Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The objective of this study is to investigate the patient acceptability/preference of Respimat® compared with Handihaler® in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) to demonstrate the superiority of Respimat®.
Interventions
DRUGTiotropium Respimat® (T1)
inhalation solution
DRUGTiotropium Handihaler® (T2)
Inhalation Powder
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* All patients must have a diagnosis of COPD and must meet the following spirometric criteria at Visit 1 (Screening). * Relatively stable, moderate to very severe airway obstruction with a post-bronchodilator FEV1 \<80% of predicted normal and FEV1/FVC \<70%. Spirometry should be done at baseline and approximately 1/2 hour following 4 inhalations of albuterol. * Male = exp \[-10.61669 + 2.27078 × ln (- in cm) + 0.06622 × ln (age in year) + Mspline\] Female = exp \[-9.69716 + 2.09385 × ln (- in cm) + 0.02006 × ln (age in year) + Mspline\] * Historical data from spirometry measurements within the past 6 either at the site or at the other hospital may be used. If the measurements are not performed at the trial site a referral letter and signed copies of the measurement printouts must be provided to the trial site for source data verification. In case several qualifying spirometry measurements are available, the most recent one should be referred to as long as it was not performed during an exacerbation. Patients may not be randomised to the study without the availability of spirometry data at the actual study site. * Male or female, age: ≥40 years of age * Patients must be current or ex-smokers with a smoking history of ≥ 10 pack years. (Patients who have never smoked cigarettes must be excluded). * Signed and dated written informed consent in accordance with International Council on Harmonization (ICH) ICH-GCP and local legislation prior to admission to the trial * Patients must be able to inhale medication from the Tiotropium Respimat® and Tiotropium HandiHaler® * Patients must be able to perform all study related procedures, and must be able to maintain records (patient diary) during the study period as required by the protocol
Exclusion criteria
* Had visual, cognitive, or motor impairment that, as judged by the investigator, did not allow the patient to independently read and complete the PASAPQ questionnaire * Patients have had used both Respimat® and HandiHaler® (including generic HandiHaler®) within one year prior to screening. * Patients with significant diseases other than COPD will be excluded. A significant disease is defined as a disease or condition which, in the opinion of the investigator, may put the patients at risk because of participation in the study or may influence either the results of the study or the patient's ability to participate in the study. * All patients with an Aspartate Transaminase (AST) (serum glutamic-oxaloacetic transaminase, SGOT) \>80 IU/L, Alanine Aminotransferase (ALT) (Serum Glutamic-pyruvic Transaminase, SGPT) \>80 IU/L, Bilirubin \>2.0 mg/dL or Creatinine \>2.0 mg/dL will be excluded regardless of the clinical condition. Repeat laboratory evaluation will not be conducted in these subjects. * Patients with a recent history (i.e., one year or less) of myocardial infarction. * Patients who have been hospitalized or being treated for heart failure within the past year. * Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the last year. * Patients with a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed). * Known active tuberculosis. * Patients with a history of asthma, cystic fibrosis, clinically not well-controlled bronchiectasis, interstitial lung disease, or pulmonary thromboembolic disease * History of thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated. * Patients with any respiratory tract infection or COPD exacerbation in the 6 weeks prior to the initial screening visit (Visit 1). * Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction. Patients whose symptoms are controlled on treatment may be included. * Patients with known narrow-angle glaucoma * 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 milligrams (mg) prednisolone per day. * Patients who regularly use daytime oxygen therapy for more than 1 hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy. * Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (i.e., oral or injectable contraceptives, intrauterine devices (IUD) or diaphragm with spermicide, or Norplant®). * Significant alcohol or drug abuse within the past 12 months * 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. * Patients currently in any pulmonary rehabilitation program or scheduled to participate in any such program during the study period. * Previous participation in this study. (The patient cannot re-enroll into this study.) * Patients who are currently participating in another interventional study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Performance Domain of the Patient Satisfaction and Preference Questionnaire (PASAPQ) After 4 Weeks of Treatment | After 4 weeks of treatment (at week 4 and week 8) | The score on the performance domain of the Patient satisfaction and preference questionnaire (PASAPQ) after 4 weeks of treatment is reported. The performance domain score is the sum of 7 questions (Q) within the domain (Q1, Q2, Q3, Q4, Q5, Q10 and Q11), the range for each question went from 1 to 7 the higher the better. The score was then transformed to a 0 (least) to 100 (most) point scale following ((Q1+Q2+Q3+Q4+Q5+Q10+Q11)/49)\*100, the higher the better performance. The performance domain of PASAPQ) was analysed using Mixed-effects Model for Repeated Measures (MMRM), with treatment and period as fixed effects, and patient as a random effect. Compound symmetry was used as a covariance structure for within-patient variation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PASAPQ Total Score After 4 Weeks of Treatment | After 4 weeks of treatment (at week 4 and week 8) | The total score on the Patient satisfaction and preference questionnaire (PASAPQ) after 4 weeks of treatment is reported. The Total score is the sum of 13 questions (Q1-Q13) and then transformed to a 0 (least) to 100 (most) point scale. This continuous secondary endpoint was analyzed using a similar MMRM model as for the primary endpoint. |
| Percentage of Patients Indicating Preference at Week 8 | At Week 8. | The percentage of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8 is reported. The questionnaire PASAPQ is a two part questionnaire, in Part II of the PASAPQ the stand-alone question 15 (Q15) was asked for a response to indicate the preference for the trial device, it had three possible answers: I prefer Respimat, I prefer Handihaler, No answer to this question and no preference. Chi-squared test was used to analyze proportion of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8. |
| Overall Satisfaction Question Score From PASAPQ After 4 Weeks of Treatment | At the end of 4 weeks of treatment | The overall satisfaction question score in the Patient satisfaction and preference questionnaire (PASAPQ) at week 4 and 8 is reported (after 4 weeks of treatment). In Part I of the questionnaire PASAPQ: the Question 14 (Q14) asked for the overall satisfaction with the device used in the study. Q14 had Likert-type response options of 1 (very dissatisfied) to 7 (very satisfied) and was then transformed to a 0 (least) to 100 (most) point scale (if a patient scored x, the transfer to 0-100 scale was x/7\*100). Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the overall satisfaction question score, with treatment and period as fixed effects, and patient as a random effect. |
| Score on Willingness to Continue at Week 8 | At Week 8. | The score on willingness to continue in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8 is reported. The PASAPQ is a two part questionnaire, in Part I of the questionnaire PASAPQ the Question 16 (Q16) asked for a response between 0 and 100 with 0 indicating not willing to continue using the trial device and 100 indicating definitely willingness to continue. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the score on willingness to continue, with treatment and period as fixed effects, and patient as a random effect. |
Countries
China
Participant flow
Recruitment details
This was a randomised, open-label, 2 -way cross-over design, to compare patient acceptability/preference of Tiotropium Respimat® (T1),with Tiotropium Handihaler® (T2) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| (T1): 5μg Tiotropium Respimat®, Then (T2): 18μg Tiotropium Handihaler® From Day 1 of Period 1 participants received Test treatment (T1): tiotropium Respimat® (Spiriva® Respimat®) 5 microgram (μg) once daily for a duration of 4 weeks, given as 2.5μg per puff, two puffs (2.5μg per puff) inhalation solution of tiotropium, orally via Respimat®.
From Day 1 of Period 2 participants received comparator treatment(T2): tiotropium Handihaler® (Spiriva®) 18μg once daily for a duration of 4 weeks, inhalation powder tiotropium with 1 Handihaler® device. | 36 |
| (T2): 18μg Tiotropium Handihaler®, Then (T1): 5μg Tiotropium Respimat® From Day 1 of Period 1 participants received comparator treatment (T2): tiotropium Handihaler® (Spiriva®) 18 microgram (μg) once daily for a duration of 4 weeks, inhalation powder tiotropium with 1 Handihaler® device.
From Day 1 of Period 2 participants received Test treatment (T1): tiotropium Respimat® (Spiriva® Respimat®) 5 microgram (μg) once daily for a duration of 4 weeks, given as 2.5μg per puff, two puffs (2.5μg per puff) inhalation solution of tiotropium, orally via Respimat®. | 35 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Treatment | Lost to Follow-up | 1 | 0 |
| First Treatment | Protocol Violation | 1 | 0 |
| First Treatment | Withdrawal by Subject | 1 | 2 |
| Second Treatment | Adverse Event | 1 | 2 |
| Second Treatment | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | (T2): 18μg Tiotropium Handihaler®, Then (T1): 5μg Tiotropium Respimat® | Total | (T1): 5μg Tiotropium Respimat®, Then (T2): 18μg Tiotropium Handihaler® |
|---|---|---|---|
| Age, Continuous | 65.2 Years STANDARD_DEVIATION 7.23 | 66.3 Years STANDARD_DEVIATION 6.93 | 67.4 Years STANDARD_DEVIATION 6.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 71 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 35 Participants | 71 Participants | 36 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 35 Participants | 69 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 0 / 69 |
| other Total, other adverse events | 0 / 69 | 0 / 69 |
| serious Total, serious adverse events | 2 / 69 | 2 / 69 |
Outcome results
Primary
Performance Domain of the Patient Satisfaction and Preference Questionnaire (PASAPQ) After 4 Weeks of Treatment
The score on the performance domain of the Patient satisfaction and preference questionnaire (PASAPQ) after 4 weeks of treatment is reported. The performance domain score is the sum of 7 questions (Q) within the domain (Q1, Q2, Q3, Q4, Q5, Q10 and Q11), the range for each question went from 1 to 7 the higher the better. The score was then transformed to a 0 (least) to 100 (most) point scale following ((Q1+Q2+Q3+Q4+Q5+Q10+Q11)/49)\*100, the higher the better performance. The performance domain of PASAPQ) was analysed using Mixed-effects Model for Repeated Measures (MMRM), with treatment and period as fixed effects, and patient as a random effect. Compound symmetry was used as a covariance structure for within-patient variation.
Time frame: After 4 weeks of treatment (at week 4 and week 8)
Population: Full analysis set (FAS) is defined as all patients who were randomized to treatment sequence and received at least one dose of one study drug and providing at least one PASAPQ score measurement. Only patients with no missing values were included for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (T1): 5μg Tiotropium Respimat® | Performance Domain of the Patient Satisfaction and Preference Questionnaire (PASAPQ) After 4 Weeks of Treatment | 79.830 Scores on a scale | Standard Deviation 15.052 |
| (T2): 18μg Tiotropium Handihaler® | Performance Domain of the Patient Satisfaction and Preference Questionnaire (PASAPQ) After 4 Weeks of Treatment | 85.112 Scores on a scale | Standard Deviation 11.583 |
Comparison: The hypothesis test was held to investigate the superiority of the test treatment. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the performance domain of PASAPQ score, with treatment and period as fixed effects, and patient as a random effect.p-value: 0.00795% CI: [-9.07, -1.48]Mixed-effects Model
Secondary
Overall Satisfaction Question Score From PASAPQ After 4 Weeks of Treatment
The overall satisfaction question score in the Patient satisfaction and preference questionnaire (PASAPQ) at week 4 and 8 is reported (after 4 weeks of treatment). In Part I of the questionnaire PASAPQ: the Question 14 (Q14) asked for the overall satisfaction with the device used in the study. Q14 had Likert-type response options of 1 (very dissatisfied) to 7 (very satisfied) and was then transformed to a 0 (least) to 100 (most) point scale (if a patient scored x, the transfer to 0-100 scale was x/7\*100). Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the overall satisfaction question score, with treatment and period as fixed effects, and patient as a random effect.
Time frame: At the end of 4 weeks of treatment
Population: Full analysis set (FAS) is defined as all patients who were randomized to treatment sequence and received at least one dose of one study drug and providing at least one PASAPQ score measurement. Only participants with non-missing endpoints were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (T1): 5μg Tiotropium Respimat® | Overall Satisfaction Question Score From PASAPQ After 4 Weeks of Treatment | 82.56 Score on a scale | Standard Deviation 19.702 |
| (T2): 18μg Tiotropium Handihaler® | Overall Satisfaction Question Score From PASAPQ After 4 Weeks of Treatment | 87.24 Score on a scale | Standard Deviation 12.257 |
Comparison: The hypothesis test was held to investigate the superiority of the test treatment. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the performance domain of PASAPQ score, with treatment and period as fixed effects, and patient as a random effect.p-value: 0.05795% CI: [-9.59, 0.15]The mixed model for repeated measures
Secondary
PASAPQ Total Score After 4 Weeks of Treatment
The total score on the Patient satisfaction and preference questionnaire (PASAPQ) after 4 weeks of treatment is reported. The Total score is the sum of 13 questions (Q1-Q13) and then transformed to a 0 (least) to 100 (most) point scale. This continuous secondary endpoint was analyzed using a similar MMRM model as for the primary endpoint.
Time frame: After 4 weeks of treatment (at week 4 and week 8)
Population: Full analysis set (FAS) is defined as all patients who were randomized to treatment sequence and received at least one dose of one study drug and providing at least one PASAPQ score measurement. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (T1): 5μg Tiotropium Respimat® | PASAPQ Total Score After 4 Weeks of Treatment | 81.51 Scores on a scale | Standard Deviation 13.67 |
| (T2): 18μg Tiotropium Handihaler® | PASAPQ Total Score After 4 Weeks of Treatment | 85.69 Scores on a scale | Standard Deviation 10.802 |
Comparison: The hypothesis test was held to investigate the superiority of the test treatment. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the performance domain of PASAPQ score, with treatment and period as fixed effects, and patient as a random effectp-value: 0.02495% CI: [-7.72, -0.56]Mixed Models Analysis
Secondary
Percentage of Patients Indicating Preference at Week 8
The percentage of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8 is reported. The questionnaire PASAPQ is a two part questionnaire, in Part II of the PASAPQ the stand-alone question 15 (Q15) was asked for a response to indicate the preference for the trial device, it had three possible answers: I prefer Respimat, I prefer Handihaler, No answer to this question and no preference. Chi-squared test was used to analyze proportion of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8.
Time frame: At Week 8.
Population: Full analysis set (FAS) is defined as all patients who were randomized to treatment sequence and received at least one dose of one study drug and providing at least one PASAPQ score measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| (T1): 5μg Tiotropium Respimat® | Percentage of Patients Indicating Preference at Week 8 | I prefer Respimat | 50.7 Percentage |
| (T1): 5μg Tiotropium Respimat® | Percentage of Patients Indicating Preference at Week 8 | I prefer Handihaler | 37.7 Percentage |
| (T1): 5μg Tiotropium Respimat® | Percentage of Patients Indicating Preference at Week 8 | No preference | 5.8 Percentage |
| (T1): 5μg Tiotropium Respimat® | Percentage of Patients Indicating Preference at Week 8 | No answer to this question | 5.8 Percentage |
Comparison: Chi-squared test was used to analyze proportion of patients indicating preference in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8. All participants have used both treatments at this point: Handihaler (4 weeks) and Respimat (4 weeks).p-value: 0.249Chi-square test
Secondary
Score on Willingness to Continue at Week 8
The score on willingness to continue in the Patient satisfaction and preference questionnaire (PASAPQ) at week 8 is reported. The PASAPQ is a two part questionnaire, in Part I of the questionnaire PASAPQ the Question 16 (Q16) asked for a response between 0 and 100 with 0 indicating not willing to continue using the trial device and 100 indicating definitely willingness to continue. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the score on willingness to continue, with treatment and period as fixed effects, and patient as a random effect.
Time frame: At Week 8.
Population: Full analysis set (FAS) is defined as all patients who were randomized to treatment sequence and received at least one dose of one study drug and providing at least one PASAPQ score measurement. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (T1): 5μg Tiotropium Respimat® | Score on Willingness to Continue at Week 8 | 82.9 Scores on a scale | Standard Deviation 28.1 |
| (T2): 18μg Tiotropium Handihaler® | Score on Willingness to Continue at Week 8 | 87.3 Scores on a scale | Standard Deviation 19.19 |
Comparison: The hypothesis test was held to investigate the superiority of the test treatment. Mixed-effects Model for Repeated Measures (MMRM) was used to analyze the performance domain of PASAPQ score, with treatment and period as fixed effects, and patient as a random effect.p-value: 0.34795% CI: [-13.63, 4.86]Mixed Models Analysis