Comparative Study of Fluticasone Furoate(FF)/Umeclidinium Bromide (UMEC)/ Vilanterol (VI) Closed Therapy Versus FF/VI Plus UMEC Open Therapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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This multicenter study will be conducted to compare the effect of FF/UMEC/VI with FF/VI plus UMEC on lung function after 24 weeks of treatment. This is a phase IIIB, 24-week, randomized, double-blind, parallel group multicenter study. This study will test the hypothesis that the difference in trough forced expiratory volume in one second (FEV1) between treatment groups is less than or equal to a pre-specified non-inferiority margin. Alternatively, this study will also test the hypothesis that the difference between treatment groups is greater than the margin. The triple therapy of FF/UMEC/VI in a single inhaler is being developed with the aim of providing a new treatment option for the management of advanced Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group D COPD which will reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, convenience, and improve lung function, health related quality of life (HRQoL) and symptom control over established dual/monotherapies. This study has a 2 week run in period where subjects will continue to have their existing COPD medications. At randomization, subjects will discontinue all existing COPD medications and will be assigned to treatment of FF/UMEC/VI, 100 microgram (mcg)/62.5 mcg/25 mcg and placebo or FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg in a 1:1 ratio for 24 weeks. Subjects will have clinical visits at Pre-Screening (Visit 0), Screening (Visit 1), Randomization (Week 0, Visit 2), Week 4 (Visit 3), Week 12 (Visit 4) and Week 24 (Visit 5). A follow-up visit will be conducted at 1 week after the end of treatment period or after early withdrawal visit. Approximately, 1020 subjects will be enrolled in this study. There will be two pharmacokinetic (PK) groups (subset A and subset B). Approximately 120 subjects will be assigned to subset A and approximately 60 subjects will be assigned to subset B. The total duration of subject participation will be approximately 27 weeks, consisting of a 2-week run-in period, 24-week treatment period and a 1-week follow-up period.

Official Title
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A Phase IIIB, 24-week Randomised, Double-blind Study to Compare 'Closed' Triple Therapy (FF/UMEC/VI) With 'Open' Triple Therapy (FF/VI + UMEC), in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: FF/UMEC/VI
* Drug: FF/VI
* Drug: UMEC
* Drug: Placebo
* Drug: Albuterol/salbutamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent: A signed and dated written informed consent prior to study participation. Type of subject: Outsubject. Age: Subjects 40 years of age or older at Screening (Visit 1). Gender: Male or female subjects. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study treatmentand until after the last dose of study treatmentand completion of the follow-up visit. 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 divided by 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 Screening (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 Screening (Visit1). Severity of COPD Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 at Screening (Visit 1). Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening (Visit 1). Note: Subjects receiving only as needed COPD medications are not eligible. History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 <50 percent predicted normal at Screening (Visit 1) and a documented history of >=1 moderate or severe COPD exacerbation in the 12 months prior to Screening or a post-bronchodilator 50 percent =< FEV1 <80 percent predicted normal at Screening (Visit 1) and a documented history of >=2 moderate exacerbations or a documented history of >=1 severe COPD exacerbation (hospitalised) in the 12 months prior to Screening (Visit 1). Notes: Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations; 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 hospitalisation (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 dyspnoea, sputum volume, or sputum purulence (colour). Subject verbal reports are not acceptable. 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, which is the primary cause of their respiratory symptoms). Alpha 1-antitrypsin deficiency: Subjects with alpha1-antitrypsin deficiency as the underlying cause of COPD. Other respiratory disorders: Subjects with active tuberculosis are excluded. Subjects with other respiratory disorders (e.g. clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases) are excluded if these conditions are the primary cause of their respiratory symptoms. Lung resection: Subjects with lung volume reduction surgery (including procedures such as endobronchial valves) within the 12 months prior to Screening (Visit 1). Risk Factors for Pneumonia: immune suppression (e.g. advanced human immune deficiency virus (HIV) with high viral load and low cluster of differentiation 4 (CD4) count, Lupus on immunosuppressants that 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). Notes: Subjects at a 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 (Visit 1) and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). Other Respiratory tract infections that have not resolved at least 7 days prior to Screening (Visit 1). Abnormal Chest x-ray: Chest x-ray 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 computerised tomography (CT) scan obtained within 3 months prior to Screening (Visit 1). Notes: Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation within 3 months of Screening (Visit 1) must provide a post pneumonia/exacerbation chest x-ray or have a chest x-ray conducted at Screening (Visit 1); 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). 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: 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 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). Notes: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis; 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. 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 4 Heart failure. Abnormal and clinically significant 12-Lead ECG finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. 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 tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM); 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). 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 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. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3 Liters per minute (Oxygen use <= 3 Liters/minute 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. 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, and 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 30 days prior to Screening (Visit 1) or requirement for their use during the study: Use of long term continuous antibiotic therapy; systemic, oral, parenteral corticosteroids (Intra-spinal and intra-articular injections are allowed); use of any other investigational drug: within 30 days or 5 half lives whichever is longer.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FF/UMEC/VI closed triple therapy plus Placebo<br>Subjects will receive FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg and placebo inhalation powder via the dry powder inhaler (DPI), once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period. | Drug: FF/UMEC/VI<br>* This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains UMEC and VI blended with lactose and magnesium stearate. It is available as dry white powder, 62.5 mcg per blister UMEC, 25 mcg per blister VI. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip).<br>Drug: Placebo<br>* This intervention is available in one strip. The strip contains lactose. The formulation is available as dry white powder. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters).<br>Drug: Albuterol/salbutamol<br>* This is a rescue medication administered via metered-dose inhaler (MDI) with a spacer which will be used when needed during the study.<br>|
| Active Comparator: FF/VI plus UMEC open triple therapy<br>Subjects will receive FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg inhalation powder via the DPI, once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period. | Drug: FF/VI<br>* This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains VI blended with lactose and magnesium stearate. It is available as dry white powder, 25 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip).<br>Drug: UMEC<br>* This intervention is available in one strip. The strip contains UMEC blended with lactose and magnesium stearate. The formulation is available as dry white powder, 62.5 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters).<br>Drug: Albuterol/salbutamol<br>* This is a rescue medication administered via metered-dose inhaler (MDI) with a spacer which will be used when needed during the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24 | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. It was measured using centralized spirometry. FEV1 values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Modified Per Protocol (mPP) Population was used which comprised of all participants in the Intent-to-Treat (ITT) Population, who do not have a full protocol deviation considered to impact efficacy. Data following a moderate/severe COPD exacerbation or pneumonia was excluded from analysis due to the potential impact of the exacerbation or the medications used to treat it. Participants with partial protocol deviations considered to impact efficacy were included in the mPP Population but had their data excluded from analysis from the time of deviation onwards. Analysis was performed using a mixed model repeated measures (MMRM) method. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders Based on the Saint (St) George Respiratory Questionnaire (SGRQ) Total Score at Week 24 | SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on health related quality of life (HRQoL) of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Response was defined as an SGRQ total score of >=4 units below Baseline. Non response was defined as a SGRQ total score <4 units below Baseline or a missing SGRQ total score with no subsequent on treatment scores. ITT Population comprised of randomized participants, excluding those who were randomized in error. A participant screened or run-in failure and also randomized was considered to be randomized in error. Analysis was performed using a generalized linear mixed model with a logit link function. | Week 24 | 
| Change From Baseline in SGRQ Total Score at Week 24 | SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Analysis was performed using a MMRM method including covariates of Baseline SGRQ Total score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction. | Baseline and Week 24 | 
| Percentage of Responders Based on Transitional Dyspnea Index (TDI) Focal Score at Week 24 | The TDI measures changes in the participant's dyspnea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was defined as a TDI focal score of less than 1 unit or a missing TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with a logit link function. | Week 24 | 
| TDI Focal Score at Week 24 | The TDI measures changes in the participant's dyspnoea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using a repeated measures model. | Week 24 | 
| Time to First Moderate or Severe Exacerbation | COPD exacerbations were identified based on the investigator's clinical judgment. Worsening symptoms of COPD that required treatment with oral/systemic corticosteroids and/or antibiotics were considered as moderate exacerbation. Worsening symptoms of COPD that required treatment with in-subject hospitalization was considered as severe exacerbation. Hazard ratio and 95% confidence interval (CI) is from a Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (0, 1, >=2 moderate/severe exacerbations, prior year), smoking status (screening), stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region and percent predicted FEV1 at Baseline. Median and inter-quartile range (first and third quartile) have been presented. | Up to 25 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open triple therapy, Chronic Obstructive Pulmonary Disease (COPD), fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI), Umeclidinium bromide (UMEC), Closed triple therapy, Placebo, fluticasone furoate/vilanterol (FF/VI)