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Comparison of Tiotropium in the HandiHaler Versus the Respimat in Chronic Obstructive Pulmonary Disease

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01126437
First received: May 6, 2010
Last updated: May 20, 2014
Last verified: May 2014
  Purpose

Direct comparison studies of the tiotropium HandiHaler® 18 µg and Respimat® 5 µg formulations have been limited to 4-week crossover studies. Therefore, prospective data from a trial of adequate size and duration is required to establish that compared to tiotropium HandiHaler®, tiotropium Respimat® will have (a) similar effects on safety and (b) similar or superior effects on exacerbations.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: tiotropium 18 mcg
Drug: tiotropium 1.25 mcg (2 actuations/day)
Drug: tiotropium 2.5 mcg (2 actuations/day)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Randomized, Active-controlled, Double-blind, Double-dummy, Parallel Group Design, Multi-center Trial to Compare the Efficacy and Safety of 2.5 µg and 5 µg Tiotropium Inhalation Solution Delivered by the Respimat Inhaler With Tiotropium Inhalation Capsules 18 µg Delivered by the HandiHaler (TIOSPIR)

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Time to All-Cause Mortality [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Number of patients with all-cause mortality

  • Time to First COPD Exacerbation [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

    Defined as "a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment" where a "complex of lower respiratory event/symptoms" was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where "a required change in treatment" includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).

    "Onset of exacerbation" was defined by the onset of first recorded symptom. The "end of exacerbation" was decided by the investigator based on clinical judgement.

    Exacerbations were classified as follows:

    Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization.



Secondary Outcome Measures:
  • Trough FEV1 Over 120 Weeks (in a Substudy of 1370 Patients) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Trough forced expiratory volume in one second (FEV1) over 120 weeks (in a substudy of 1370 patients)

  • Number of COPD Exacerbations [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The number of COPD exacerbations. COPD exacerbation defined as "a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment" where a "complex of lower respiratory event/symptoms" was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where "a required change in treatment" includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).

  • Time to First Hospitalization Associated With COPD Exacerbation [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The results presented below are for the patients with hospitalizations due to COPD exacerbations.

  • Number of Hospitalizations Associated With COPD Exacerbation [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Total number of hospitalizations associated with COPD exacerbation.

  • Time to First Moderate to Severe COPD Exacerbation [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

    COPD exacerbation defined as "a complex of lower respiratory events/symptoms (increase of new onset) related to the underlying COPD, with duration of three days or more, requiring a change in treatment" where a "complex of lower respiratory event/symptoms" was defined as having at least two of the following: shortness of breath, sputum production (volume), occurrence of purulent sputum, cough, wheezing, chest tightness and where "a required change in treatment" includes the following:Prescription of antibiotics and/or systemic steroids, and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines).

    Exacerbations classified as follows:

    Mild:a new prescription of maintenance bronchodilator only Moderate:antibiotics or systemic steroids without hospitalization Severe:hospitalization.

    Results presented below are number of patients with moderate to severe exacerbations.


  • Time to Onset of First Major Adverse Cardiovascular Event (MACE) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Time to onset of first major adverse cardiovascular event (MACE). MACE was defined as: Fatal event in the system organ classes of cardiac and vascular disorders, Preferred terms: sudden death, cardiac death, sudden cardiac death, Outcome events of myocardial infarction (serious and non-serious), Outcome events of stroke (serious and non-serious) and Outcome events of TIA (serious and non-serious). The results presented below are for the number of patients with MACE.

  • Time to Death From Major Adverse Cardiovascular Event (MACE) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The results presented below are number of patients with death from MACE.


Enrollment: 17183
Study Start Date: May 2010
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: tiotropium 2.5 mcg and placebo
Patients receive one of the active tiotropium arms daily
Drug: tiotropium 1.25 mcg (2 actuations/day)
soft mist inhaler 2 actuations=2 puffs/day
Active Comparator: tiotropium 18 mcg and placebo
Patients receive one of the active tiotropium arms daily
Drug: tiotropium 18 mcg
HandiHaler
Experimental: tiotropium 5 mcg and placebo
Patients receive one of the active tiotropium arms daily
Drug: tiotropium 2.5 mcg (2 actuations/day)
soft mist inhaler (2 actuations=2 puffs/day)

  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 sign an informed consent consistent with International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions.
  2. Male or female patients 40 years of age or older.
  3. Patients must be current or ex-smokers with a smoking history of ≥10 pack-years. (Patients who have never smoked cigarettes must be excluded)
  4. All patients must have a diagnosis of COPD (P06-12085), and must meet the following criteria: Relatively stable airway obstruction with a post-bronchodilator FEV1 ≤ 70% of predicted normal and post-bronchodilator FEV1 / FVC ≤70%.

    Pulmonary function tests (PFTs) were conducted after the inhalation of 400 μg salbutamol / albuterol (preferred), however testing with either 200 μg salbutamol/albuterol or a combination of salbutamol / albuterol with ipratropium bromide (2 to 4 actuations) was acceptable. Other short-acting beta agonists, such as terbutaline, may have been used for the testing. The medication used for the testing was documented. Further, historical data from measurements within the past 6 months either at the site or at a referral site may have been used (see Section 6.2.1 of the CTP, located in Appendix 16.1.1). Subjects were not to have been randomized to the study without the availability of spirometry data at the actual study site.

    Eligibility for PFT sub-study: For subjects participating in the spirometry sub-study, historical data may not have been used for inclusion. These subjects must have qualified in the clinic at Visit 1 after performing a baseline measurement. These subjects performed a pre-dose PFT which was followed by the administration of 400 μg salbutamol / albuterol only (no other short-acting beta agonist was allowed), followed by a post-dose PFT for qualification.

  5. Able to inhale from the HandiHaler® and the Respimat® devices.

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 the patients ability to participate in the study.
  2. Patients with a recent history (i.e., six months or less) of myocardial infarction.
  3. Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the last year.
  4. Hospitalisation for cardiac failure (New York Heart Association (NYHA) Class III or IV) during the past year.
  5. Known active tuberculosis.
  6. Patients with a history of asthma, cystic fibrosis, clinically evident bronchiectasis, interstitial lung disease, or pulmonary thromboembolic disease.
  7. History of thoracotomy with pulmonary resection. Subjects with a history of thoracotomy for other reasons were to have been evaluated per exclusion criterion 1.
  8. Subject was planning to undergo lung transplant or lung volume reduction surgery (LVRS).
  9. Malignancy for which the subject had undergone resection, radiation, chemotherapy or biological treatments within the last 5 years. Subjects with treated basal cell carcinoma were allowed.
  10. Known respiratory infection or exacerbation of COPD in the 4 weeks prior to randomization.
  11. Known hypersensitivity to anticholinergic drugs, lactose, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the HandiHaler® or Respimat® inhalation solution delivery system.
  12. Known moderate to severe renal impairment (as judged by the investigator).
  13. Known narrow angle glaucoma.
  14. Known significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Subjects whose symptoms were controlled on treatment may have been included.
  15. Use of systemic corticosteroid medication at unstable doses (i.e., less than 6 weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day.
  16. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception for at least 3 months prior to and for the duration of the trial.
  17. Significant alcohol or drug abuse within the past 12 months.
  18. Subjects requiring the use of supplemental oxygen therapy for > 12 hours per day.
  19. Subjects who had completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit or subjects who were currently in a pulmonary rehabilitation program that was not maintained throughout the duration of the study.
  20. Subjects who had taken an investigational drug within 30 days prior to the Screening Visit.
  21. Previous participation (receipt of randomized treatment) in this study.
  22. Subjects who were currently participating in an interventional study.
  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: NCT01126437

  Show 1191 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
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
ClinicalTrials.gov Identifier: NCT01126437     History of Changes
Other Study ID Numbers: 205.452, 2009-015713-51
Study First Received: May 6, 2010
Results First Received: May 20, 2014
Last Updated: May 20, 2014
Health Authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia Medica
Australia: Dept of Health and Ageing Therapeutic Goods Admin
Austria: Medicines and Medical Devices Agency
Belgium: Federal Agency for Medicinal and Health Products
Brazil: National Health Surveillance Agency
Bulgaria: Bulgarian Drug Agency
Canada: Health Canada
China: Food and Drug Administration
Columbia: Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Croatia: Agency for Medicinal Product and Medical Devices
Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Georgia: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
Greece: Ethics Committee
Guatemala: Ministry of Public Health and Social Assistance
Hungary: National Institute of Pharmacy
India: Drugs Controller General of India
Ireland: Irish Medicines Board
Israel: Israeli Health Ministry Pharmaceutical Administration
Italy: Ethics Committee
Latvia: State Agency of Medicines
Lithuania: State Medicine Control Agency - Ministry of Health
Malaysia: Ministry of Health
Mexico: Federal Commission for Sanitary Risks Protection
Netherlands: Central Committee Research Involving Human Subjects
New Zealand: Multi-Regional Ethics Committee
Norway: Norwegian Medicines Agency
Panama: Ministry of Health
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
Philippines: Bureau of Food and Drugs
Poland: Registration Medicinal Product Medical Device Biocidal Product
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Russia: Pharmacological Committee, Ministry of Health
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
South Korea: Ministry of Food and Drug Safety (MFDS)
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Switzerland: Swissmedic
Taiwan: Department of Health
Thailand: Food and Drug Administration
Tunisia: Ministry of Public Health
Turkey: Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Additional relevant MeSH terms:
Chronic Disease
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Disease Attributes
Pathologic Processes
Respiratory Tract Diseases
Tiotropium
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

ClinicalTrials.gov processed this record on August 28, 2014