Cystic Fibrosis
Conditions
Brief summary
This trial aims to provide prospective evidence of the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above. We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the mean change from baseline FEV1 (mL) compared to control over the 26-week treatment period in adult subjects with cystic fibrosis. Any improvement in FEV1 is considered clinically meaningful, however, this trial has set a threshold of 80 mL for the purposes of determining an appropriate sample size for statistical power while retaining trial feasibility in an orphan disease population
Detailed description
This is a double-blind, randomized, parallel arm, controlled, multicenter, and interventional clinical trial. Potential subjects will sign the informed consent form (ICF) and be assessed for eligibility. After satisfying all inclusion & exclusion criteria, subjects will be given a mannitol tolerance test (MTT). Those subjects that pass the MTT will be randomized to receive inhaled mannitol (400 mg b.i.d.) or control b.i.d. for a period of 26-weeks.
Interventions
DRUGInhaled mannitol
Inhaled mannitol 400 mg BD for 26 weeks
DRUGPlacebo Comparator: Arm B - Control
Placebo Comparator: Arm B - Control BD for 26 weeks
Sponsors
Syntara
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Have given written informed consent to participate in this trial in accordance with local regulations; 2. Have a confirmed diagnosis of cystic fibrosis (positive sweat chloride value ≥ 60 mEq/L) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype); 3. Be aged at least 18 years old; 4. Have FEV1 \> 40 % and \< 90% predicted (using NHanes III \[1\]); 5. Be able to perform all the techniques necessary to measure lung function; 6. Be adherent with maintenance therapies (antibiotics and or rhDNase), if used, for at least 80% of the time in the two weeks prior to visit 1 and 7. If rhDNase and/or maintenance antibiotic are being used treatment must have been established at least 1 month prior to screening (Visit 0). The subject should remain on the rhDNase and / or maintenance antibiotics for the duration of the trial. The subject should not commence treatment with rhDNase or maintenance antibiotics during the trial
Exclusion criteria
1. Be investigators, site personnel directly affiliated with this trial, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted; 2. Be considered terminally ill or eligible for lung transplantation; 3. Have had a lung transplant; 4. Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1; 5. Have had a significant episode of hemoptysis (\> 60 mL) in the three months prior to Visit 0; 6. Have had a myocardial infarction in the three months prior to Visit 0; 7. Have had a cerebral vascular accident in the three months prior to Visit 0; 8. Have had major ocular surgery in the three months prior to Visit 0; 9. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0; 10. Have a known cerebral, aortic or abdominal aneurysm; 11. Be breast feeding or pregnant, or plan to become pregnant while in the trial; 12. Be using an unreliable form of contraception (female subjects at risk of pregnancy only); 13. Be participating in another investigative drug trial, parallel to, or within 4 weeks of screening (Visit 0); 14. Have a known allergy to mannitol; 15. Be using non-selective oral beta blockers; 16. Have uncontrolled hypertension -i.e. systolic BP \> 190 and / or diastolic BP \> 100; 17. Have a condition or be in a situation which in the Investigator's opinion may put the subject at significant risk, may confound results or may interfere significantly with the subject's participation in the trial;or 18. Have a failed or incomplete MTT at trial entry (as evaluated in Section 8.1.1.1). 19. The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). | 26 weeks | The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits. Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period | 26 weeks | To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for improving lung function as measured by mean change from baseline forced vital capacity (FVC) (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF). The mean absolute change from baseline FVC (mL) over 26 weeks will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Days in Hospital Due to Pulmonary Exacerbation | 26 weeks | To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days in hospital due to protocol defined pulmonary exacerbation. |
| Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 26 weeks | To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of protocol defined pulmonary exacerbations over the 26-week treatment period compared to control in adult subjects with CF. Protocol defined pulmonary exacerbations defined by having 4 or more symptoms and treated with IV antibiotics. |
| Time to First Pulmonary Exacerbation Over the 26-week Treatment Period | 26 weeks | To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in increasing the time to first protocol defined pulmonary exacerbation over the 26-week treatment period in adult subjects with CF. Protocol defined pulmonary exacerbations are those where 4 or more symptoms are recorded and are treated with IV antibiotics |
| Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks | 26 weeks | To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for improving ease of expectoration. The visual analogue scale (VAS) was 10cm. The position marked by the subject was converted into a score from 0 to 100 where 0 was the worst possible outcome and 100 was the best possible outcome. The VAS was completed at baseline, 6, 14 and 26 weeks. The mean absolute change from baseline over 26 weeks (ie the average of the changes at 6,14 and 26 weeks) is the outcome measure and will be compared between the two treatment groups with a REML based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF). |
| Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score | 26 weeks | To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for improving respiratory symptoms measured by Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain. The CFQ-R respiratory domain score is a scale from 0 to 100. Higher scores are a more favourable response. The mean absolute change from baseline over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF). |
| The Incidence of Pulmonary Exacerbations | 26 weeks | To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing incidence of protocol defined pulmonary exacerbations, where incidence is defined as the proportion of subjects with 1 or more exacerbation during the 26 week period. |
| Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation | 26 weeks | To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days on antibiotics due to protocol defined pulmonary exacerbations. Overlapping antibiotics are counted separately. |
Countries
Argentina, Australia, Belgium, Canada, Czechia, Hungary, Israel, Italy, Mexico, New Zealand, Poland, Romania, Russia, Slovakia, South Africa, Spain, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm A Active treatment. Inhaled Mannitol
Inhaled mannitol: Inhaled mannitol 400 mg BD for 26 weeks | 209 |
| Arm B - Control Arm B
Control BD (mannitol 50mg) for 26 weeks | 214 |
| Total | 423 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 6 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other - Patient's Choice | 0 | 1 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Relocation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 13 |
Baseline characteristics
| Characteristic | Arm B - Control | Total | Experimental Arm A |
|---|---|---|---|
| Age, Continuous | 28.6 years STANDARD_DEVIATION 10.75 | 27.7 years STANDARD_DEVIATION 9.37 | 26.8 years STANDARD_DEVIATION 7.63 |
| CFTR Mutation At least one other known mutation | 37 Participants | 65 Participants | 28 Participants |
| CFTR Mutation Both deltaF508 | 48 Participants | 103 Participants | 55 Participants |
| CFTR Mutation Both unknown | 40 Participants | 75 Participants | 35 Participants |
| CFTR Mutation One deltaF508 | 89 Participants | 180 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 21 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 207 Participants | 402 Participants | 195 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Exacerbations treated with IV antibiotics in 12 months before screening 0 | 120 Participants | 229 Participants | 109 Participants |
| Exacerbations treated with IV antibiotics in 12 months before screening 1 | 47 Participants | 105 Participants | 58 Participants |
| Exacerbations treated with IV antibiotics in 12 months before screening 2 | 32 Participants | 60 Participants | 28 Participants |
| Exacerbations treated with IV antibiotics in 12 months before screening 3 | 11 Participants | 24 Participants | 13 Participants |
| Exacerbations treated with IV antibiotics in 12 months before screening 4 | 3 Participants | 4 Participants | 1 Participants |
| Exacerbations treated with IV antibiotics in 12 months before screening >4 | 1 Participants | 1 Participants | 0 Participants |
| Hospitalisations due to exacerbations in 12 months prior to screening 0 | 135 Participants | 256 Participants | 121 Participants |
| Hospitalisations due to exacerbations in 12 months prior to screening 1 | 43 Participants | 100 Participants | 57 Participants |
| Hospitalisations due to exacerbations in 12 months prior to screening 2 | 23 Participants | 43 Participants | 20 Participants |
| Hospitalisations due to exacerbations in 12 months prior to screening 3 | 9 Participants | 20 Participants | 11 Participants |
| Hospitalisations due to exacerbations in 12 months prior to screening 4 | 3 Participants | 3 Participants | 0 Participants |
| Hospitalisations due to exacerbations in 12 months prior to screening >4 | 1 Participants | 1 Participants | 0 Participants |
| %Predicted FEV1 at Screening >40% to <=70% | 135 Participants | 259 Participants | 124 Participants |
| %Predicted FEV1 at Screening >70% to <=80% | 52 Participants | 106 Participants | 54 Participants |
| %Predicted FEV1 at Screening >80% to <=90% | 27 Participants | 58 Participants | 31 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 209 Participants | 411 Participants | 202 Participants |
| Region of Enrollment Argentina | 2 participants | 6 participants | 4 participants |
| Region of Enrollment Australia | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Belgium | 3 participants | 6 participants | 3 participants |
| Region of Enrollment Bulgaria | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Canada | 6 participants | 13 participants | 7 participants |
| Region of Enrollment Czechia | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Greece | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Hungary | 8 participants | 17 participants | 9 participants |
| Region of Enrollment Israel | 7 participants | 11 participants | 4 participants |
| Region of Enrollment Italy | 8 participants | 15 participants | 7 participants |
| Region of Enrollment Mexico | 2 participants | 5 participants | 3 participants |
| Region of Enrollment New Zealand | 3 participants | 5 participants | 2 participants |
| Region of Enrollment Poland | 22 participants | 44 participants | 22 participants |
| Region of Enrollment Romania | 5 participants | 10 participants | 5 participants |
| Region of Enrollment Russia | 20 participants | 41 participants | 21 participants |
| Region of Enrollment Slovakia | 9 participants | 17 participants | 8 participants |
| Region of Enrollment South Africa | 6 participants | 10 participants | 4 participants |
| Region of Enrollment Spain | 5 participants | 11 participants | 6 participants |
| Region of Enrollment Turkey | 4 participants | 8 participants | 4 participants |
| Region of Enrollment Ukraine | 32 participants | 63 participants | 31 participants |
| Region of Enrollment United States | 59 participants | 116 participants | 57 participants |
| Sex: Female, Male Female | 107 Participants | 199 Participants | 92 Participants |
| Sex: Female, Male Male | 107 Participants | 224 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 207 | 1 / 213 |
| other Total, other adverse events | 144 / 207 | 140 / 213 |
| serious Total, serious adverse events | 31 / 207 | 29 / 213 |
Outcome results
Primary
Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4).
The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits. Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Time frame: 26 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental Arm A | Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). | 63 mL |
| Arm B - Control | Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). | 8 mL |
p-value: 0.0295% CI: [8, 100]Mixed Models Analysis
Secondary
Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period
To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for improving lung function as measured by mean change from baseline forced vital capacity (FVC) (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF). The mean absolute change from baseline FVC (mL) over 26 weeks will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Time frame: 26 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental Arm A | Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period | 28 mL |
| Arm B - Control | Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period | -12 mL |
p-value: 0.12895% CI: [-12, 92]Mixed Models Analysis
Post Hoc
Absolute Change in Forced Expiratory Flow From 25% to 75% of Vital Capacity (FEF25-75) Over the 26-week Treatment Period.
The mean absolute change from baseline FEF25-75 (mL/s) over weeks 6, 14 and 26 will be compared between the two treatment groups with a REML based repeated measures approach Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Time frame: 26 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental Arm A | Absolute Change in Forced Expiratory Flow From 25% to 75% of Vital Capacity (FEF25-75) Over the 26-week Treatment Period. | 109 mL/s |
| Arm B - Control | Absolute Change in Forced Expiratory Flow From 25% to 75% of Vital Capacity (FEF25-75) Over the 26-week Treatment Period. | 22 mL/s |
p-value: 0.01295% CI: [20, 155]Mixed Models Analysis
Other Pre-specified
Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score
To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for improving respiratory symptoms measured by Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain. The CFQ-R respiratory domain score is a scale from 0 to 100. Higher scores are a more favourable response. The mean absolute change from baseline over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Time frame: 26 weeks
Population: Intent to Treat (ITT) - All patients randomised.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental Arm A | Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score | 0.308 score on a scale |
| Arm B - Control | Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score | -0.562 score on a scale |
p-value: 0.45395% CI: [-1.406, 3.145]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks
To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for improving ease of expectoration. The visual analogue scale (VAS) was 10cm. The position marked by the subject was converted into a score from 0 to 100 where 0 was the worst possible outcome and 100 was the best possible outcome. The VAS was completed at baseline, 6, 14 and 26 weeks. The mean absolute change from baseline over 26 weeks (ie the average of the changes at 6,14 and 26 weeks) is the outcome measure and will be compared between the two treatment groups with a REML based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).
Time frame: 26 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Experimental Arm A | Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks | 0.795 cm |
| Arm B - Control | Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks | 0.537 cm |
p-value: 0.08395% CI: [-0.034, 0.551]Mixed Models Analysis
Other Pre-specified
Number of Days in Hospital Due to Pulmonary Exacerbation
To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days in hospital due to protocol defined pulmonary exacerbation.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental Arm A | Number of Days in Hospital Due to Pulmonary Exacerbation | 0 days | 192 Participants |
| Experimental Arm A | Number of Days in Hospital Due to Pulmonary Exacerbation | 1-7 days | 1 Participants |
| Experimental Arm A | Number of Days in Hospital Due to Pulmonary Exacerbation | 8-14 days | 4 Participants |
| Experimental Arm A | Number of Days in Hospital Due to Pulmonary Exacerbation | 15-21 days | 5 Participants |
| Experimental Arm A | Number of Days in Hospital Due to Pulmonary Exacerbation | 22-28 days | 3 Participants |
| Experimental Arm A | Number of Days in Hospital Due to Pulmonary Exacerbation | >28 days | 4 Participants |
| Arm B - Control | Number of Days in Hospital Due to Pulmonary Exacerbation | 22-28 days | 2 Participants |
| Arm B - Control | Number of Days in Hospital Due to Pulmonary Exacerbation | 0 days | 199 Participants |
| Arm B - Control | Number of Days in Hospital Due to Pulmonary Exacerbation | 15-21 days | 3 Participants |
| Arm B - Control | Number of Days in Hospital Due to Pulmonary Exacerbation | 1-7 days | 4 Participants |
| Arm B - Control | Number of Days in Hospital Due to Pulmonary Exacerbation | >28 days | 0 Participants |
| Arm B - Control | Number of Days in Hospital Due to Pulmonary Exacerbation | 8-14 days | 6 Participants |
p-value: 0.73595% CI: [0.315, 5.154]Negative binomial model
Other Pre-specified
Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation
To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days on antibiotics due to protocol defined pulmonary exacerbations. Overlapping antibiotics are counted separately.
Time frame: 26 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental Arm A | Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation | 8.1 days | Standard Deviation 31.25 |
| Arm B - Control | Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation | 5.5 days | Standard Deviation 17.94 |
p-value: 0.67395% CI: [0.198, 2.846]Negative binomial model
Other Pre-specified
Rate of Pulmonary Exacerbations Over the 26-week Treatment Period
To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of protocol defined pulmonary exacerbations over the 26-week treatment period compared to control in adult subjects with CF. Protocol defined pulmonary exacerbations defined by having 4 or more symptoms and treated with IV antibiotics.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental Arm A | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 1 protocol defined pulm exac | 24 Participants |
| Experimental Arm A | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 0 protocol defined pulm exac | 181 Participants |
| Experimental Arm A | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 2 protocol defined pulm exac | 3 Participants |
| Experimental Arm A | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | >2 protocol defined pulm exac | 1 Participants |
| Arm B - Control | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | >2 protocol defined pulm exac | 0 Participants |
| Arm B - Control | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 2 protocol defined pulm exac | 0 Participants |
| Arm B - Control | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 0 protocol defined pulm exac | 185 Participants |
| Arm B - Control | Rate of Pulmonary Exacerbations Over the 26-week Treatment Period | 1 protocol defined pulm exac | 29 Participants |
Comparison: Patients withdrawing early without an exacerbation had rate imputed based on number of exacerbations in 12 months prior to screening.p-value: 0.05595% CI: [0.99, 2.411]Negative binomial model
Comparison: Sensitivity analysis with no imputation of missing data.p-value: 0.24695% CI: [0.81, 2.275]Negative binomial model
Other Pre-specified
The Incidence of Pulmonary Exacerbations
To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing incidence of protocol defined pulmonary exacerbations, where incidence is defined as the proportion of subjects with 1 or more exacerbation during the 26 week period.
Time frame: 26 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental Arm A | The Incidence of Pulmonary Exacerbations | 28 Participants |
| Arm B - Control | The Incidence of Pulmonary Exacerbations | 29 Participants |
p-value: 0.97695% CI: [0.555, 1.836]Regression, Logistic
Other Pre-specified
Time to First Pulmonary Exacerbation Over the 26-week Treatment Period
To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in increasing the time to first protocol defined pulmonary exacerbation over the 26-week treatment period in adult subjects with CF. Protocol defined pulmonary exacerbations are those where 4 or more symptoms are recorded and are treated with IV antibiotics
Time frame: 26 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm A | Time to First Pulmonary Exacerbation Over the 26-week Treatment Period | NA days |
| Arm B - Control | Time to First Pulmonary Exacerbation Over the 26-week Treatment Period | NA days |
p-value: 0.62995% CI: [0.671, 1.936]Regression, Cox