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

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00563381
First received: November 22, 2007
Last updated: November 27, 2013
Last verified: July 2012
  Purpose

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.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: Tiotropium bromide
Drug: Salmeterol
Drug: Placebo Salmeterol
Drug: Placebo Tiotropium
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: 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).

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • First Occurrence of (Moderate or Severe) COPD Exacerbation [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • COPD Exacerbations Per Patient-year Leading to Hospitalisation [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • First Occurrence of COPD Exacerbation Leading to Hospitalization [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • First Occurrence of COPD Exacerbation or Discontinuation of Trial Medication Because of Worsening of Underlying Disease, Whichever Comes First [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    PEFR means peak expiratory flow rate and is measured in liter per minute


Enrollment: 7376
Study Start Date: January 2008
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tiotropium + Placebo
patients inhale Tiotropium 18mcg once daily via HandiHaler and Placebo MDI twice daily
Drug: Tiotropium bromide
18 mcg/daily
Drug: Placebo Salmeterol
Placebo identical to Salmeterol device
Active Comparator: Salmeterol + Placebo
patients inhale Salmeterol 50mcg twice daily via MDI and Placebo HandiHaler once daily
Drug: Salmeterol
100 mcg/daily
Drug: Placebo Tiotropium
Placebo identical to Tiotropium device

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  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: NCT00563381

  Show 752 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Pfizer
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided by Boehringer Ingelheim

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00563381     History of Changes
Other Study ID Numbers: 205.389, EUDRACT2007-001840-33
Study First Received: November 22, 2007
Results First Received: March 29, 2011
Last Updated: November 27, 2013
Health Authority: Austria: AGES, Oesterreichische Agentur für Gesundheit und Ernaehrungssicherheit
Belgium: AFMPS - Agence Fédérale des Médicaments et des Produits des Santé
Bulgaria: Bulgarian Drug Agency
Czech Republic: State Institute for Drug Control
Denmark: The Danish Medicines Agency
Finland: Finnish Medicines Agency
France: AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé)
Germany: BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte)
Great Britain: Medicines and Heathcare Products Regulatory Agency
Hungary: ORSZÁGOS GYÓGYSZERÉSZETI INTÉZET
Israel: not applicable
Italy: COMITATO ETICO DELLA PROVINCIA DI FERRARA
Latvia: State Agency of Medicines
Lithuania: Lithuanian Bioethics Committee
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Norway: Norwegian Medicines Agency
Poland: Agency for Registration of Medicinal Products, Medical Devices & Biocides
Portugal: INFARMED - Instituto Nacional da Farmácia e do Medicamento
Romania: National Medicines Agency
Russia: Federal Service On Surveillance In Healthcare And Social Development Of Russian Federation
Slovakia: State Institute for Drug Control
Slovenia: Agency for Medicinal Products and Medical Devices of the Republic of Slovenia
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Turkey: Ministery Of Health / Central Ethics Committee
Ukraine: The State Pharmacological Center of Ministry of Health of Ukraine
United States: Food and Drug Administration

Additional relevant MeSH terms:
Lung Diseases
Chronic Disease
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Lung Diseases, Obstructive
Tiotropium
Salmeterol
Albuterol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Tocolytic Agents
Reproductive Control Agents

ClinicalTrials.gov processed this record on September 18, 2014