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

Sponsor:	Boehringer Ingelheim Pharmaceuticals
Collaborator:	Pfizer
Information provided by:	Boehringer Ingelheim Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00563381

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 IV

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:

MedlinePlus related topics: Antibiotics COPD (Chronic Obstructive Pulmonary Disease)

Drug Information available for: Salmeterol Salmeterol xinafoate Tiotropium bromide Tiotropium

U.S. FDA Resources

Further study details as provided by Boehringer Ingelheim Pharmaceuticals:

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:

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
All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial.
Male or female patients 40 years of age or older.
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.
Patients must be current or ex-smokers with a smoking history of >= 10 pack-years. (Patients who have never smoked cigarettes must be excluded.)
Patients must be able to perform all study-related procedures including technically acceptable pulmonary function tests (PFTs).
Patients must be able to inhale medication in a competent manner from the HandiHaler and a metered dose inhaler (MDI).
Patients must be able to maintain records (patient daily diary card) during the study period as required in the protocol.

Exclusion Criteria:

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.
Patients with a diagnosis of asthma.
Patients with a life-threatening pulmonary obstruction, or a history of cystic fibrosis.
Patients with known active tuberculosis.
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.
Patients with known narrow-angle glaucoma.
Patients with a history of myocardial infarction within the year prior to Visit 1.
Patients with a history of hospital admission for heart failure within the year prior to Visit 1.
Patients with cardiac arrhythmia requiring medical or surgical treatment.
Patients with severe cardiovascular disorders.
Patients with a known hypersensitivity to anticholinergic drugs, beta-adrenergics, lactose or any other component of the medication delivery system.
Patients with known moderate or severe renal insufficiency (known creatinine clearance of <= 50 mL/min).
Patients with untreated known hypokalaemia.
Patients with untreated known thyrotoxicosis.
Patients with brittle/unstable diabetes mellitus.
Patients with a history of and/or active significant alcohol or drug abuse. See exclusion criterion 1.
Patients who have taken an investigational drug within 30 days or six half-lives (whichever is greater) prior to Screening Visit (Visit 1).
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.
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.
Previous participation (receipt of randomised treatment) in this study.
Patients who are currently participating in another study.
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00563381

Show 752 Study Locations

Sponsors and Collaborators

Boehringer Ingelheim Pharmaceuticals

Pfizer

Investigators

Study Chair:

Boehringer Ingelheim

Boehringer Ingelheim Pharmaceuticals

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

No publications provided by Boehringer Ingelheim Pharmaceuticals

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri LM; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011 Mar 24;364(12):1093-103.

Beeh KM, Hederer B, Glaab T, Müller A, Rutten-van Moelken M, Kesten S, Vogelmeier C. Study design considerations in a large COPD trial comparing effects of tiotropium with salmeterol on exacerbations. Int J Chron Obstruct Pulmon Dis. 2009;4:119-25. Epub 2009 Apr 15.

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:	August 11, 2011
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:

Chronic Disease
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Pathologic Processes
Respiratory Tract Diseases
Lung Diseases, Obstructive
Bromides
Salmeterol
Tiotropium
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions

Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents

ClinicalTrials.gov processed this record on February 09, 2012