Evaluation of the Long- Term Effects of Spiriva on Lung Function in COPD Patients

Study Overview
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Brief Summary
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The primary objective of this trial is to determine whether daily treatment with tiotropium (Spiriva®, Bromuro de Tiotropio®) inhalation capsule via HandiHaler® reduces the rate of decline in lung function over time in patients with COPD.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group Trial Assessing the Rate of Decline of Lung Function With Tiotropium 18 mcg Inhalation Capsule Once Daily in Patients With Chronic Obstructive Pulmonary Disease (COPD).

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: tiotropium
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Male or female patients 40 years of age or older. Smoking history of at least 10 pack years. Diagnosis of COPD with post bronchodilator FEV1 less than or equal to 70% of predicted normal and FEV1<70% of FVC and on stable respiratory medication. Exclusion Criteria: Significant diseases other than COPD which in the opinion of the investigator may put the patient at risk or influence the patients ability to participate. Myocardial infarction in past 6 months. Unstable or life threatening arrhythmia in past year. Hospitalization for NYHA heart failure class III or IV in past year. Active tuberculosis. Asthma. Pulmonary resection. Malignancy treated with radiation or chemotherapy in past 5 years. Respiratory infection in 4 weeks prior to screening. Known hypersensitivity to anticholinergic drugs or components. Known moderate to severe renal impairment. Known narrow angle glaucoma. Significant symptomatic BPH or bladder neck obstruction. Need for oxygen therapy >12 hr/day. Use of oral corticosteroids at unstable doses or >10 mg/day.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: tiotropium|nan|
|Drug: placebo|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years | Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1. | From day 30 to 4 years | 
| Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years | Rate of decline of forced expiratory volume in one second (FEV1) measured after bronchodilation. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1. | From day 30 to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment | Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1 | Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days. | 
| Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment | Rate of decline of forced expiratory volume in one second (FEV1) measured after the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1 | Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days | 
| Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years | Rate of decline of forced vital capacity (FVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC | From day 30 to 4 years | 
| Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years | Rate of decline of forced vital capacity (FVC) measured after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC | From day 30 to 4 years | 
| Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years | Rate of decline of slow vital capacity (SVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC | From day 30 to 4 years | 
| Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years | Rate of decline of slow vital capacity (SVC) measured after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC | From day 30 to 4 years | 
| Rate of Decline of St George's Respiratory Questionnaire (SGRQ) Total Score | SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health). | From month 6 to 4 years | 
| Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment | Rate of decline of forced vital capacity (FVC) before bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC | Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days. | 
| Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment | Rate of decline of forced vital capacity (FVC) after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC | Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days | 
| Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment | Rate of decline slow vital capacity (SVC) before bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC | Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days | 
| Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment | Rate of decline of slow vital capacity (SVC) after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC | Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days | 
| Time to First Exacerbation | Chronic obstructive pulmonary disease (COPD) exacerbation | From Day 1 to 4 years | 
| Number of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Patient Year |  | Day 1 to 4 years | 
| Number and Percentage of Patients With at Least One Chronic Obstructive Pulmonary Disease (COPD) Exacerbation |  | Day 1 to 4 years | 
| Number of Exacerbation Days Per Patient Year | Number of exacerbation days normalized by treatment exposure | Day 1 to 4 years | 
| Time to First COPD Exacerbation Leading to Hospitalization (for 25% Patients) |  | Day 1 to 4 years | 
| Number and Percentage of Patients With at Least on COPD Exacerbation Leading to Hospitalization |  | From Day 1 to 4 years | 
| Number of Exacerbation Leading to Hospitalization | Estimated number of exacerbations leading to hospitalizations per patient year | From Day 1 to 4 years | 
| Days of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization | Number of days with chronic obstructive pulmonary disease (COPD) exacerbation leading to hospitalization (normalized by treatment exposure) | From Day 1 to 4 years | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1 | Estimated FEV1 before bronchodilator at Month 1 | Month 1 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1 | Estimated forced expiratory volume in one second (FEV1) after bronchodilator at month 1 | Month 1 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6 | Estimated forced expiratory volume in one second (FEV1) before bronchodilator at month 6 | Month 6 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6 |  | Month 6 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12 |  | Month 12 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12 |  | Month 12 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18 |  | Month 18 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18 |  | Month 18 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24 |  | Month 24 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24 |  | Month 24 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30 |  | Month 30 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30 |  | Month 30 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36 |  | Month 36 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36 |  | Month 36 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42 |  | Month 42 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42 | Estimated FEV1 after bronchodilator at Month 42 | Month 42 | 
| Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48 |  | Month 48 | 
| Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48 |  | Month 48 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 1 |  | Month 1 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 1 |  | Month 1 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 6 |  | Month 6 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 6 |  | Month 6 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 12 |  | Month 12 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 12 |  | Month 12 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 18 |  | Month 18 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 18 |  | Month 18 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 24 |  | Month 24 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 24 |  | Month 24 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 30 |  | Month 30 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 30 |  | Month 30 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 36 |  | Month 36 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 36 |  | Month 36 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 42 |  | Month 42 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 42 |  | Month 42 | 
| Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 48 |  | Month 48 | 
| Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 48 |  | Month 48 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 1 |  | Month 1 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 1 |  | Month 1 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 6 |  | Month 6 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 6 |  | Month 6 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 12 |  | Month 12 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 12 |  | Month 12 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 18 |  | Month 18 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 18 |  | Month 18 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 24 |  | Month 24 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 24 |  | Month 24 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 30 |  | Month 30 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 30 |  | Month 30 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 36 |  | Month 36 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 36 |  | Month 36 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 42 |  | Month 42 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 42 |  | Month 42 | 
| Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 48 |  | Month 48 | 
| Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 48 |  | Month 48 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 6 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 6 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 12 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 12 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 18 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 18 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 24 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 24 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 30 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 30 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 36 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 36 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 42 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 42 | 
| Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 48 | SGRQ total score summarizes the impact of COPD on overall patient's health status. Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. The scale is continuous. Rate of decline shows the yearly change of SGRQ total score. | Month 48 | 
| Number and Percentage of Participants With All Cause Death and Time to Event Analysis (On-treatment) | On-treatment defined as day 1 to completion of double blinded treatment plus 30 days | Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days | 
| Number and Percentage of Participants With All Cause Death (Including Vital Status Follow-up, Cutoff at 1470 Days) | All cause mortality vital status information was followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used. | Day 1 to day 1470 | 
| Number and Percentage of Participants With Lower Respiratory Death (On-treatment; Adjudicated Primary Cause) | The primary cause of death was adjudicated by an external committee prior to unblinding; on-treatment defined as day 1 to completion of double blinded treatment plus 30 days | Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days | 
| Number and Percentage of Participants With a Lower Respiratory Death (Adjudicated; Including Vital Status Follow-up, Cutoff at 1470 Days) | The primary cause of death was adjudicated by an external committee prior to unblinding; vital status was information followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used | Day 1 to day 1470 |