A Non-inferiority Study to Evaluate the Efficacy, Safety, and Tolerability of Fluticasone Propionate/Salmeterol (FSC) 250/50 Microgram (mcg) Through a Capsule-Based Inhaler and a Multi-Dose Inhaler Administered Twice Daily (BID) in Adults With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: FSC; Placebo
Intervention description: Subject will be administered FSC 250 mcg/50 mcg via dry powder inhalation device -or multi-dose dry powder inhalation device BID for each treatment periods; Subject will be administered placebo via dry powder inhalation device or multi-dose dry powder inhalation device BID for each treatment periods
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 665.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: efficacy; tolerability; capsule-based inhaler; quality of life; safety; multi-dose inhaler; fluticasone propionate/salmeterol (FSC) 250/50 mcg; Chronic obstructive pulmonary disease

Summary:

      This is a multi-centre, randomised, double-blind, double-dummy, two way cross-over, 12 weeks
      noninferiority study to evaluate the efficacy, safety, and tolerability of FSC 250/50 mcg
      capsule-based inhaler and a multi-dose inhaler administered BID in adults with COPD. The
      primary objective of this study is to establish the non-inferiority of the efficacy of the
      FSC 250/50 mcg capsule-based inhaler compared to the FSC 250/50 mcg multi-dose inhaler
      administered BID. The study consists of 6 phases: Pre-screening, Screening/Run-in (3 weeks),
      Treatment Period 1 (12 weeks), Washout (minimum 4 weeks), Treatment Period 2 (12 weeks) and
      Follow-up (1 week). The total duration of the study for each subject will be at least 32
      weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female >=40 and <=80 years of age at the time of signing the informed consent.

          -  A female subject is eligible to participate if she is of:

        Non-childbearing potential defined as premenopausal females with a documented tubal
        ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea
        (in questionable cases a blood sample with simultaneous follicle stimulating hormone >40
        milli international unit per milliliter (mIU/mL) and oestradiol <40 picogram [pg]/mL [<147
        picomole per liter (pmol/L)] is confirmatory); females on hormone replacement therapy (HRT)
        and whose menopausal status is in doubt will be required to use one of the contraception
        methods (i.e., in accordance with the approved product label and the instructions of the
        physician for the duration of the study from Screening to follow-up contact) if they wish
        to continue their HRT during the study. Otherwise, they must discontinue HRT to allow
        confirmation of postmenopausal status before study enrolment. For most forms of HRT, at
        least 2 to 4 weeks should elapse between the cessation of therapy and the blood draw; this
        interval depends on the type and dosage of HRT. After confirmation of their postmenopausal
        status, they can resume use of HRT during the study without use of a contraceptive method;
        child-bearing potential and is abstinent or agrees to use one of the contraception methods
        for an appropriate period of time (as determined by the product label or investigator)
        before the start of dosing to sufficiently minimise the risk of pregnancy at that point.
        Female subjects must agree to use contraception until at least 2 days post the last dose of
        study treatment; abstinence from penile-vaginal intercourse must be consistent with the
        preferred and usual lifestyle of the subject.

          -  COPD Diagnosis: An established clinical history of COPD in accordance with the
             following definition by the American Thoracic Society/European Respiratory Society.

          -  Severity of Disease:

        A measured pre- and post-salbutamol/albuterol FEV1/forced vital capacity (FVC) ratio of
        <0.70 at Visit 1 (Screening and Run-in Visit) A measured pre-salbutamol/albuterol FEV1 <50%
        of predicted normal values at Visit 1 (Screening and Run-in Visit).

        A measured post-salbutamol/albuterol FEV1 >=30% of predicted normal values at Visit 1
        (Screening and Run-in Visit). Predicted values will be calculated using the National Health
        and Nutrition Examination Survey (NHANES) III reference equations.

          -  Tobacco Use: Current or prior history of at least 10 pack-years of cigarette smoking
             (e.g., 20 cigarettes/day for 10 years). One pack-year is defined as 20 manufactured
             cigarettes (1 pack) smoked per day for 1 year. Former smokers are defined as those who
             have stopped smoking for at least 6 months prior to Visit 1 (Screening and Run-in
             Visit). Former smokers are eligible to enter the study provided they have at least 10
             pack-years smoking history. Subjects making a conscious decision to stop smoking at
             any time during the study and who refrain from smoking for >4 weeks will be
             discontinued from the study. Additionally, subjects who start smoking during the study
             and smoke for at least 7 consecutive days will be discontinued from the study.

          -  Dyspnoea: A score of >=2 on the Modified Medical Research Council Dyspnoea Scale
             (mMRC) at Visit 1 (Screening and Run-in Visit)

          -  Liver Safety Criteria: Alanine aminotransferase (ALT) <=2 the upper limit of normal
             (ULN), alkaline phosphatase and bilirubin <=1.5 ULN (isolated bilirubin >1.5 ULN is
             acceptable if bilirubin is fractionated and direct bilirubin is <35%) at Visit 1
             (Screening and Run-in Visit)

          -  Electrocardiogram (ECG) Safety Criteria: The subject must have no ECG abnormalities
             that would, in the opinion of investigator, compromise subject safety, or
             significantly affect subject's ability to complete the trial. As such the investigator
             will determine the clinical significance of any ECG abnormality and determine if a
             subject is precluded from entering the study. At Visit 1 (Screening and Run-in Visit),
             ECG safety criteria must be:

        QT interval corrected for heart rate (QTc) or QT interval corrected for heart rate
        according to Fridericia formula (QTcF) <450 milliseconds (msec) or QTc <480 msec for
        subjects with a bundle branch block. Investigators will be responsible for ensuring
        appropriate clinical interpretation of ECGs

          -  Able to use the inhaler devices adequately after training

          -  Capable of giving informed consent, which includes compliance with the study
             requirements and restrictions listed in the consent form.

        Exclusion Criteria:

          -  A current diagnosis of asthma

          -  Any clinically significant and uncontrolled disease, including but not limited to the
             following: neurological, psychiatric, renal, immunological, endocrine/metabolic
             (including uncontrolled diabetes, hypokalaemia or thyroid disease), cardiovascular,
             neuromuscular, hepatic, gastric, or haematological abnormalities, or peripheral
             vascular disease. Significant is defined as any disease that, in the opinion of the
             investigator, would put the safety of the subject at risk or would affect the efficacy
             analysis if the disease/condition exacerbated during the study

          -  A respiratory diagnosis other than COPD (e.g., lung cancer, bronchiectasis,
             sarcoidosis, tuberculosis, lung fibrosis), including subjects with a diagnosis of
             alpha-1-antitrypsin deficiency. Allergic rhinitis is not exclusionary

          -  An abnormal and clinically significant chest X-ray film or computed tomography scan
             not believed to be a result of the presence of COPD. A chest X-ray must be taken if
             the subject has not had 1 within 6 months of Visit 1 (Screening and Run in Visit)

          -  Lung resection surgery (e.g., lung volume reduction surgery, or lobectomy) within 1
             year of Visit 1 (Screening and Run-in Visit)

          -  A COPD exacerbation and/or infection of the upper or lower respiratory tract requiring
             treatment with systemic (oral or parenteral) corticosteroids and/or antibiotics that
             has not resolved within 30 days of Visit 1 (Screening and Run-in Visit)

          -  A COPD exacerbation that resulted in hospitalisation that has not resolved within 3
             months of Visit 1 (Screening and Run-in Visit)

          -  Use of nocturnal-positive pressure (e.g., continuous positive airway pressure or
             bilevel positive airway pressure)

          -  Oropharyngeal Examination: A subject will not be eligible for the Run-in Period if
             he/she has clinical visual evidence of candidiasis at Visit 1 (Screening and Run-in
             Visit)

          -  An abnormal and clinically significant 12-lead ECG result. For the purposes of this
             study, an abnormal ECG result is defined as a 12-lead tracing that is interpreted as
             demonstrating (but not limited to) any of the following: Myocardial ischemia,
             clinically significant conduction abnormalities (e.g., left bundle branch block,
             Wolff-Parkinson-White syndrome), clinically significant arrhythmias (e.g., atrial
             fibrillation, ventricular tachycardia). The study investigator will determine the
             clinical significance of any ECG abnormality and determine if a subject is precluded
             from entering the study.

          -  Cancer: Subjects with carcinoma that has not been in complete remission for at least 5
             years. Carcinoma in situ of the cervix, squamous cell carcinoma, and basal cell
             carcinoma of the skin would not be excluded if the subject has been considered cured
             within 5 years since diagnosis

          -  Investigational Medications: A subject must not have used any investigational drug
             within 30 days prior to Visit 1 (Screening and Run-in Visit) or within 5 half lives of
             the prior investigational drug (whichever is longer of the two). The prior
             investigational drug half life may be confirmed with the prior investigational study
             sponsor or by consulting relevant study documentation

          -  Allergies: Drug allergy: Any adverse reaction including immediate or delayed
             hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal,
             inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the
             constituents of the capsule-based and multi-dose inhaler (i.e., lactose), milk protein
             allergy: History of severe milk protein allergy

          -  Initiation of systemic beta-blocker medications and beta-blocker eye drops for at
             least 30 days prior to Visit 1 (Screening and Run-in Visit)

          -  Concomitant Medication: Administration of prescription or over-the-counter medication
             that would significantly affect the course of COPD, or interact with study treatment,
             such as: anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic
             antidepressants; phenothiazines; and monoamine oxidase (MAO) inhibitors;
             Immunosuppressive medications: A subject must not be using or require use of
             immunosuppressive medications during the study; cytochrome P450 3A4 (CYP3A4)
             inhibitors: Subjects who have received a potent CYP3A4 inhibitor within 4 weeks of
             Visit 1 (Screening and Run-in Visit) (e.g., ritonavir, ketoconazole, itraconazole) and
             at any time during the study; unable to refrain from the use of prescription or
             nonprescription drugs, including vitamins, herbal and dietary supplements (including
             St John's wort) within 7 days (or 14 days if the drug is a potential enzyme inducer)
             or 5 half lives (whichever is longer) prior to the first dose of study treatment,
             unless in the opinion of the investigator and medical monitor the medication will not
             interfere with the study procedures or compromise subject safety

          -  Compliance: A subject will not be eligible if he/she or his/her parent or legal
             guardian has any infirmity, disability, disease, or geographical location that seems
             likely (in the opinion of the investigator) to impair compliance with any aspect of
             this study protocol, including visit schedule and completion of the daily paper Diary
             Cards

          -  Medications Prior to Screening: Use of the following medications within the defined
             times prior to Visit 1 (Screening and Run-in Visit): Short-acting beta-agonists (e.g.,
             albuterol; 6 hours), Ipratropium; 6 hours, Ipratropium/albuterol combination product;
             6 hours, Oral beta-agonists; 48 hours, Salmeterol and formoterol; 48 hours,
             Indacaterol; 5 days, Theophylline preparations; 12 hours, Tiotropium; 14 days,
             Phosphodiesterase 4 (PDE4) inhibitors (e.g., roflumilast); 14 days, Oral leukotriene
             inhibitors (zafirlukast, montelukast, zileuton); 48 hours, Long-acting beta
             -agonist/inhaled corticosteroid combination products (e.g., fluticasone/salmeterol or
             budesonide/formoterol); 30 days, Inhaled corticosteroids; 30 days, Oral or parenteral
             corticosteroids; 30 days, any investigational drug; 30 days or 5 half-lives, whichever
             is longer.

          -  Any intellectual deficiency including illiteracy, history of substance abuse in the 2
             years prior to Visit 1 (including drug and alcohol), or other conditions, which will
             limit the validity of informed consent to participate in the study

          -  Subjects who have participated in the acute phase of a pulmonary rehabilitation
             program within 4 weeks prior to Visit 1 (Screening and Run-in Visit) or who will 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.

          -  Supplemental oxygen, with the following exceptions:

        Use at high altitude (>5000 feet) provided subject does not require a flow rate of >2
        L/minute Use for exertion provided subject does not require >2 hours per day of oxygen and
        does not require a flow rate of >2 L/minute Use for nocturnal therapy provided subject does
        not require a flow rate of >2 L/minute

          -  Pregnant females as determined by urine test at Visit 1(Screening and Run-in Visit) or
             prior to dosing. A confirmatory serum pregnancy test is required if the urine test is
             questionable or positive

          -  Lactating females

          -  A known history of a positive hepatitis B surface antigen or a positive hepatitis C.

          -  Unable to comply with study procedures