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Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.

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ClinicalTrials.gov Identifier: NCT00563381
Recruitment Status : Completed
First Posted : November 26, 2007
Results First Posted : May 17, 2011
Last Update Posted : December 24, 2013
Sponsor:
Collaborator:
Pfizer
Information provided by:
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE November 22, 2007
First Posted Date  ICMJE November 26, 2007
Results First Submitted Date  ICMJE March 29, 2011
Results First Posted Date  ICMJE May 17, 2011
Last Update Posted Date December 24, 2013
Study Start Date  ICMJE January 2008
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2011)
First Occurrence of (Moderate or Severe) COPD Exacerbation [ Time Frame: 52 weeks ]
First occurrence analysed by Cox regression as time to first exacerbation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
Original Primary Outcome Measures  ICMJE
 (submitted: November 23, 2007)
The primary endpoint is the time to first COPD exacerbation.
Change History Complete list of historical versions of study NCT00563381 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2011)
  • COPD Exacerbations Per Patient-year Leading to Hospitalisation [ Time Frame: 52 weeks ]
    An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • Number of Participants With at Least One COPD Exacerbation [ Time Frame: 52 weeks ]
    An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • COPD Exacerbations Per Patient-year [ Time Frame: 52 weeks ]
  • First Occurrence of COPD Exacerbation Leading to Hospitalization [ Time Frame: 52 weeks ]
    First occurrence analysed by Cox regression as time to first exacerbation leading to hospitalisation and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • Number of Participants With at Least One COPD Exacerbation Leading to Hospitalisation [ Time Frame: 52 weeks ]
    An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • Occurrence of Premature Discontinuation of Trial Medication [ Time Frame: 52 weeks ]
    Occurrence analysed by Cox regression as time to premature discontinuation of trial medication and reported as hazard ratio
  • Number of Participants With Premature Discontinuation of Trial Medication [ Time Frame: 52 weeks ]
  • First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First [ Time Frame: 52 weeks ]
    First occurrence analysed by Cox regression as time to first exacerbation or discontinuation of trial medication because of worsening of underlying disease, whichever comes first and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • First Occurrence of COPD Exacerbations Treated With Systemic Steroids [ Time Frame: 52 weeks ]
    First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • First Occurrence of COPD Exacerbations Treated With Antibiotics [ Time Frame: 52 weeks ]
    First occurrence analysed by Cox regression as time to first exacerbation treated with antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • First Occurrence of COPD Exacerbations Treated With Systemic Steroids and Antibiotics [ Time Frame: 52 weeks ]
    First occurrence analysed by Cox regression as time to first exacerbation treated with systemic steroids and antibiotics and reported as hazard ratio. An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • COPD Exacerbations Treated With Systemic Steroids Per Patient-year [ Time Frame: 52 weeks ]
    An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • COPD Exacerbations Treated With Antibiotics Per Patient-year [ Time Frame: 52 weeks ]
    An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • COPD Exacerbations Treated With Systemic Steroids and Antibiotics Per Patient-year [ Time Frame: 52 weeks ]
    An exacerbation was defined as an increase or new onset of more than 1 symptom (cough, sputum, wheezing, dyspnoea, chest tightness), with at least 1 symptom lasting at least 3 days and requiring treatment with systemic steroids and/or antibiotics (moderate exacerbation) or hospitalisation (severe exacerbation).
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 1 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 2 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 3 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 4 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 5 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 6 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 7 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 8 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 9 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 10 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 11 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 12 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 13 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 14 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 15 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
  • Pre-dose Morning PEFR Measured by Patients at Home During the First Four Months of Randomised Treatment (Weekly Means Will be Calculated), Week 16 [ Time Frame: 16 weeks ]
    PEFR means peak expiratory flow rate and is measured in liter per minute
Original Secondary Outcome Measures  ICMJE
 (submitted: November 23, 2007)
  • Occurrence of at least one exacerbation
  • Number of COPD exacerbations
  • Time to first hospitalisation due to COPD exacerbation
  • Number of hospitalisations due to COPD exacerbations
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients.
Official Title  ICMJE Effect of Inhalation of Tiotropium Once Daily 18 Mcg Versus Salmeterol Twice Daily 50 Mcg on Time to First Exacerbation in COPD Patients (a Randomised, Double-blind, Double-dummy, Parallel Group, One-year Study).
Brief Summary

This is a randomised, double-blind, double-dummy, multinational, multicentre, parallel group trial comparing tiotropium (18 mcg) inhalation capsule via HandiHaler and salmeterol (50 mcg) via MDI in patients with COPD. There will be a two-week run-in period followed by a 52-week randomised treatment phase. Patients who withdraw prematurely from trial medication will be encouraged to remain in the trial and participate in follow-up telephone contacts until their predicted normal exit date from the trial (i.e. 52 weeks after taking the first dose of randomised treatment). The phone calls will be made at all scheduled visits.

The primary objective of this study is to compare the effect of tiotropium (18 mcg) inhalation capsule via HandiHaler with that of salmeterol (50 mcg) via MDI on COPD exacerbations.

The primary endpoint is time to first COPD exacerbation during the 52 week randomised treatment period. A COPD exacerbation will be defined as a complex of respiratory events / symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnoea or chest tightness with at least one symptom lasting at least three days requiring treatment with antibiotics and/or systemic steroids and/or hospitalisation.

The onset of an exacerbation is defined as the onset of the first new or increased reported symptom. The end of the exacerbation should be recorded as defined by the investigator.

Only COPD exacerbations with onset during randomised treatment will be included in the analysis.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Disease, Chronic Obstructive
Intervention  ICMJE
  • Drug: Tiotropium bromide
    18 mcg/daily
  • Drug: Salmeterol
    100 mcg/daily
  • Drug: Placebo Salmeterol
    Placebo identical to Salmeterol device
  • Drug: Placebo Tiotropium
    Placebo identical to Tiotropium device
Study Arms  ICMJE
  • Active Comparator: Tiotropium + Placebo
    patients inhale Tiotropium 18mcg once daily via HandiHaler and Placebo MDI twice daily
    Interventions:
    • Drug: Tiotropium bromide
    • Drug: Placebo Salmeterol
  • Active Comparator: Salmeterol + Placebo
    patients inhale Salmeterol 50mcg twice daily via MDI and Placebo HandiHaler once daily
    Interventions:
    • Drug: Salmeterol
    • Drug: Placebo Tiotropium
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 14, 2010)
7376
Original Enrollment  ICMJE
 (submitted: November 23, 2007)
6800
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. All patients must have a diagnosis of chronic obstructive pulmonary disease (COPD) and must meet the following criteria at Visit 1:

    Patients must have relatively stable, moderate to very severe airway obstruction with a post-bronchodilator FEV1 <=70% of predicted normal and FEV1 <=70% of FVC post-bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 µg salbutamol or equivalent SABA). Predicted normal values will be calculated according to ECSC.

    For Height measured in inches Males: FEV1 predicted (L) = 4.30 x (height (inches) / 39.37)-0.029 x age (yrs) - 2.49 Females:FEV1 predicted (L) = 3.95 x (height (inches) / 39.37)-0.025 x age (yrs) - 2.60 For Height measured in metres Males: FEV1 predicted (L) = 4.30 x (height (metres)) - 0.029 x age (years) - 2.49 Females: FEV1 predicted (L) = 3.95 x (height (metres)) - 0.025 x age (years) - 2.60

  2. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial.
  3. Male or female patients 40 years of age or older.
  4. Patients with a history of at least one exacerbation within the past year requiring treatment with either antibiotics and/or systemic steroids and/or hospitalisation.
  5. Patients must be current or ex-smokers with a smoking history of >= 10 pack-years. (Patients who have never smoked cigarettes must be excluded.)
  6. Patients must be able to perform all study-related procedures including technically acceptable pulmonary function tests (PFTs).
  7. Patients must be able to inhale medication in a competent manner from the HandiHaler and a metered dose inhaler (MDI).
  8. Patients must be able to maintain records (patient daily diary card) during the study period as required in the protocol.

Exclusion Criteria:

  1. Significant diseases other than COPD. A significant disease is defined as a disease or condition which, in the opinion of the investigator, may put the patient at risk because of participation in the study or may influence either the results of the study or the patients' ability to participate in the study.
  2. Patients with a diagnosis of asthma.
  3. Patients with a life-threatening pulmonary obstruction, or a history of cystic fibrosis.
  4. Patients with known active tuberculosis.
  5. Patients with a known symptomatic prostatic hyperplasia or bladder neck obstruction. Patients with symptomatically-controlled prostatic hyperplasia on medication may be included and should continue their medication.
  6. Patients with known narrow-angle glaucoma.
  7. Patients with a history of myocardial infarction within the year prior to Visit 1.
  8. Patients with a history of hospital admission for heart failure within the year prior to Visit 1.
  9. Patients with cardiac arrhythmia requiring medical or surgical treatment.
  10. Patients with severe cardiovascular disorders.
  11. Patients with a known hypersensitivity to anticholinergic drugs, beta-adrenergics, lactose or any other component of the medication delivery system.
  12. Patients with known moderate or severe renal insufficiency (known creatinine clearance of <= 50 mL/min).
  13. Patients with untreated known hypokalaemia.
  14. Patients with untreated known thyrotoxicosis.
  15. Patients with brittle/unstable diabetes mellitus.
  16. Patients with a history of and/or active significant alcohol or drug abuse. See exclusion criterion 1.
  17. Patients who have taken an investigational drug within 30 days or six half-lives (whichever is greater) prior to Screening Visit (Visit 1).
  18. Use of systemic corticosteroid medication at unstable doses (i.e less than six weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day or 20 mg every other day.
  19. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (i.e oral contraceptives, intrauterine devices, diaphragm or subdermal implants e.g Norplant) for at least three months prior to, and for the duration of the trial.
  20. Previous participation (receipt of randomised treatment) in this study.
  21. Patients who are currently participating in another study.
  22. Patients with any respiratory infection or COPD exacerbation in the four weeks prior to the Screening Visit (Visit 1) or during the run-in period should be postponed. In the case of a respiratory infection or COPD exacerbation during the run-in period, the latter may be extended up to four weeks.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Belgium,   Bulgaria,   Czech Republic,   Denmark,   Finland,   France,   Germany,   Hungary,   Israel,   Italy,   Latvia,   Lithuania,   Netherlands,   Norway,   Poland,   Portugal,   Romania,   Russian Federation,   Slovakia,   Slovenia,   Spain,   Turkey,   Ukraine,   United Kingdom
Removed Location Countries Greece
 
Administrative Information
NCT Number  ICMJE NCT00563381
Other Study ID Numbers  ICMJE 205.389
EUDRACT2007-001840-33
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date July 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP