Long Term Administration of Inhaled Mannitol in Cystic Fibrosis

Cystic Fibrosis Clinical Trial

Official title:

Long Term Administration of Inhaled Mannitol in Cystic Fibrosis- A Safety and Efficacy Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00630812
• Other study ID #: DPM-CF-302
• Status: Completed
• Phase: Phase 3
• Start date: September 2008
• Est. completion date: November 2010

Study information

• Verified date: October 2020
• Source: Pharmaxis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 318
• Est. completion date: November 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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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Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• inhaled mannitol
400 mg BD for 26 + 26 weeks
• Placebo comparator
BD for 26 weeks followed by 26 weeks of inhaled mannitol in the open label phase

Locations

Country	Name	City	State
Argentina	Hospital Interzonal Dr Jose Penna Bahia Blanca	Bahia Blanca	Buenos Aires
Argentina	Atención Integral en Reumatologia (AIR)	Buenos Aires
Argentina	Hospital de Ninos Dr Ricardo Gutierrez, Pediatria	Caba	Buenos Aires
Argentina	Hospital Gral. de Ninos Pedro de Elizalde	Ciudad Autonoma	Buenos Aires
Argentina	Clinica Universitaria Privada Reina Fabiola - Universidad Cotolica de Cordoba	Cordoba
Argentina	Hospital de Ninos del la Santisima Trinidad	Cordoba
Argentina	Hospital Pediatrico Dr Humberto J Notti	Guaymallen	Mendosa
Argentina	Hospital de Ninos Superiora Sor Maria Ludovica de La Plata	La Plata	Buenos Aires
Belgium	UZ Brussel Laarbeeklan 101	Brussel
Belgium	Hopital Universitaire Reine Fabiola	Bruxelles	Brussel
Belgium	Pediatrics Respiratory Medicine	Edegem	Antwerpen
Belgium	UZ Gasthuisberg	Leuven
Canada	Foothills medical center	Calgary	Alberta
Canada	QEII Health Sciences Center	Halifax	Nova Scotia
Canada	The Children's Asthma Clinic	London	Ontario
France	Hopital Femme-Mere-Enfents	Bron Cedex	Lyon
France	Hopital Andre Mignot	Le Chesnay	Cedix
France	Hopital Jeanne de Flandre	Lille CEDEX	Lille
France	Hopital Mere-Enfant	Nantes	Cedex
France	Hopital Robert Debre	Paris
France	Hopital de Hautepierre	Strasbourg CEDEX	Strasbourg
Germany	University of Munich Medizinischen Klinik Innenstadt	Munchen
Germany	Universitats Kinderklinik Tubungen Wurzburg	Tubingen
Germany	Universitats Kinderklinik Wurzburg	Wurzburg
Netherlands	Academic Medical Centre	Amsterdam
United States	Children's Chest Associates of Austin	Austin	Texas
United States	John Hopkins	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Women and Childrens Hospital of Buffalo	Buffalo	New York
United States	Medical University of SC	Charleston	South Carolina
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	University of Missouri	Columbia	Missouri
United States	Central Connecticut Cystic Fibrosis Center	Hartford	Connecticut
United States	Baylor College of Medicine	Houston	Texas
United States	St Lukes CF Center of Idaho	Idaho	Idaho
United States	Nemours Childrens Clinic	Jacksonville	Florida
United States	University of Wisconsin	Madison	Wisconsin
United States	Le Bonheur Children's Medical Center	Memphis	Tennessee
United States	Batchelor Children's Research Institute - University of Miami	Miami	Florida
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Medical Center - Nebraska Regional CF Center	Omaha	Nebraska
United States	Nemours Children's Clinic Orlando	Orlando	Florida
United States	St Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Maine Pediatric Specialty Group	Portland	Maine
United States	Pediatric Research, VCU Medical Centre	Richmond	Virginia
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Alamo Clinical Research Associates	San Antonio	Texas
United States	Christus Santa Rosa Children's Hospital Cystic Fibrosis Center	San Antonio	Texas
United States	University of Washington medical centre	Seattle	Washington
United States	Louisiana State University Health Sciences Center	Shreveport	Louisiana
United States	Sanford Children's Specialty Clinic	Sioux Falls	South Dakota
United States	The Toledo Hospital and Toledo Childrens Hospital	Toledo	Ohio
United States	University of Arizona	Tucson	Arizona

Sponsors (4)

Lead Sponsor	Collaborator
Pharmaxis	Argentina: Resolution Latin America; Buenos Aires, Argentina, ethica Clinical Research Inc., Europe: KasaConsult bvba, Hoegaarden, Belgium

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Canada,  France,  Germany,  Netherlands, 

References & Publications (9)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Daviskas E, Anderson SD. Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med. 2006 Spring;19(1):100-9. Review. — View Citation

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. — View Citation

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. — View Citation

Robinson M, Bye PT. Mucociliary clearance in cystic fibrosis. Pediatr Pulmonol. 2002 Apr;33(4):293-306. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	26 weeks
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	26 weeks
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.	26 weeks
Secondary	Hospitalisations Associated With Protocol Defined Pulmonary Exacerbations (PDPEs)	The number of hospitalisations is summarised and then the rate per person is analysed.	26 weeks
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.	26 weeks
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	26 weeks
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)	26 weeks
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.	26 weeks
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.	up to 30 mins after first dose of trial treatment