A 3 Way Cross-over Study Evaluating the Effects of ADOAIR Twice Daily Plus Tiotropium Bromide Once Daily Compared With the Individual Treatments of Japanese Subjects
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: fluticasone propionate/salmeterol; tiotropium bromide; fluticasone propionate/salmeterol plus tiotropium bromide
Intervention description: 250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design); 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design); 250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Intervention MeSH terms: Fluticasone; Xhance; Bromides; Tiotropium Bromide; Salmeterol Xinafoate; Fluticasone-Salmeterol Drug Combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 53.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the effects on lung function of a combination of
      ADOAIR 50/250mcg twice daily plus tiotropium bromide 18mcg once daily compared with the
      individual treatments (tiotropium bromide 18mcg once daily alone and ADOAIR 50/250mcg twice
      daily alone) in Japanese subjects with COPD. The study will utilize a three-way cross-over
      design with a 2-week wash-out period between each 4-week consecutive treatment period. The
      aim is to support the rationale for "triple combination" therapy by demonstrating that
      treatment with both ADOAIR and tiotropium can potentially produce improved, clinically
      relevant effects compared with either treatment alone.

      This study will utilize a range of lung function measures in order to fully assess the
      benefits of triple therapy. The primary endpoint will be based on airways conductance
      measured using plethysmography (sGaw measured over 4hours post dose (AUC 0-4hr) on Day 28).
      Secondary endpoints will include lung function measures based on plethysmography and
      spirometry. The lung function measures will be supported by measurement of the use of relief
      salbutamol .
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female aged 40 - 80 years inclusive

          -  Has an established clinical history of COPD (defined as per the GOLD definition)

          -  A signed and dated written informed consent is obtained from the subject prior to
             study participation

          -  The subject has a post-bronchodilator FEV1 of >=30% to =<75% of predicted normal at
             Visit 1

          -  The subject has a post-bronchodilator FEV1/ FVC ratio <70% at Visit 1

          -  The subject achieves a score of 1 on the Modified Medical Research Council (mMRC)
             Dyspnoea Scale at Visit 1

          -  The subject is a current or ex-smoker with a smoking history of > 10 pack-years (10
             pack years is defined as 20 cigarettes per day for 10 years, or 10 cigarettes (or
             equivalent if subject smoked cigars or a pipe) per day for 20 years). Ex-smokers are
             required to have stopped smoking for at least 6 months prior to visit 1. Ex-smokers
             who stopped smoking less than 6 months ago will be defined as current smokers.

          -  QTc <450 msec at Visit 1; or for patients with Bundle Branch Block QTc should be <480
             msec.

        (QTc(F) <450msec, or <480 in subjects with right bundle branch block, should be confirmed
        by the mean of three readings or one reading)

          -  ALT < 2xULN and bilirubin/ALP < 1.5xULN (>35% direct bilirubin)

          -  A female is eligible to enter this study if she is: i)of non-childbearing potential
             (i.e. physiologically incapable of becoming pregnant, including any female who is
             post-menopausal), ii)of child-bearing potential, but has a negative urinary pregnancy
             test at screening and agrees to take contraceptive precautions (including abstinence)
             which are adequate to prevent pregnancy during the study or iii)not a nursing mother

        Exclusion Criteria:

          -  Has had a COPD exacerbation within the 4 weeks prior to Visit 1

          -  Had any changes in COPD medication in the 4 weeks prior to Visit 1

          -  Has plan to change the dosage of Xanthines or to stop receiving it during the study

          -  Has a current medical diagnosis of asthma

          -  Has a medical diagnosis of narrow-angle glaucoma, prostatic hyperplasia or bladder
             neck obstruction that in the opinion of the investigator should prevent them from
             entering the study Note: As with other anticholinergic drugs, subjects with
             narrow-angle glaucoma, prostatic hyperplasia or bladder neck obstruction should only
             be entered into the study at the Investigator's discretion

          -  Has known respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis,
             tuberculosis or lung fibrosis)

          -  Has undergone lung surgery e.g., lung transplant and/or lung volume reduction

          -  Is currently receiving pulmonary rehabilitation

          -  Had a chest X-ray indicating diagnosis other than COPD that might interfere with the
             study (chest X-ray to be taken at entry, if subject has not had one or CT image taken
             within 3 months of Visit 1)

          -  Requires regular (daily) or long term oxygen therapy (LTOT). (LTOT is defined as . 12
             hours oxygen use per day)

          -  Requires regular treatment with oral, parenteral, or depot corticosteroids or has
             received 2 or more periods of oral corticosteroids for COPD exacerbation in the last 6
             months

          -  Received oral, parenteral, or depot corticosteroids in the 4 weeks prior to Visit 1

          -  Received antibiotic therapy for either a lower respiratory tract infection or for COPD
             exacerbation within the 4 weeks prior to Visit 1

          -  Has been hospitalized for a COPD exacerbation in the last year

          -  Receiving non-selective β-blockers (except eye drops)

          -  Has serious, uncontrolled disease likely to interfere with the study (e.g. Left
             Ventricular failure, anaemia, renal or hepatic disease or serious psychological
             disorders)

          -  Received any other investigational drugs within 4 weeks (or 5 half lives) prior to
             Visit 1

          -  Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse

          -  Has a known or suspected hypersensitivity to β2-agonists, inhaled steroids,
             anticholinergic treatments or any components of the formulations (e.g. lactose or milk
             protein)

          -  Has previously been enrolled and randomized to this study

          -  Are not considered able to tolerate three 2-weeks wash-out periods according to the
             study schedule with all COPD medications removed apart from rescue use of SALBUTAMOL
             via MDI (inhaled PRN use).

          -  Is not eligible to participate this study in the opinion of the
             investigator/subinvestigator.