Efficacy and Safety of Tiotropium Compared to Salmeterol and Placebo in Patients With Chronic Obstructive Bronchitis (COPD)

A Multiple Dose Comparison of Tiotropium Inhalation Capsules, Salmeterol Inhalation Aerosol and Placebo in a Six-Month, Double-Blind, Double-Dummy, Safety and Efficacy Study in Patients With Chronic Obstructive Pulmonary Disease (COPD)

The objective of this study is to compare the long-term (six month) bronchodilator efficacy and safety of tiotropium inhalation capsules, salmeterol inhalation aerosol and placebo inpatients with COPD.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Tiotropium inhalation powder capsules; Drug: Placebo inhalation aerosol; Drug: Salmeterol inhalation aerosol; Drug: Placebo inhalation powder capsules

• Study Type: Interventional
• Enrollment (Actual): 584
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 40 years.

• A diagnosis of relatively stable, moderate to severe COPD with:

  • Screening FEV1 ≤ 60% of predicted normal value (calculated according to European Community for Coal and Steel (ECCS) criteria and screening FEV1/FVC ≤ 70%
• Smoking history ≥ 10 pack-years (a pack-year is 20 cigarettes per day for one year or equivalent)
• Ability to be trained in the proper use of the HandiHaler® device and Metered Dose Inhaler (MDI).
• Ability to perform all study related tests including the Shuttle Walking Test, acceptable pulmonary function tests, including Peak expiratory flow rate (PEFR) measurements, and maintenance of diary card records.
• Ability to give written informed consent in accordance with Good Clinical Practice and local regulations.

Exclusion Criteria:

• Clinically significant diseases other than COPD.
• Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis, if the abnormality defines a disease listed as an exclusion criterion, will be excluded.
• All patients with a serum glutamic oxaloacetic transaminase (SGOT) > 80 IU/L, serum glutamic pyruvic transaminase (SGPT) > 80 IU/L, bilirubin >2.0 mg/dL or creatinine > 2.0 mg/dL will be excluded regardless of clinical condition.
• A recent history (i.e., one year or less) of myocardial infarction.
• Any cardiac arrhythmia requiring drug therapy or hospitalisation for heart failure within the past three years.
• Inability to abstain from regular daytime use of oxygen therapy for more than 1 hour per day.
• Known active tuberculosis.
• History of cancer within the last five years (excluding basal cell carcinoma)
• History of life-threatening pulmonary obstruction, or a history of cystic fibrosis or bronchiectasis.
• Patients who have undergone thoracotomy with pulmonary resection.
• Any upper respiratory infection in the past six weeks prior to the screening visit or during the run-in period.
• Current participation in a pulmonary rehabilitation programme or completion of a pulmonary rehabilitation programme in the six week prior to the screening visit.
• Known hypersensitivity to anticholinergic drugs, salmeterol, or any of the components of the lactose powder capsule or MDI delivery systems.
• Known symptomatic prostatic hypertrophy or bladder neck obstruction.
• Patients with known narrow-angle glaucoma.
• Current treatment with cromolyn sodium or nedocromil sodium.
• Current treatment with antihistamines (H1 receptor antagonists).
• Oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisolone per day or 20 mg every other day.
• Current use of β-blocker medication.
• Current treatment with monoamine oxidase inhibitors or tricyclic antidepressants.
• Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception.
• Patients with a history of asthma, allergic rhinitis or atopy or who have a total blood eosinophil count > 600mm3.
• History of and/or active significant alcohol or drug abuse.
• Concomitant or recent use of an investigational drug within one month or six half lives (whichever is greater) prior to the screening visit.
• Changes in the pulmonary therapeutic plan within the six weeks prior to the screening visit.
• Inability to comply with the medication restrictions specified in Section 4.2 of the trial protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo inhalation aerosol; Drug: Placebo inhalation powder capsules
Active Comparator: Salmeterol	Drug: Salmeterol inhalation aerosol; Drug: Placebo inhalation powder capsules
Experimental: Tiotropium	Drug: Tiotropium inhalation powder capsules; Drug: Placebo inhalation aerosol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Trough forced expiratory volume in one second (FEV1) response	6 months
Transition Dyspnoea Index (TDI) focal score	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average FEV1 response		30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24
Peak FEV1 response		30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24
Trough FVC (forced vital capacity) response		30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24
Average FVC (forced vital capacity) response		30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24
Peak FVC (forced vital capacity) response		30 and 60 min prior to and 30 and 60 min, 2 and 3 h post treatment on day 1, week 2, 8, 16, 24
Individual FEV1 measurement		Day 1, weeks 2, 8, 16, 24
Individual FVC measurement		Day 1, weeks 2, 8, 16, 24
Patient peak expiratory flow rates (PEFR) twice daily		27 weeks
Physician's global evaluation on an 8-point-scale		27 weeks
COPD symptom scores (wheezing, shortness of breath, coughing and tightness of chest)		27 weeks
Amount of salbutamol therapy used during the treatment period		27 weeks
Number and length of exacerbations of COPD		27 weeks
Number and length of hospitalizations for respiratory disease		27 weeks
Changes from baseline in St. George's Hospital Respiratory Questionnaire (SGRQ)		Day 1, week 8, 16, 24 and 27
Changes from baseline in Mahler Dyspnoea Index (Baseline Dyspnoea Index /Transitional Dyspnoea Index (BDI/TDI))		Baseline, week 8, 16, 24, 27
Health resource utilisation		27 weeks
Patient preference measures	patient satisfaction questionnaire score	Day 1 and week 24
Changes from baseline in Shuttle walking tests (SWT) and Borg dyspnea score		Day 1, week 8, 16, 24, 27
Occurrence of Adverse Events		27 weeks
Changes from baseline in pulse rate and blood pressure in conjunction with spirometry		baseline, Day 1, week 2, 8, 16 and 24
Changes from baseline in physical examination and ECG		baseline and week 24
Changes from baseline in laboratory tests		baseline and week 24

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 1999
• Primary Completion (Actual): May 1, 2000
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: June 20, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimate): June 25, 2014

Study Record Updates

• Last Update Posted (Estimate): June 26, 2014
• Last Update Submitted That Met QC Criteria: June 25, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Salmeterol Xinafoate; Tiotropium Bromide
• Other Study ID Numbers: 205.137

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No