A Safety and Efficacy Trial of Inhaled Mannitol in Adult Cystic Fibrosis Subjects

• ClinicalTrials.gov Identifier: NCT02134353
• Recruitment Status: Completed
• First Posted: May 9, 2014
• Results First Posted: September 3, 2020
• Last Update Posted: October 28, 2020
• Sponsor: Pharmaxis
• Information provided by (Responsible Party): Pharmaxis

Tracking Information

• First Submitted Date: April 16, 2014
• First Posted Date: May 9, 2014
• Results First Submitted Date: August 3, 2020
• Results First Posted Date: September 3, 2020
• Last Update Posted Date: October 28, 2020
• Actual Study Start Date: September 2014
• Actual Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 18, 2020)

Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). [ Time Frame: 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).

Original Primary Outcome Measures (submitted: May 7, 2014)

Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). [ Time Frame: 26 weeks ]

The mean absolute change from baseline FEV1 (mL) over weeks 6, 14 and 26 will be compared between the two treatment groups with a REML based repeated measures approach

Current Secondary Outcome Measures (submitted: August 18, 2020)

Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: May 7, 2014)

Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period [ Time Frame: 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 FVC (mL) over the 26-week treatment period in adult subjects with CF.

Current Other Pre-specified Outcome Measures (submitted: August 18, 2020)

• Time to First Pulmonary Exacerbation Over the 26-week Treatment Period [ Time Frame: 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
• Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation [ Time Frame: 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.
• Number of Days in Hospital Due to Pulmonary Exacerbation [ Time Frame: 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 [ Time Frame: 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.
• The Incidence of Pulmonary Exacerbations [ Time Frame: 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.
• Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks [ Time Frame: 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 [ Time Frame: 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).

Original Other Pre-specified Outcome Measures (submitted: May 7, 2014)

• Time to First Pulmonary Exacerbation Over the 26-week Treatment Period [ Time Frame: 26 weeks ]
  To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in increasing the time to first pulmonary exacerbation over the 26-week treatment period in adult subjects with CF
• Rate of Pulmonary Exacerbations Over the 26-week Treatment Period [ Time Frame: 26 weeks ]
  To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of pulmonary exacerbations over the 26-week treatment period compared to control in adult subjects with CF
• Number of Days in Hospital Due to Pulmonary Exacerbation [ Time Frame: 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 pulmonary exacerbation.
• The Incidence of Pulmonary Exacerbations [ Time Frame: 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 pulmonary exacerbations
• Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation [ Time Frame: 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 pulmonary exacerbation.
• Ease of expectoration measured using a visual analogue scale [ Time Frame: 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
• CFQ-R respiratory domain score [ Time Frame: 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 CFQ-R respiratory domain

Descriptive Information

• Brief Title: A Safety and Efficacy Trial of Inhaled Mannitol in Adult Cystic Fibrosis Subjects
• Official Title: Long Term Administration of Inhaled Mannitol in Cystic Fibrosis - A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects

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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cystic Fibrosis

Intervention

• Drug: Inhaled mannitol
  Inhaled mannitol 400 mg BD for 26 weeks
• Drug: Placebo Comparator: Arm B - Control
  Placebo Comparator: Arm B - Control BD for 26 weeks

Study Arms

• Experimental: Experimental arm A
  Active treatment. Inhaled Mannitol
  Intervention: Drug: Inhaled mannitol
• Placebo Comparator: Arm B - Control
  Arm B
  Intervention: Drug: Placebo Comparator: Arm B - Control

• Publications *: Flume PA, Amelina E, Daines CL, Charlton B, Leadbetter J, Guasconi A, Aitken ML. Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study. J Cyst Fibros. 2021 Mar 11. pii: S1569-1993(21)00046-1. doi: 10.1016/j.jcf.2021.02.011. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 7, 2018): 423
• Original Estimated Enrollment (submitted: May 7, 2014): 440
• Actual Study Completion Date: February 2017
• Actual Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Canada, Czechia, Hungary, Israel, Italy, Mexico, New Zealand, Poland, Romania, Russian Federation, Slovakia, South Africa, Spain, Ukraine, United States
• Removed Location Countries: Czech Republic, France

Administrative Information

• NCT Number: NCT02134353
• Other Study ID Numbers: DPM-CF-303
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pharmaxis
• Study Sponsor: Pharmaxis
• Collaborators: Not Provided

Investigators

• Principal Investigator: Moira Aitken, MD
• Study Director: Brett Charlton, MD; Medical Director

• PRS Account: Pharmaxis
• Verification Date: October 2020