (isolated bilirubin >1.5 x ULN is
   acceptable if bilirubin is fractionated and direct bilirubin <35%)

   - French subjects: In France, a subject will be eligible for inclusion in this study
   only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

   - Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant
   during the study

   - Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of
   asthma are eligible if they have a current diagnosis of COPD)

   - Alpha1-antitrypsin deficiency: Subjects with Alpha1-antitrypsin deficiency as the
   underlying cause of COPD

   - Other respiratory disorders: Subjects with active tuberculosis, lung cancer,
   significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension,
   interstitial lung diseases or other active pulmonary diseases

   - Lung resection: Subjects with lung volume reduction surgery within the 12 months prior
   to Screening

   - Risk Factors for Pneumonia: immune suppression (e.g. human immunodeficiency virus
   [HIV], Lupus) or other risk factors for pneumonia (e.g. neurological disorders
   affecting control of the upper airway, such as Parkinson's Disease, Myasthenia
   Gravis). Patients at potentially high risk (e.g. very low 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). In addition, any subject that
   experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in
   period will be excluded

   - Other Respiratory tract infections that have not resolved at least 7 days prior to

   - Abnormal Chest x-ray(CXR): 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 CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All
   subjects will have a chest x-ray at Screening Visit 1 (or historical radiograph or
   computerised tomography (CT) scan obtained within 3 months prior to screening) that
   will be over-read by a central vendor. Note: Subjects who have experienced pneumonia
   and/or moderate or severe COPD exacerbation within 3 months of screening must provide
   a post pneumonia/exacerbation chest x-ray to be over-read by the central vendor or
   have a chest x-ray conducted at 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 (Bundesamt für Strahlenschutz [BfS])

   - Other diseases/abnormalities: 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 as defined by the presence of ascites, encephalopathy,
   coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice,
   cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or
   asymptomatic gallstones).

   - Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets
   entry criteria

   - Unstable or life threatening cardiac disease: 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:
   Investigators will be provided with ECG reviews conducted by a centralized independent
   cardiologist to assist in evaluation of subject eligibility. The Principal
   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 tracing
   that is interpreted as, but not limited to, any of the following: atrial fibrillation
   (AF) with rapid ventricular rate >120 beats per minute); sustained or nonsustained
   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 (QTcF) >=500 milliseconds (msec) in patients with QRS <120
   msec and QTcF >=530 msec in patients with QRS >=120 msec

   - Contraindications: 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

   - Cancer: Subjects with carcinoma that has not been in complete remission for at least 5
   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 5 year waiting
   period if the subject has been considered cured by treatment

   - Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen
   therapy >3 Liter/minute (L/min) (Oxygen use =<3L/min flow is not exclusionary)

   - Medication prior to spirometry: Subjects who are medically unable to withhold their
   albuterol/salbutamol for the 4-hour period required prior to spirometry testing at
   each study visit

   - Pulmonary rehabilitation: Subjects who have participated in the acute phase of a
   Pulmonary Rehabilitation Program 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

   - Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug
   abuse within the last 2 years

   - Non-compliance: 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

   - Questionable validity of consent: 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

   - Affiliation with investigator site: 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

   - Inability to read: In the opinion of the Investigator, any subject who is unable to
   read and/or would not be able to complete study related materials

   - Medication prior to screening: Use of the following medications within the following
   time intervals prior to Screening (Visit 1) or during the study: Long term antibiotic
   therapy Subjects receiving antibiotics for long term therapy are not eligible for the
   study (Antibiotics are allowed for the short term treatment of an exacerbation or for
   short term treatment of other acute infections during the study); Systemic, Oral,
   parenteral corticosteroids 30 days (Except during the study oral/systemic
   corticosteroids may be used to treat COPD exacerbations/pneumonia) Intra-articular
   injections are allowed; Any other investigational drug (30 days or 5 half lives
   whichever is longer)


drug: fluticasone furoate (FF)

drug: vilanterol (VI)

drug: umeclidinium bromide (UMEC)

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305