Cystic Fibrosis
Conditions
Brief summary
To date, there have been no formal clinical studies completed using tiotropium in CF patients. While there is a large body of evidence demonstrating the efficacy and safety of tiotropium in patients with Chronic Obstructive Pulmonary Disease (COPD), relatively little is known about its efficacy and safety in patients with a diagnosis of cystic fibrosis. Therefore, Boehringer Ingelheim proposed to profile the long acting anticholinergic tiotropium and to generate adequate clinical data for use as a bronchodilator in paediatric and adult CF. The phase III trial (205.438) is a part of the approved Paediatric Investigation Plan (PIP) agreed for Spiriva® Respimat® in Cystic Fibrosis.
Interventions
DRUGtiotropium Respimat® inhaler
to evaluate safety and efficacy tiotropium delivered with Respimat® inhaler compared to placebo.
DRUGPlacebo Respimat® inhaler
patient to receive placebo matching active drug once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Patients with a documented diagnosis of Cystic Fibrosis (CF) (positive sweat chloride \>=60 mEq/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations. 2. Male or female patients (children less than 12 years and adolescents \>12 years). 3. Patients \>=5 years of age must be able to perform acceptable spirometric maneuvers, according to the American Thoracic Society (ATS) standards. 4. Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) \>25% of predicted values. 5. Pre-bronchodilator FEV1 at Visit 2 must be within 15% of FEV1 at Visit 1. 6. No evidence of respiratory tract infection and no pulmonary exacerbation requiring use of intravenous/oral/inhaled antibiotics, or oral corticosteroids within 2 weeks of screening. 7. The patient or the patient's legally acceptable representative must be able to give informed consent. 8. Patients who are on a cycling TOBI® regimen must have completed at least 2 cycles every other month TOBI® administration prior to the screening visit. 9. Patients who are on daily inhaled antibiotic use must be stabilized for at least 6 weeks prior to Visit 1 (screening). 10. Patients having previously participated in study 205.339 can also be selected.
Exclusion criteria
1. Patients with a known hypersensitivity to study drug 2. Patients who have participated in another study with an Investigational drug within one month preceding the screening visit. 3. Patients who are currently participating in another trial. Observational studies are allowed. Permission should be obtained from sponsor of other study. 4. Patients with known relevant substance abuse, including alcohol or drug abuse. 5. Adolescent and adult female patients who are pregnant or lactating, including females who have a positive serum pregnancy test at screening. 6. Female patients of child bearing potential who are not using a medically approved form of contraception. 7. Clinically significant disease or medical condition other than CF or CF-related conditions that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data. Patients with diabetes may participate if their disease is under good control prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0-4 Hours (AUC0-4h) Response | 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks. | Mixed Model Repeated Measurement (MMRM) results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. FEV1 AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). |
| Trough FEV1 Response | Baseline and 12 weeks | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FEV1 was defined as the pre-dose FEV1 measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre-bronchodilator Forced Expiratory Flow Between 25 Percent and 75 Percent of the FVC (FEF25-75) Response | Baseline and 12 weeks | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. FEF25-75 is also known as maximum mid-expiratory flow and was measured before bronchodilator (salbutamol) use. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. |
| Forced Vital Capacity (FVC) Area Under the Curve 0-4 Hours (AUC0-4h) Response | 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks. | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. FVC AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h). |
| Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Baseline and 12 weeks | Different format of CFQ-R are used depending of the patients' age. Adolescent and adult format of CFQ-R is used for patients of 14 years and older, for younger children a parent version and a children format is used. In case parent and children questionnaires were filled out, the children questionnaire is taken into account. Scores were calculated for each domain of the CFQ-R which are presented separately. A score of 100 corresponds to the highest quality of life possible, whereas a score of 0 corresponds to the lowest quality of life possible. Increasing score indicates better health. |
| Percentage of Participants With at Least 1 Pulmonary Exacerbation During Double-blind Treatment | 12 weeks | Selected questions from the Respiratory and Systemic Symptoms Questionnaire (RSSQ), the investigator assessment of physical findings and pulmonary function, and the use of intravenous antibiotics as a concomitant therapy were used to determine if a cystic fibrosis-related pulmonary exacerbation had occurred. |
| Trough FVC Response | Baseline and 12 weeks | MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FCV was defined as the pre-dose FVC measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Ireland, Israel, Italy, Poland, Portugal, Russia, Slovakia, South Africa, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
First part: double-blind, duration was 12 weeks, 464 patients were randomised to either Tio R5 or placebo in a 2:1 ratio, but 1 randomised patient was not treated. Second part: open-label, all patients received the active treatment for a minimum of 12 weeks to enlarge the safety database.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo once daily (qd) delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis. | 155 |
| Tio R5 qd Tiotropium 5 mcg qd delivered by the Respimat inhaler as add-on therapy to usual care in patients with cystic fibrosis. | 308 |
| Total | 463 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Period (12 Weeks) | Adverse Event | 2 | 6 |
| Double-blind Period (12 Weeks) | Lost to Follow-up | 1 | 2 |
| Double-blind Period (12 Weeks) | Other | 2 | 4 |
| Double-blind Period (12 Weeks) | Protocol Violation | 2 | 0 |
| Double-blind Period (12 Weeks) | Withdrawal by Subject | 1 | 2 |
| Open-label Period (12 Weeks) | Adverse Event | 5 | 9 |
| Open-label Period (12 Weeks) | Lack of Efficacy | 0 | 2 |
| Open-label Period (12 Weeks) | Lost to Follow-up | 1 | 0 |
| Open-label Period (12 Weeks) | Other | 7 | 4 |
| Open-label Period (12 Weeks) | Protocol Violation | 1 | 0 |
| Open-label Period (12 Weeks) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Tio R5 qd | Total |
|---|---|---|---|
| Age, Continuous | 20.6 years STANDARD_DEVIATION 13.6 | 19.3 years STANDARD_DEVIATION 12 | 19.8 years STANDARD_DEVIATION 12.5 |
| Sex: Female, Male Female | 65 Participants | 139 Participants | 204 Participants |
| Sex: Female, Male Male | 90 Participants | 169 Participants | 259 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 155 | 63 / 308 | 56 / 147 | 186 / 308 |
| serious Total, serious adverse events | 13 / 155 | 36 / 308 | 24 / 147 | 62 / 308 |
Outcome results
Primary
Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0-4 Hours (AUC0-4h) Response
Mixed Model Repeated Measurement (MMRM) results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. FEV1 AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h).
Time frame: 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks.
Population: Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance. The FAS was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients \<5 years of age were included in the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0-4 Hours (AUC0-4h) Response | 0.87 Percent of predicted | Standard Error 0.8 |
| Tio R5 qd | Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0-4 Hours (AUC0-4h) Response | 2.51 Percent of predicted | Standard Error 0.57 |
Comparison: Hierarchical testing procedure was applied for both co-primary endpoints to maintain the overall alpha level. If and only if statistical superiority of the Tio R5 qd compared to Placebo in FEV1 AUC0-4h was demonstrated at the 1 sided alpha level of 0.025, confirmatory comparison in the second co-primary endpoint, at the same alpha level of 0.025 could be done .p-value: 0.09295% CI: [-0.27, 3.55]Mixed Models Analysis
Primary
Trough FEV1 Response
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FEV1 was defined as the pre-dose FEV1 measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance. The FAS was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients \<5 years of age were included in the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FEV1 Response | 0.72 Percent of predicted | Standard Error 0.8 |
| Tio R5 qd | Trough FEV1 Response | 2.12 Percent of predicted | Standard Error 0.58 |
Comparison: Hierarchical testing for co-primary endpoints, confirmatory only if previous hypotheses had been successful,p-value: 0.1595% CI: [-0.5, 3.3]Mixed Models Analysis
Secondary
Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score
Different format of CFQ-R are used depending of the patients' age. Adolescent and adult format of CFQ-R is used for patients of 14 years and older, for younger children a parent version and a children format is used. In case parent and children questionnaires were filled out, the children questionnaire is taken into account. Scores were calculated for each domain of the CFQ-R which are presented separately. A score of 100 corresponds to the highest quality of life possible, whereas a score of 0 corresponds to the lowest quality of life possible. Increasing score indicates better health.
Time frame: Baseline and 12 weeks
Population: FAS reduced to patients having CFQ-R information at baseline and at week 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Physical (N=83, N=162) | -0.85 Units on a scale | Standard Deviation 14.4 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Role (N=78, N=157) | 0.85 Units on a scale | Standard Deviation 12.99 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Vitality (N=82, N=161) | -1.22 Units on a scale | Standard Deviation 18.06 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Emotion (N=82, N=161) | -1.54 Units on a scale | Standard Deviation 12.05 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Social (N=82, N=159) | -1.69 Units on a scale | Standard Deviation 10.09 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Body Image (N=82, N=159) | 0.14 Units on a scale | Standard Deviation 16.14 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Eating (N=82, N=161) | -1.49 Units on a scale | Standard Deviation 14.89 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Treatment burden (N=82, N=160) | 0.95 Units on a scale | Standard Deviation 14.73 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Health perseptions (N=82, N=159) | -0.81 Units on a scale | Standard Deviation 13.83 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Weight (N=80, N=160) | -2.08 Units on a scale | Standard Deviation 29.22 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Respiratory (N=80, N=159) | 0.97 Units on a scale | Standard Deviation 13.83 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Digestion (N=80, N=159) | -0.83 Units on a scale | Standard Deviation 17.03 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Physical (N=47, N=93) | -2.84 Units on a scale | Standard Deviation 15.67 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Social (N=46, N=93) | 2.80 Units on a scale | Standard Deviation 15.73 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Emotion (N=47, N=93) | -1.24 Units on a scale | Standard Deviation 12.83 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Eating (N=47, N=93) | 2.84 Units on a scale | Standard Deviation 19.03 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Treatment burden (N=46, N=93) | 0.72 Units on a scale | Standard Deviation 15.43 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Respiratory (N=46, N=93) | -0.91 Units on a scale | Standard Deviation 15.34 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Digestion (N=46, N=92) | 2.17 Units on a scale | Standard Deviation 22.66 |
| Placebo | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Body Image (N=46, N=93) | -1.21 Units on a scale | Standard Deviation 18.48 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Respiratory (N=46, N=93) | -1.61 Units on a scale | Standard Deviation 16.81 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Physical (N=83, N=162) | -0.15 Units on a scale | Standard Deviation 12.95 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Respiratory (N=80, N=159) | -0.77 Units on a scale | Standard Deviation 15.19 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Role (N=78, N=157) | -0.42 Units on a scale | Standard Deviation 13.3 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Eating (N=47, N=93) | 0.72 Units on a scale | Standard Deviation 20.18 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Vitality (N=82, N=161) | 0.05 Units on a scale | Standard Deviation 14.08 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Digestion (N=80, N=159) | 0.49 Units on a scale | Standard Deviation 12.4 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Emotion (N=82, N=161) | -0.99 Units on a scale | Standard Deviation 12.96 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Body Image (N=46, N=93) | 4.66 Units on a scale | Standard Deviation 25.71 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Social (N=82, N=159) | 0.70 Units on a scale | Standard Deviation 10.19 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Physical (N=47, N=93) | 1.43 Units on a scale | Standard Deviation 15.19 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Body Image (N=82, N=159) | 3.14 Units on a scale | Standard Deviation 15.11 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Treatment burden (N=46, N=93) | -0.48 Units on a scale | Standard Deviation 19.1 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Eating (N=82, N=161) | 1.38 Units on a scale | Standard Deviation 10.74 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Social (N=46, N=93) | 1.59 Units on a scale | Standard Deviation 15.7 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Treatment burden (N=82, N=160) | 0.56 Units on a scale | Standard Deviation 14.84 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Digestion (N=46, N=92) | -1.09 Units on a scale | Standard Deviation 29.84 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Health perseptions (N=82, N=159) | 0.77 Units on a scale | Standard Deviation 16.68 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Children: Emotion (N=47, N=93) | 1.12 Units on a scale | Standard Deviation 12.18 |
| Tio R5 qd | Change From Baseline in Revised Cystic Fibrosis Questionnaire (CFQ-R) Score | Adolescents: Weight (N=80, N=160) | 3.75 Units on a scale | Standard Deviation 26.96 |
Secondary
Forced Vital Capacity (FVC) Area Under the Curve 0-4 Hours (AUC0-4h) Response
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction. FVC AUC0-4h was normalised for time and was calculated using the trapezoidal rule divided by the observation time (4 h).
Time frame: 30 minutes (min) before first dosing of study drug (defined as baseline), at 1 hour (h), 2 h , 3 h, and 4 h post dosing at day 1 and at 30 min before dosing, at 1 hour, 2 h , 3 h, and 4 h post dosing after 12 weeks.
Population: Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance. The FAS was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients \<5 years of age were included in the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Forced Vital Capacity (FVC) Area Under the Curve 0-4 Hours (AUC0-4h) Response | 0.17 Percent of predicted | Standard Error 0.75 |
| Tio R5 qd | Forced Vital Capacity (FVC) Area Under the Curve 0-4 Hours (AUC0-4h) Response | 1.27 Percent of predicted | Standard Error 0.53 |
p-value: 0.2395% CI: [-0.68, 2.86]Mixed Models Analysis
Secondary
Percentage of Participants With at Least 1 Pulmonary Exacerbation During Double-blind Treatment
Selected questions from the Respiratory and Systemic Symptoms Questionnaire (RSSQ), the investigator assessment of physical findings and pulmonary function, and the use of intravenous antibiotics as a concomitant therapy were used to determine if a cystic fibrosis-related pulmonary exacerbation had occurred.
Time frame: 12 weeks
Population: FAS reduced to patients having RSSQ information on day 29, 57 or 85.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With at Least 1 Pulmonary Exacerbation During Double-blind Treatment | 7.8 Percentage of Participants |
| Tio R5 qd | Percentage of Participants With at Least 1 Pulmonary Exacerbation During Double-blind Treatment | 8.9 Percentage of Participants |
p-value: 0.8495% CI: [0.453, 2.633]Regression, Logistic
Secondary
Pre-bronchodilator Forced Expiratory Flow Between 25 Percent and 75 Percent of the FVC (FEF25-75) Response
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. FEF25-75 is also known as maximum mid-expiratory flow and was measured before bronchodilator (salbutamol) use. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance. The FAS was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients \<5 years of age were included in the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pre-bronchodilator Forced Expiratory Flow Between 25 Percent and 75 Percent of the FVC (FEF25-75) Response | 2.15 Percent of predicted | Standard Error 1.48 |
| Tio R5 qd | Pre-bronchodilator Forced Expiratory Flow Between 25 Percent and 75 Percent of the FVC (FEF25-75) Response | 3.02 Percent of predicted | Standard Error 1.05 |
p-value: 0.6295% CI: [-2.59, 4.32]Mixed Models Analysis
Secondary
Trough FVC Response
MMRM results. Response was defined as change from baseline in percent of predicted at the end of 12-week double-blind treatment period and is therefore expressed in percent of predicted. Trough FCV was defined as the pre-dose FVC measured just prior to the administration of randomised treatment. Means are adjusted for treatment, visit, treatment-by-visit interaction, age group (\<= 11, \>=12), baseline and baseline-by-visit interaction.
Time frame: Baseline and 12 weeks
Population: Full Analysis Set (FAS) with imputation reduced to patients with observed wash-out compliance. The FAS was defined as all patients in the treated set who had at least 1 baseline pulmonary function test (PFT) measurement and at least 1 post-baseline on-treatment PFT measurement. No patients \<5 years of age were included in the FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Trough FVC Response | 0.30 Percent of predicted | Standard Error 0.77 |
| Tio R5 qd | Trough FVC Response | 1.51 Percent of predicted | Standard Error 0.55 |
p-value: 0.1995% CI: [-0.62, 3.02]Mixed Models Analysis