Cystic Fibrosis
Conditions
Keywords
cystic fibrosis, mannitol, mucoactive
Brief summary
The purpose of this study is to examine the efficacy and safety of 26 weeks treatment with inhaled mannitol in subjects with cystic fibrosis. Previous studies have demonstrated improvements in lung function, mucociliary clearance, changes in physical properties of mucus, 24 hour sputum weight and quality of life. The results of this study are to further investigate and confirm these findings in addition to examine the effect on antibiotic use and chest infections. It is hypothesised that inhaled mannitol will have beneficial effects compared to a control treatment. An open label phase of 26 weeks duration will follow the blinded 26 week phase. During the open label phase all subjects will receive active treatment.
Interventions
DRUGinhaled mannitol
400 mg BD for 26 + 26 weeks
DRUGPlacebo comparator
BD for 26 weeks followed by 26 weeks of inhaled mannitol in the open label phase
Sponsors
ethica Clinical Research Inc.
Europe: KasaConsult bvba, Hoegaarden, Belgium
Resolution Latin America
Syntara
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have given written informed consent to participate in this study 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 \> 6 years old 4. Have FEV1 \>40 % and \< 90% predicted 5. Be able to perform all the techniques necessary to measure lung function
Exclusion criteria
1. Investigators, site personnel directly affiliated with this study, 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 nebulized hypertonic saline in the 4 weeks prior to visit 1 5. Have had a significant episode of hemoptysis (\>60 mL) in the three months prior to enrolment 6. Have had a myocardial infarction in the three months prior to enrolment 7. Have had a cerebral vascular accident in the three months prior to enrolment 8. Have had major ocular surgery in the three months prior to enrolment 9. Have had major abdominal, chest or brain surgery in the three months prior to enrolment 10. Have a known cerebral, aortic or abdominal aneurysm 11. Be breast feeding or pregnant, or plan to become pregnant while in the study 12. Be using an unreliable form of contraception (female subjects at risk of pregnancy only) 13. Be participating in another investigative drug study, parallel to, or within 4 weeks of visit 0 14. Have a known allergy to mannitol 15. Be using beta blockers 16. Have uncontrolled hypertension - 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 patient's participation in the study 18. Be 'Mannitol Tolerance Test positive' \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Absolute FEV1 From Baseline Over 26 Weeks | 26 weeks | Change from baseline in forced expiratory volume at one second (FEV1) averaged over 26 weeks (measured at 6,14 and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | 26 weeks | Exacerbations treated with IV antibiotics and with at least 4 signs and symptoms according to Fuchs criteria (1994). Summary table presents the number with 0, 1,2 and 3 PDPEs during the 26 week treatment period. |
| Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 26 weeks | The number of hospitalisations is summarised and then the rate per person is analysed. |
| Antibiotic Use Associated With PDPEs | 26 weeks | Number of courses per person in the 26 week period is summarised and then the rate per person analysed. |
| Change in FEV1 From Baseline Over 26 Weeks - Dornase Users | 26 weeks | In the subset of dornase users, the mean absolute change from baseline FEV1 (mL) averaged 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. Change from baseline over 26 weeks (measured at 6,14, 26 weeks) in subset of dornase users |
| Change in FVC (mL) Across 26 Weeks | 26 weeks | Change from baseline in forced vital capacity (FVC) across 26 weeks (measured at 6,14 and 26 weeks) |
| Change From Baseline FEF25-75 (mL/s) Over 26 Weeks | 26 weeks | Change from baseline in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75) (mL/s) averaged over 26 weeks (measured at 6,14 and 26 weeks) The mean absolute change from baseline over 26 weeks (measured at week 6, 14 and 26) was 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. |
| Sputum Weight at Baseline in Response to First Dose of Treatment | up to 30 mins after first dose of trial treatment | Sputum was collected during and for 30 minutes following the administration of the first dose of study treatment. |
| Absolute Change in FEV1 Percent Predicted at 26 Weeks | 26 weeks | Change from baseline at 26 weeks in FEV1 percent predicted with BOCF for those with missing values at week 26 |
Countries
Argentina, Belgium, Canada, France, Germany, Netherlands, United States
Participant flow
Pre-assignment details
Patients underwent a mannitol tolerance test (MTT) to gauge tolerance to a test dose of mannitol. 318 patients were then randomised - only 305 of the randomised patients went on to receive a dose of study medication. Patients who did not start medication (13) were not included in the modified ITT population (mITT)
Participants by arm
| Arm | Count |
|---|---|
| Mannitol 400mg active treatment
inhaled mannitol: 400 mg BD for 26 + 26 weeks | 184 |
| Control Control (40mg inhaled mannitol) : BD for 26 weeks followed by 26 weeks of inhaled mannitol in the open label phase | 121 |
| Total | 305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment Period | Adverse Event | 13 | 5 |
| Double Blind Treatment Period | Lost to Follow-up | 1 | 0 |
| Double Blind Treatment Period | Non-compliance | 0 | 1 |
| Double Blind Treatment Period | Physician Decision | 2 | 1 |
| Double Blind Treatment Period | Protocol Violation | 1 | 0 |
| Double Blind Treatment Period | Wanted to take drug in non-protocol way | 1 | 0 |
| Double Blind Treatment Period | Withdrawal by Subject | 13 | 7 |
| Randomisation to First Dose | Adverse Event | 1 | 1 |
| Randomisation to First Dose | Lost to Follow-up | 1 | 0 |
| Randomisation to First Dose | Protocol Violation | 4 | 1 |
| Randomisation to First Dose | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Mannitol 400mg | Total | Control |
|---|---|---|---|
| Age, Categorical <=18 years | 91 Participants | 154 Participants | 63 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 151 Participants | 58 Participants |
| CF mutation At least one other known mutation | 15 Participants | 20 Participants | 5 Participants |
| CF mutation Both deltaF508 | 77 Participants | 122 Participants | 45 Participants |
| CF mutation Both unknown | 35 Participants | 54 Participants | 19 Participants |
| CF mutation One deltaF508 | 57 Participants | 109 Participants | 52 Participants |
| Hospitalisations in year prior to study participation 0 hospitalisations | 114 Participants | 190 Participants | 76 Participants |
| Hospitalisations in year prior to study participation 1 hospitalisation | 41 Participants | 71 Participants | 30 Participants |
| Hospitalisations in year prior to study participation 2 hospitalisations | 21 Participants | 30 Participants | 9 Participants |
| Hospitalisations in year prior to study participation >3 hospitalisations | 4 Participants | 6 Participants | 2 Participants |
| Hospitalisations in year prior to study participation 3 hospitalisations | 4 Participants | 8 Participants | 4 Participants |
| Pulmonary exacerbations in year prior to study participation 0 exacerbations | 104 Participants | 178 Participants | 74 Participants |
| Pulmonary exacerbations in year prior to study participation 1 exacerbation | 45 Participants | 73 Participants | 28 Participants |
| Pulmonary exacerbations in year prior to study participation 2 exacerbations | 26 Participants | 40 Participants | 14 Participants |
| Pulmonary exacerbations in year prior to study participation >3 exacerbations | 5 Participants | 7 Participants | 2 Participants |
| Pulmonary exacerbations in year prior to study participation 3 exacerbations | 4 Participants | 7 Participants | 3 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 | 4 Participants | 2 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 | 182 Participants | 301 Participants | 119 Participants |
| Region of Enrollment Argentina | 48 participants | 80 participants | 32 participants |
| Region of Enrollment Belgium | 10 participants | 16 participants | 6 participants |
| Region of Enrollment Canada | 11 participants | 20 participants | 9 participants |
| Region of Enrollment France | 14 participants | 23 participants | 9 participants |
| Region of Enrollment Germany | 14 participants | 23 participants | 9 participants |
| Region of Enrollment Netherlands | 2 participants | 4 participants | 2 participants |
| Region of Enrollment United States | 85 participants | 139 participants | 54 participants |
| Sex: Female, Male Female | 90 Participants | 148 Participants | 58 Participants |
| Sex: Female, Male Male | 94 Participants | 157 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 184 | 1 / 121 |
| other Total, other adverse events | 165 / 184 | 106 / 121 |
| serious Total, serious adverse events | 31 / 184 | 30 / 121 |
Outcome results
Primary
Change in Absolute FEV1 From Baseline Over 26 Weeks
Change from baseline in forced expiratory volume at one second (FEV1) averaged over 26 weeks (measured at 6,14 and 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.
Time frame: 26 weeks
Population: mITT (modified intent to treat) - patients randomised and treated with at least one dose of study medication)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol 400mg | Change in Absolute FEV1 From Baseline Over 26 Weeks | 106.53 mL |
| Control | Change in Absolute FEV1 From Baseline Over 26 Weeks | 52.38 mL |
p-value: 0.05995% CI: [-1.97, 110.26]Mixed Models Analysis
p-value: 0.04195% CI: [1.02, 2.8]Regression, Logistic
Secondary
Absolute Change in FEV1 Percent Predicted at 26 Weeks
Change from baseline at 26 weeks in FEV1 percent predicted with BOCF for those with missing values at week 26
Time frame: 26 weeks
Population: Baseline Observation carried forward (BOCF) implemented for those with missing values at visit 4
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol 400mg | Absolute Change in FEV1 Percent Predicted at 26 Weeks | 3.14 % of predicted |
| Control | Absolute Change in FEV1 Percent Predicted at 26 Weeks | 0.72 % of predicted |
p-value: 0.02495% CI: [0.33, 4.51]ANCOVA
Secondary
Antibiotic Use Associated With PDPEs
Number of courses per person in the 26 week period is summarised and then the rate per person analysed.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mannitol 400mg | Antibiotic Use Associated With PDPEs | 0 courses | 156 Participants |
| Mannitol 400mg | Antibiotic Use Associated With PDPEs | 1 course | 22 Participants |
| Mannitol 400mg | Antibiotic Use Associated With PDPEs | 2 courses | 5 Participants |
| Mannitol 400mg | Antibiotic Use Associated With PDPEs | 3 courses | 1 Participants |
| Control | Antibiotic Use Associated With PDPEs | 3 courses | 2 Participants |
| Control | Antibiotic Use Associated With PDPEs | 0 courses | 98 Participants |
| Control | Antibiotic Use Associated With PDPEs | 2 courses | 2 Participants |
| Control | Antibiotic Use Associated With PDPEs | 1 course | 19 Participants |
p-value: 0.36895% CI: [0.69, 1.15]Poisson regression
Secondary
Change From Baseline FEF25-75 (mL/s) Over 26 Weeks
Change from baseline in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75) (mL/s) averaged over 26 weeks (measured at 6,14 and 26 weeks) The mean absolute change from baseline over 26 weeks (measured at week 6, 14 and 26) was 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.
Time frame: 26 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol 400mg | Change From Baseline FEF25-75 (mL/s) Over 26 Weeks | 84.65 mL/s |
| Control | Change From Baseline FEF25-75 (mL/s) Over 26 Weeks | 50.31 mL/s |
p-value: 0.4995% CI: [-63.47, 132.14]Mixed Models Analysis
Secondary
Change in FEV1 From Baseline Over 26 Weeks - Dornase Users
In the subset of dornase users, the mean absolute change from baseline FEV1 (mL) averaged 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. Change from baseline over 26 weeks (measured at 6,14, 26 weeks) in subset of dornase users
Time frame: 26 weeks
Population: Note these are subset of dornase users - effect in dornase users was estimated using a model fitted using data from all patients
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol 400mg | Change in FEV1 From Baseline Over 26 Weeks - Dornase Users | 78.60 mL |
| Control | Change in FEV1 From Baseline Over 26 Weeks - Dornase Users | 35.11 mL |
p-value: 0.17795% CI: [-19.8, 106.78]Mixed Models Analysis
Secondary
Change in FVC (mL) Across 26 Weeks
Change from baseline in forced vital capacity (FVC) across 26 weeks (measured at 6,14 and 26 weeks)
Time frame: 26 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Mannitol 400mg | Change in FVC (mL) Across 26 Weeks | 136.33 mL |
| Control | Change in FVC (mL) Across 26 Weeks | 64.98 mL |
p-value: 0.02295% CI: [10.57, 132.13]Mixed Models Analysis
Secondary
Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs)
The number of hospitalisations is summarised and then the rate per person is analysed.
Time frame: 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mannitol 400mg | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 0 hospitalisations | 162 Participants |
| Mannitol 400mg | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 1 hospitalisation | 18 Participants |
| Mannitol 400mg | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 2 hospitalisations | 3 Participants |
| Mannitol 400mg | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 3 hospitalisations | 1 Participants |
| Control | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 3 hospitalisations | 0 Participants |
| Control | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 0 hospitalisations | 102 Participants |
| Control | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 2 hospitalisations | 5 Participants |
| Control | Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs) | 1 hospitalisation | 14 Participants |
p-value: 0.32895% CI: [0.42, 1.33]Poisson regression
Secondary
Rate of Protocol Defined Pulmonary Exacerbations (PDPE)
Exacerbations treated with IV antibiotics and with at least 4 signs and symptoms according to Fuchs criteria (1994). Summary table presents the number with 0, 1,2 and 3 PDPEs during the 26 week treatment period.
Time frame: 26 weeks
Population: mITT (randomised and treated)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mannitol 400mg | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | With 1 PDPE | 21 Participants |
| Mannitol 400mg | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | With 2 PDPE | 6 Participants |
| Mannitol 400mg | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | With 3 PDPE | 1 Participants |
| Mannitol 400mg | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | No PDPEs | 156 Participants |
| Control | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | No PDPEs | 98 Participants |
| Control | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | With 1 PDPE | 18 Participants |
| Control | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | With 3 PDPE | 1 Participants |
| Control | Rate of Protocol Defined Pulmonary Exacerbations (PDPE) | With 2 PDPE | 4 Participants |
p-value: 0.5295% CI: [0.51, 1.41]Poisson regression
Secondary
Sputum Weight at Baseline in Response to First Dose of Treatment
Sputum was collected during and for 30 minutes following the administration of the first dose of study treatment.
Time frame: up to 30 mins after first dose of trial treatment
Population: Patients randomised and treated who have sputum weight results available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mannitol 400mg | Sputum Weight at Baseline in Response to First Dose of Treatment | 4.9 g | Standard Deviation 6.18 |
| Control | Sputum Weight at Baseline in Response to First Dose of Treatment | 3.5 g | Standard Deviation 4.4 |
p-value: 0.042Wilcoxon (Mann-Whitney)