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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 (SCO116572)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01751113
First received: December 13, 2012
Last updated: September 15, 2014
Last verified: September 2014
  Purpose

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 .


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: fluticasone propionate/salmeterol
Drug: tiotropium bromide
Drug: fluticasone propionate/salmeterol plus tiotropium bromide
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised, Double-blind, Double Dummy, 3 Way Cross-over Study Evaluating the Effects of ADOAIR 50/250mcg Twice Daily Plus Tiotropium Bromide 18mcg Once Daily Compared With the Individual Treatments (Tiotropium Bromide 18mcg Alone and ADOAIR 50/250mcg Alone) in the Treatment of Japanese Subjects With COPD

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Area Under the Curve Calculated From 0 to 4 Hours (AUC[0-4hr]) Specific Conductance (sGaw) After the Morning Dose of Study Medication at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sGaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the Least Square (LS) means.


Secondary Outcome Measures:
  • AUC (0-4hr) Specific Airway Resistance (sRaw) After the Morning Dose of Each Study Medication at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. The AUC was determined by using the trapezoidal rule and then dividing by the relevant time interval. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, period and Baseline sRaw fitted as fixed effects and participants fitted as a random effect. Treatment ratios of all statistical comparisons were calculated by taking the anti-log of the difference between the LS means.

  • Post-dose sGaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sGaws. A natural logarithmic transformation was applied and the data was analyzed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sGaw fitted as fixed effects and participant fitted as a random effect.

  • Post-dose sRaw at 30, 75, 120 and 240 Minutes Post Dose at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Plethysmography was performed to assess sRaw. A natural logarithmic transformation was applied and the data was analysed by a mixed model including treatment, time, period, a treatment by time interaction and Baseline sRaw fitted as fixed effects and participant fitted as a random effect.

  • Trough Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), Inspiratory Capacity (IC), RV, TLC, and TGVFRC at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the residual volume (RV). RV is defined as the volume of air remaining in the lungs. after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGVFRC) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration. Trough values were the values taken pre-dose.

  • Trough FEV1/FVC Ratio, at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. Trough values were the values taken pre-dose.

  • Trough sRaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    sRaw is a measure of airways resistance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.

  • Trough sGaw Measured at Each Clinic Visit Prior to the Morning Dose and Before the Use of Rescue Medication at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    sGaw is a measure of airways conductance and is intimately related to the diameter of the airways and consequently the level of bronchodilation. Trough values were the values taken pre-dose.

  • Post-dose FEV1, FVC, IC, RV, TLC and TGVFRC (Measured at Trough) at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements. IC is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Total lung capacity (TLC) is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort; it is equal to the vital capacity (VC) plus the RV. RV is defined as the volume of air remaining in the lungs after a maximal exhalation. Thoracic gas volume at functional residual capacity (TGVFRC) is defined as the volume of intrathoracic gas at the time the airway is occluded for the plethysmographic measurement at the end of a normal expiration.

  • Post-dose FEV1/FVC Ratio (Measured at Trough) at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can forcibly be blown out after a full inspiration. FEV1 and FVC data was obtained by spirometry measurements.

  • Use of Rescue Medication (Number of Occasions Per 24-hour Period) as Recorded in the Daily Record Card at Day 28 of Each Treatment Period [ Time Frame: Day 28 of each treatment period (up to 35 days) ] [ Designated as safety issue: No ]
    Participants were given daily record cards for daily completion during the run-in, washout and treatment periods. Each morning, participants recorded the number of occasions in the last 24 hours when they had used their rescue medication (salbutamol) for symptomatic relief of COPD symptoms.


Enrollment: 53
Study Start Date: February 2013
Study Completion Date: November 2013
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: fluticasone propionate/salmeterol
250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design)
Drug: fluticasone propionate/salmeterol
250mcg fluticasone + 50 mcg salmeterol, twice daily 4 week treatment in each treatment sequence (crossover design)
Other Name: ADOAIR is a registered trade mark of the GlaxoSmithKlline group of companies.
Active Comparator: tiotropium bromide
18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Drug: tiotropium bromide
18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Active Comparator: fluticasone propionate/salmeterol plus tiotropium bromide
250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Drug: fluticasone propionate/salmeterol plus tiotropium bromide
250mcg fluticasone + 50 mcg salmeterol, twice daily plus 18 mcg tiotropium bromide, once daily 4 week treatment in each treatment sequence (crossover design)
Other Name: ADOAIR is a registered trade mark of the GlaxoSmithKlline group of companies.

  Eligibility

Ages Eligible for Study:   40 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01751113

Locations
Japan
GSK Investigational Site
Hokkaido, Japan, 070-8644
GSK Investigational Site
Ibaraki, Japan, 319-1113
GSK Investigational Site
Osaka, Japan, 530-0001
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01751113     History of Changes
Other Study ID Numbers: 116572
Study First Received: December 13, 2012
Results First Received: July 10, 2014
Last Updated: September 15, 2014
Health Authority: Japan: Ministry of Health, Labor and Welfare

Additional relevant MeSH terms:
Chronic Disease
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Lung Diseases, Obstructive
Pathologic Processes
Respiratory Tract Diseases
Albuterol
Bromides
Fluticasone
Salmeterol
Tiotropium
Adrenergic Agents
Adrenergic Agonists
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Anti-Allergic Agents
Anti-Asthmatic Agents
Anti-Inflammatory Agents
Anticonvulsants
Autonomic Agents
Bronchodilator Agents
Central Nervous System Agents
Cholinergic Agents
Cholinergic Antagonists
Dermatologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Parasympatholytics
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on November 20, 2014