Long Term Administration of Inhaled Mannitol in Cystic Fibrosis

• ClinicalTrials.gov Identifier: NCT00630812
• Recruitment Status: Completed
• First Posted: March 7, 2008
• Results First Posted: October 9, 2020
• Last Update Posted: October 9, 2020
• Sponsor: Pharmaxis
• Collaborators: ethica Clinical Research Inc.; Europe: KasaConsult bvba, Hoegaarden, Belgium; Argentina: Resolution Latin America; Buenos Aires, Argentina
• Information provided by (Responsible Party): Pharmaxis

Tracking Information

• First Submitted Date: February 27, 2008
• First Posted Date: March 7, 2008
• Results First Submitted Date: August 11, 2020
• Results First Posted Date: October 9, 2020
• Last Update Posted Date: October 9, 2020
• Study Start Date: September 2008
• Actual Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 6, 2020)

Change in Absolute FEV1 From Baseline Over 26 Weeks [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: February 27, 2008): FEV1 [ Time Frame: 26 weeks ]

Current Secondary Outcome Measures (submitted: October 6, 2020)

• Change in FEV1 From Baseline Over 26 Weeks - Dornase Users [ Time Frame: 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
• Rate of Protocol Defined Pulmonary Exacerbations (PDPE) [ Time Frame: 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) [ Time Frame: 26 weeks ]
  The number of hospitalisations is summarised and then the rate per person is analysed.
• Antibiotic Use Associated With PDPEs [ Time Frame: 26 weeks ]
  Number of courses per person in the 26 week period is summarised and then the rate per person analysed.
• Absolute Change in FEV1 Percent Predicted at 26 Weeks [ Time Frame: 26 weeks ]
  Change from baseline at 26 weeks in FEV1 percent predicted with BOCF for those with missing values at week 26
• Change in FVC (mL) Across 26 Weeks [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Long Term Administration of Inhaled Mannitol in Cystic Fibrosis
• Official Title: Long Term Administration of Inhaled Mannitol in Cystic Fibrosis- A Safety and Efficacy Study
• 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.
• Detailed Description: Not Provided
• 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
  400 mg BD for 26 + 26 weeks
• Drug: Placebo comparator
  BD for 26 weeks followed by 26 weeks of inhaled mannitol in the open label phase

Study Arms

• Experimental: A
  active treatment
  Intervention: Drug: inhaled mannitol
• Placebo Comparator: B
  Intervention: Drug: Placebo comparator

Publications *

• Daviskas E, Anderson SD. Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med. 2006 Spring;19(1):100-9. Review.
• Daviskas E, Anderson SD, Gomes K, Briffa P, Cochrane B, Chan HK, Young IH, Rubin BK. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Respirology. 2005 Jan;10(1):46-56.
• Daviskas E, Robinson M, Anderson SD, Bye PT. Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction. J Aerosol Med. 2002 Fall;15(3):331-41. Review.
• Robinson M, Bye PT. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002 Apr;33(4):293-306. Review.
• Daviskas E, Anderson SD, Eberl S, Chan HK, Young IH. The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis. Chest. 2001 Feb;119(2):414-21.
• Robinson M, Daviskas E, Eberl S, Baker J, Chan HK, Anderson SD, Bye PT. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study. Eur Respir J. 1999 Sep;14(3):678-85.
• Daviskas E, Anderson SD, Eberl S, Chan HK, Bautovich G. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. Am J Respir Crit Care Med. 1999 Jun;159(6):1843-8.
• Daviskas E, Anderson SD, Brannan JD, Chan HK, Eberl S, Bautovich G. Inhalation of dry-powder mannitol increases mucociliary clearance. Eur Respir J. 1997 Nov;10(11):2449-54.
• Jaques A, Daviskas E, Turton JA, McKay K, Cooper P, Stirling RG, Robertson CF, Bye PTP, LeSouëf PN, Shadbolt B, Anderson SD, Charlton B. Inhaled mannitol improves lung function in cystic fibrosis. Chest. 2008 Jun;133(6):1388-1396. doi: 10.1378/chest.07-2294. Epub 2008 Mar 13.
• Nevitt SJ, Thornton J, Murray CS, Dwyer T. Inhaled mannitol for cystic fibrosis. Cochrane Database Syst Rev. 2020 May 1;5:CD008649. doi: 10.1002/14651858.CD008649.pub4.
• Aitken ML, Bellon G, De Boeck K, Flume PA, Fox HG, Geller DE, Haarman EG, Hebestreit HU, Lapey A, Schou IM, Zuckerman JB, Charlton B; CF302 Investigators. Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study. Am J Respir Crit Care Med. 2012 Mar 15;185(6):645-52. doi: 10.1164/rccm.201109-1666OC. Epub 2011 Dec 28.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 23, 2010): 318
• Original Estimated Enrollment (submitted: February 27, 2008): 250
• Actual Study Completion Date: November 2010
• Actual Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

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'

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Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Canada, France, Germany, Netherlands, United States

Administrative Information

• NCT Number: NCT00630812
• Other Study ID Numbers: DPM-CF-302
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pharmaxis
• Study Sponsor: Pharmaxis

Collaborators

• ethica Clinical Research Inc.
• Europe: KasaConsult bvba, Hoegaarden, Belgium
• Argentina: Resolution Latin America; Buenos Aires, Argentina

Investigators

• Principal Investigator: Moira L Aitken, MD; University of Washington Medical Centre, Seattle WA

• PRS Account: Pharmaxis
• Verification Date: October 2020