Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The aim of the study is to investigate whether the early introduction of maintenance bronchodilator therapy during an acute symptomatic episode of the disease shows benefits on the recovery of symptoms. It also represents an opportunity to identify COPD patients earlier in their disease state and start maintenance therapy, if appropriate.
Interventions
DRUGtiotropium
18mcg
DRUGPlacebo
placebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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 and conducting any study procedures. 2. Male or female patients 40 years of age or older. 3. Ability to independently read and understand English and/or Spanish. 4. Any self-reported history of smoking (e.g. = 100 cigarettes (\ 5 packs) during life-time). 5. Acute respiratory symptoms for up to 7 days 6. All patients must have a diagnosis of COPD, and must have an airway obstruction with a post-bronchodilator (Forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity (FVC)) \<0.7. The diagnosis of COPD can be made at Visit 1. 7. The clinical assessment of the enrolled patient in the judgement of the investigator supports the introduction of COPD maintenance therapy. 8. Patients must be able to inhale medication in a competent manner from the HandiHaler® device and from a metered dose inhaler (MDI)
Exclusion criteria
1. Therapy with any long-acting bronchodilator, short-acting anticholinergic, inhaled corticosteroid or regular maintenance use (\>14 consecutive days) of systemic corticosteroid (the latter for respiratory indications) during the previous 6 months (short course of systemic corticosteroid for up to 14 days for respiratory indications allowed); in case of use of systemic corticosteroid medication for other than respiratory conditions, then exclusion of unstable doses (i.e., less than six weeks on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone-equivalent per day. In addition, daily use of short-acting beta2-agonist for more than a week prior to Visit 0 not allowed. The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough FEV1 After 12 Weeks on Study Drug | 12 weeks | The primary endpoint was trough forced expiratory volume in 1 second (FEV1) after 12 weeks on study drug. Trough forced expiratory volume in 1 second (FEV1)was defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responder Status at Week 12 Clinic Visit | 12 weeks | Responder status was determined at each clinic visit. The number and percentage of subjects in each of the following 3 classes were presented: * Subject recovered without change of therapy (subjects who received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1 were not included). * Subject recovered but had a change in therapy (subject received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1). * Subject did not recover. |
| Time to Recovery From Acute Respiratory Symptoms | 12 weeks | Time to recovery was assessed with the EXACT-PRO questionnaire tool. The EXACT-PRO was designed to collect data to quantify frequency, severity, and duration of exacerbations in patients with COPD including the onset of and the recovery from COPD exacerbations. The EXACT-PRO is a 14-item questionnaire. Each attribute or item was assessed on a five- or six-point ordinal scale and summed to yield a total score that was converted to a 0-100 scale, with higher scores indicating a more severe health state or exacerbation. The EXACT-PRO was answered by the patients on a daily basis in the evening. |
| Trough FVC (in Litres) at 12 Weeks | 12 weeks | The trough Forced Vital Capacity (FVC) was defined as the FVC measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of study drug. |
| Responder Status at Week 4 Clinic Visit | 4 weeks | Responder status was determined at each clinic visit. The number and percentage of subjects in each of the following 3 classes were presented: * Subject recovered without change of therapy (subjects who received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1 were not included). * Subject recovered but had a change in therapy (subject received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1). * Subject did not recover. |
| Weekly Rescue Medication Use Over the 12 Weeks of Study | 12 weeks | Daily rescue albuterol use was recorded in the diary in response to the following question: How many puffs of rescue medication did you use during the last 24 hours? The weekly rescue medication use was derived by summing the daily uses over the 12 weeks and dividing this total by 12 weeks. |
Countries
United States
Participant flow
Recruitment details
In this 12-week, randomised, double-blind, placebo-controlled, parallel group, multi-center Phase IV trial in chronic obstructive pulmonary disease (COPD), 140 patients were randomised to either Tiotropium 18 mcg or Placebo. Sixty eight (68) patients received Tiotropium 18 mcg and seventy two (72) patients received Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo - Placebo Inhalation capsule, HandiHaler® | 72 |
| Tiotropium 18mcg active - Tiotropium bromide Inhalation capsule 18 mcg, HandiHaler® | 68 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Due to other reason | 1 | 0 |
| Overall Study | Refused to continue medication | 2 | 1 |
Baseline characteristics
| Characteristic | Tiotropium 18mcg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 13 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 59 Participants | 112 Participants |
| Age, Continuous | 59.2 years STANDARD_DEVIATION 8.5 | 56.8 years STANDARD_DEVIATION 8.7 | 58.0 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 43 Participants | 34 Participants | 77 Participants |
| Sex: Female, Male Male | 25 Participants | 38 Participants | 63 Participants |
| Trough forced expiratory value (FEV1) | 1.56 Litre STANDARD_DEVIATION 0.61 | 1.75 Litre STANDARD_DEVIATION 0.65 | 1.65 Litre STANDARD_DEVIATION 0.64 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 72 | 6 / 68 |
| serious Total, serious adverse events | 3 / 72 | 3 / 68 |
Outcome results
Primary
Trough FEV1 After 12 Weeks on Study Drug
The primary endpoint was trough forced expiratory volume in 1 second (FEV1) after 12 weeks on study drug. Trough forced expiratory volume in 1 second (FEV1)was defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of study drug.
Time frame: 12 weeks
Population: Treated Set (TS) with non missing FEV1 data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 After 12 Weeks on Study Drug | 0.0378 Litre | Standard Error 0.0383 |
| Tiotropium 18 mcg | Trough FEV1 After 12 Weeks on Study Drug | 0.0947 Litre | Standard Error 0.039 |
Comparison: Tiotropium 18 mcg minus Placebop-value: 0.302595% CI: [-0.0516, 0.1654]Mixed effect repeated measures (MMRM)
Secondary
Responder Status at Week 12 Clinic Visit
Responder status was determined at each clinic visit. The number and percentage of subjects in each of the following 3 classes were presented: * Subject recovered without change of therapy (subjects who received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1 were not included). * Subject recovered but had a change in therapy (subject received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1). * Subject did not recover.
Time frame: 12 weeks
Population: TS with non missing responder data at week 12. Responder defined by \>= 20% improvement. .
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Responder Status at Week 12 Clinic Visit | Week 12: Responder without therapy change | 34 participants |
| Placebo | Responder Status at Week 12 Clinic Visit | Week 12: Responder with changed therapy | 0 participants |
| Placebo | Responder Status at Week 12 Clinic Visit | Week 12: Non-responder | 32 participants |
| Tiotropium 18 mcg | Responder Status at Week 12 Clinic Visit | Week 12: Responder without therapy change | 34 participants |
| Tiotropium 18 mcg | Responder Status at Week 12 Clinic Visit | Week 12: Responder with changed therapy | 0 participants |
| Tiotropium 18 mcg | Responder Status at Week 12 Clinic Visit | Week 12: Non-responder | 24 participants |
Secondary
Responder Status at Week 4 Clinic Visit
Responder status was determined at each clinic visit. The number and percentage of subjects in each of the following 3 classes were presented: * Subject recovered without change of therapy (subjects who received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1 were not included). * Subject recovered but had a change in therapy (subject received an additional course of antibiotics and/or systemic corticosteroids starting after Visit 1). * Subject did not recover.
Time frame: 4 weeks
Population: Responder defined by \>= 20% improvement. TS with non missing responder data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Responder Status at Week 4 Clinic Visit | Week 4: Responder without therapy change | 38 participants |
| Placebo | Responder Status at Week 4 Clinic Visit | Week 4: Responder with changed therapy | 1 participants |
| Placebo | Responder Status at Week 4 Clinic Visit | Week 4: Non-responder | 31 participants |
| Tiotropium 18 mcg | Responder Status at Week 4 Clinic Visit | Week 4: Non-responder | 26 participants |
| Tiotropium 18 mcg | Responder Status at Week 4 Clinic Visit | Week 4: Responder without therapy change | 39 participants |
| Tiotropium 18 mcg | Responder Status at Week 4 Clinic Visit | Week 4: Responder with changed therapy | 2 participants |
Secondary
Time to Recovery From Acute Respiratory Symptoms
Time to recovery was assessed with the EXACT-PRO questionnaire tool. The EXACT-PRO was designed to collect data to quantify frequency, severity, and duration of exacerbations in patients with COPD including the onset of and the recovery from COPD exacerbations. The EXACT-PRO is a 14-item questionnaire. Each attribute or item was assessed on a five- or six-point ordinal scale and summed to yield a total score that was converted to a 0-100 scale, with higher scores indicating a more severe health state or exacerbation. The EXACT-PRO was answered by the patients on a daily basis in the evening.
Time frame: 12 weeks
Population: TS with non missing EXACT-PRO data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to Recovery From Acute Respiratory Symptoms | 48.44 units on a scale | Standard Deviation 12.33 |
| Tiotropium 18 mcg | Time to Recovery From Acute Respiratory Symptoms | 47.86 units on a scale | Standard Deviation 11.95 |
Comparison: Comparison Tiotropium 18 mcg Vs Placebop-value: 0.782395% CI: [0.9053, 1.078]2sample t quantiles with pooled variance
Secondary
Trough FVC (in Litres) at 12 Weeks
The trough Forced Vital Capacity (FVC) was defined as the FVC measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of study drug.
Time frame: 12 weeks
Population: TS with non missing FVC data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC (in Litres) at 12 Weeks | 3.1537 Litres | Standard Deviation 0.9772 |
| Tiotropium 18 mcg | Trough FVC (in Litres) at 12 Weeks | 2.9097 Litres | Standard Deviation 0.9675 |
p-value: 0.902595% CI: [-0.1489, 0.1686]Mixed effects repeated measures (MMRM)
Secondary
Weekly Rescue Medication Use Over the 12 Weeks of Study
Daily rescue albuterol use was recorded in the diary in response to the following question: How many puffs of rescue medication did you use during the last 24 hours? The weekly rescue medication use was derived by summing the daily uses over the 12 weeks and dividing this total by 12 weeks.
Time frame: 12 weeks
Population: TS with non missing rescue medication use.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Weekly Rescue Medication Use Over the 12 Weeks of Study | 17.0 puffs | Standard Deviation 18.9 |
| Tiotropium 18 mcg | Weekly Rescue Medication Use Over the 12 Weeks of Study | 12.9 puffs | Standard Deviation 16.6 |
Comparison: Comparison Tiotropium 18 mcg Vs Placebo Over 12 Weeksp-value: 0.179795% CI: [-10.0157, 1.8938]t-test, 2 sided