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Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01762800
First received: December 6, 2012
Last updated: September 23, 2016
Last verified: August 2016
  Purpose
The purpose of this study is to assess the control of COPD using a symptom and exacerbation risk based treatment strategy based on GOLD 2011. This study is conducted in Japanese subjects with COPD and assess whether the GOLD 2011 strategy is effective in medical practice in Japan.

Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: fluticasone propionate/salmeterol 50/250mcg
Drug: fluticasone propionate/salmeterol placebo
Drug: tiotropium bromide 18mcg
Drug: tiotropium bromide placebo
Drug: fluticasone propionate/salmeterol 50/250mcg and tiotropium 18mcg
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Percentage of Participants Who Were Able to Remain on the Randomized Treatment [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) is not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. The percentage of participants who were able to remain on the randomized treatment was calculated by the following formula: 100 minus percentage of participants who switched over to TRIPLE therapy.


Secondary Outcome Measures:
  • Percentage of Participants Who Switched to TRIPLE Therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Switched to TRIPLE therapy is defined as: 1. Date of switch: when SAL/FLU or TIO was administered additionally to randomised treatment. 2. Date of randomisation was a start point and timing of switching (first switch if there are more than once) to TRIPLE was event. For participants without switching, last day of study or follow up period was regarded as censored. Percentage of participants who switched to TRIPLE therapy was calculated as: number of participants who switched to TRIPLE therapy divided by number of evaluable population and then multiplied by 100.

  • Percentage of Participants Managed by TRIPLE Therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Percentage of participants managed by TRIPLE therapy was calculated as [(number of participants who switched to TRIPLE therapy) - (number of participants who stepped down)/ number of evaluable population]*100

  • Continuation Percentage of Participants Managed by Randomized Treatment Plus TRIPLE Therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) was not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. Continuation TRIPLE proportion is defined as [(number of subjects who switched to TRIPLE) - (number of subjects who stepped down)/ number of evaluable population]*100. Randomised treatment continuation proportion is calculated by a formula: (100 - switch proportion).

  • Time to First Switching to TRIPLE Therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The day of first switch to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) for the first switching participant in each arm.

  • Time to First Exacerbation by Physician's Diagnosis [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The day of detection of first exacerbation in any participant in each arm as diagnosed by physician. Exacerbation is defined primarily by physician's judgment. Date of randomisation will be start point and timing of exacerbation (first exacerbation if there are more than one) will be event. For subjects without exacerbation, last day of study or follow up period is regarded as censor.

  • Time to First Exacerbation by EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The EXAcerbations of Chronic pulmonary disease Tool (EXACT) is a 14-item patient-reported outcome (PRO) daily diary used to quantify and measure exacerbations of chronic obstructive pulmonary disease (COPD). Reported as units on a 0 [best health status] to 100 [worst possible status] scale). The day of detection of first exacerbation in any participant in each arm by EXACT.

  • EXACT Total Score. [ Time Frame: Baseline and up to 24 weeks ] [ Designated as safety issue: No ]

    EXACT is a 14-item patient questionnaire used as a measure of respiratory symptoms (reported as units on a 0 [best health status] to 100 [worst possible status] scale). Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score.

    Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores.


  • EXACT Respiratory Symptoms (E-RS) Total Score [ Time Frame: Baseline and up to 24 weeks ] [ Designated as safety issue: No ]

    The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score.

    Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. Scores range from 0-100, high value in score indicate worse outcome.


  • E-RS Subscale Score [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. The E-RS subscale scores for respiratory symptoms (RS)-breathlessness (RS-BRL), RS-cough and sputum (RS-CSP), and RS-chest symptoms (RS-CSY) are presented. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score. Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. RS total scores range from 0 to 40, high value in score indicate worse outcome.

  • Comparison of Number of Exacerbations Between Two Detection Methods: EXACT and Physician Diagnosis [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The comparison of number of exacerbation between two detection methods EXACT and physician diagnosis: number of exacerbations detected by EXACT and number of exacerbations judged by physician.

  • Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Scores were assessed at Visit 1 (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome.

  • Change From Baseline in CAT Total Score [ Time Frame: Baseline and up to 24 weeks ] [ Designated as safety issue: No ]
    Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Baseline was the value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. Scores were assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome.

  • Forced Expiratory Volume in One Second (FEV1) [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
    FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. At Screening (Visit 1) spirometric assessments were conducted before (Visit 1A) and 30 to 60 minutes after a bronchodilator challenge (400 µg of salbutamol) (Visit 1B). FEV1 during each visit are presented. FEV1 was assessed at Visit 1A (Screening), Visit 1B (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

  • Change From Baseline in FEV1 [ Time Frame: Baseline (Visit 2) and up to 24 weeks ] [ Designated as safety issue: No ]
    FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. Baseline was a value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. FEV1 was assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

  • Percentage of Participants Who Used Relief Medication (Salbutamol) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Each evening participants recorded the number of occasions in the last 24 hours when they used their salbutamol for symptomatic relief of COPD symptoms. The percentage of participants who used relief medication in the study are presented.

  • Percentage of Participants Who Stepped Down From TRIPLE Therapy to Initial Randomized Treatment [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The percentage of participants who stepped down from TRIPLE therapy to initial randomized treatment was calculated as number of participants who step-down from TRIPLE therapy divided by number of participants who switch to TRIPLE therapy and then multiplied by 100.

  • Percentage of Participants Who Required Additional Treatment to TRIPLE Therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The percentage of participants who required additional treatment to TRIPLE therapy is defined as number of participants who took additional medicine or therapy in TRIPLE therapy divided by number of participants who switch to TRIPLE therapy multiplied by 100.

  • Percentage of Participants Who Dropped Out [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The percentage of participants who were withdrawn from the study.

  • Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]
    Participants evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

  • Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Physician evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).


Enrollment: 407
Study Start Date: February 2013
Study Completion Date: September 2015
Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: fluticasone propionate/salmeterol
Randomised treatment at Visit 2
Drug: fluticasone propionate/salmeterol 50/250mcg
Active, 50/250mcg, Twice daily (morning and evening)
Other Name: ADOAIR is a registered trade mark of the GlaxoSmithKline group of companies
Drug: tiotropium bromide placebo
Placebo, Once daily(morning)
Drug: fluticasone propionate/salmeterol 50/250mcg and tiotropium 18mcg
Active. The randomized treatment may be switched to TRIPLE therapy when COPD symptoms are uncontrolled or the subject is not satisfied with the randomized treatment at each scheduled or unscheduled visit.
Other Name: TRIPLE therapy
Experimental: tiotropium bromide
Randomised treatment at Visit 2
Drug: fluticasone propionate/salmeterol placebo
Placebo, Twice daily (morning and evening)
Drug: tiotropium bromide 18mcg
Active, 18mcg, Once daily(morning)
Drug: fluticasone propionate/salmeterol 50/250mcg and tiotropium 18mcg
Active. The randomized treatment may be switched to TRIPLE therapy when COPD symptoms are uncontrolled or the subject is not satisfied with the randomized treatment at each scheduled or unscheduled visit.
Other Name: TRIPLE therapy

Detailed Description:

PROTOCOL SUMMARY Rationale Both ADOAIR and tiotropium bromide ( hereinafter tiotropium)are now well established, effective treatments for COPD and are frequently co-prescribed (hereinafter TRIPLE therapy). The addition of ADOAIR to tiotropium improves lung function and quality of life and may further reduce exacerbations. GOLD 2011 thus recommends TRIPLE therapy as the second choice of COPD treatment strategy. However, the criteria for switching from each individual treatment to TRIPLE therapy are not clearly shown so far.

This study will be conducted in Japanese subjects with COPD and will assess whether the GOLD 2011 strategy is effective in medical practice in Japan.

Objective(s) The objective of the study is to assess the control of COPD using a symptom and exacerbation risk based treatment strategy based on GOLD 2011.

Study Design Multicenter, randomized, double-dummy, 24-weeks, observational study Study Endpoints/Assessments Primary

  • Proportion of patients who were able to remain on the randomized therapy Secondary
  • Proportion of patients who switched to TRIPLE therapy
  • Proportion of patients who controlled by TRIPLE therapy
  • Proportion of patients controlled by randomized therapy plus TRIPLE therapy
  • Time to switching to TRIPLE therapy
  • Time to first exacerbation
  • Proportion of diagnosed exacerbation confirmed by Daily Record Card
  • Proportion of exacerbations detected by Daily Record Card not diagnosed
  • CAT score change
  • Change in FEV1
  • Use of relief medication
  • Proportion of patients who decreased treatment from TRIPLE therapy
  • Proportion of patients who required additional treatment to TRIPLE therapy
  • Proportion of patients who dropped out
  • Patients' judgment of treatment efficacy
  • Physician's judgment of treatment efficacy

Safety

  • Adverse event reporting
  • Exacerbations of COPD
  Eligibility

Ages Eligible for Study:   40 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female aged 40 - 80 years inclusive
  2. Has an established clinical history of COPD (defined as per the GOLD definition)
  3. The subject achieves a grade of ≥1 on mMRC at Visit 1
  4. A signed and dated written informed consent is obtained from the subject prior to study participation
  5. The subject has a post-bronchodilator FEV1 of ≥ 30% to ≤ 80% of predicted normal
  6. The subject has a post-bronchodilator FEV1 / FVC ratio < 70%
  7. The subject is a current or ex-smoker with a smoking history of > 10 pack-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.
  8. QTc < 450 msec at Visit 1; or for patients with bundle branch block QTc should be < 480 msec.

(QTc(F) < 450 msec, or < 480 msec in subjects with right bundle branch block, should be confirmed by the mean of three readings or one reading) 9. ALT < 2 x ULN and bilirubin/ALP ≤ 1.5 x ULN (> 35% direct bilirubin) 10. 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), or 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 iii) not a nursing mother

Exclusion Criteria:

  1. Has a predominant asthma (comorbid asthma is not an exclusion criteria)
  2. 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
  3. Has known respiratory disorders other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis)
  4. Has undergone lung surgery e.g., lung transplant and/or lung volume reduction
  5. Had a chest X-ray indicating diagnosis other than COPD that might interfere with the study (chest X-ray to be taken at Visit 1, if subject has not had one and/or CT image taken within 3 months of Visit 1)
  6. Requires regular (daily) or long term oxygen therapy (LTOT). (LTOT is defined as ≥ 12 hours oxygen use per day)
  7. Has plan to start or to change the pulmonary rehabilitation program during the study period
  8. Requires regular treatment with oral, parenteral, or depot corticosteroids
  9. Has serious, uncontrolled disease likely to interfere with the study (e.g. Left Ventricular failure, anaemia, renal or hepatic disease or serious psychological disorders)
  10. Received any other investigational drugs within 4 weeks (or 5 half lives) prior to Visit 1
  11. Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse
  12. Has a known or suspected hypersensitivity to β2-agonists, steroids, anticholinergic treatments or any components of the formulations
  13. Has previously been enrolled to this study and investigational drugs has been administered
  14. Is not eligible to participate this study in the opinion of the investigator/subinvestigator

The investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study:

  1. ADOAIR DISKUS package insert
  2. Tiotropium/ HandiHaler package insert
  3. Salbutamol package insert
  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: NCT01762800

Locations
Japan
GSK Investigational Site
Fukuoka, Japan, 814-0180
GSK Investigational Site
Fukuoka, Japan, 816-0813
GSK Investigational Site
Hiroshima, Japan, 720-0001
GSK Investigational Site
Hiroshima, Japan, 734-8530
GSK Investigational Site
Hiroshima, Japan, 737-0023
GSK Investigational Site
Hiroshima, Japan, 737-0811
GSK Investigational Site
Hokkaido, Japan, 070-8644
GSK Investigational Site
Hyogo, Japan, 670-0849
GSK Investigational Site
Ibaraki, Japan, 300-0053
GSK Investigational Site
Ibaraki, Japan, 302-0022
GSK Investigational Site
Ibaraki, Japan, 309-1793
GSK Investigational Site
Ibaraki, Japan, 311-3193
GSK Investigational Site
Ibaraki, Japan, 319-1113
GSK Investigational Site
Kagawa, Japan, 760-0018
GSK Investigational Site
Kagawa, Japan, 760-8538
GSK Investigational Site
Kagawa, Japan, 761-8073
GSK Investigational Site
Kanagawa, Japan, 233-0013
GSK Investigational Site
Kanagawa, Japan, 253-0083
GSK Investigational Site
Kochi, Japan, 780-0901
GSK Investigational Site
Kyoto, Japan, 602-8026
GSK Investigational Site
Kyoto, Japan, 610-0113
GSK Investigational Site
Nara, Japan, 630-0293
GSK Investigational Site
Niigata, Japan, 950-1197
GSK Investigational Site
Niigata, Japan, 950-2085
GSK Investigational Site
Niigata, Japan, 950-8725
GSK Investigational Site
Okinawa, Japan, 901-2132
GSK Investigational Site
Okinawa, Japan, 904-2143
GSK Investigational Site
Okinawa, Japan, 904-2293
GSK Investigational Site
Osaka, Japan, 530-0001
GSK Investigational Site
Osaka, Japan, 559-0011
GSK Investigational Site
Osaka, Japan, 560-0005
GSK Investigational Site
Osaka, Japan, 560-8552
GSK Investigational Site
Saga, Japan, 840-8571
GSK Investigational Site
Shizuoka, Japan, 434-8511
GSK Investigational Site
Tokyo, Japan, 103-0027
GSK Investigational Site
Tokyo, Japan, 103-0028
GSK Investigational Site
Tokyo, Japan, 158-0083
GSK Investigational Site
Tokyo, Japan, 187-8510
GSK Investigational Site
Yamaguchi, Japan, 755-0241
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01762800     History of Changes
Other Study ID Numbers: 116717 
Study First Received: December 6, 2012
Results First Received: May 2, 2016
Last Updated: September 23, 2016
Health Authority: Japan: Ministry of Health, Labor and Welfare

Additional relevant MeSH terms:
Lung Diseases
Chronic Disease
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Lung Diseases, Obstructive
Fluticasone
Tiotropium Bromide
Fluticasone Propionate, Salmeterol Xinafoate Drug Combination
Salmeterol Xinafoate
Bromides
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Sympathomimetics

ClinicalTrials.gov processed this record on December 02, 2016