Crossover Trial Determining the Efficacy of Dry Powder Mannitol to Improve Lung Function in Subjects Aged 6-17 Years

A Randomised, Multicentre, Double-blind, Placebo-controlled, Crossover Trial Determining the Efficacy of Dry Powder Mannitol in Improving Lung Function in Subjects With Cystic Fibrosis Aged Six to Seventeen Years

It is hypothesised that inhaled mannitol 400 mg b.d. will lead to a significant improvement in the absolute change in percentage of predicted FEV1 from baseline following eight-weeks of trial treatment compared to treatment with inhaled placebo b.d.

Any improvement in FEV1 is considered clinically meaningful; however, this trial has set a threshold of 3% for the purposes of determining an appropriate sample size for statistical power whilst retaining trial feasibility in an orphan disease population.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Inhaled Placebo; Drug: Inhaled Mannitol

Detailed Description

Drug Name: Dry powder mannitol for inhalation Phase: 2 Indication: Paediatric and adolescent cystic fibrosis Trial Centres: Multicentre Sponsor: Pharmaxis Limited, 20 Rodborough Road, Frenchs Forest, NSW 2086 Australia Trial Duration: 27 weeks Number of Subjects: 160 Trial Design: Randomised, multicentre, double-blind, placebo-controlled, crossover Primary Objective: To determine the effect of eight weeks of twice-daily treatment with inhaled dry powder mannitol on lung function (FEV1) in subjects with CF who are aged six to seventeen years Dosage and Administration: Trial drug is to be administered via a dry powder inhaler.

• Mannitol 400 mg b.d. for 8 weeks followed by a 8-week washout followed by placebo b.d. for 8 weeks; or
• Placebo b.d. for 8 weeks followed by a 8-week washout followed by mannitol 400 mg b.d. for 8 weeks.

Statistical Methods:

• The primary and secondary efficacy analyses will be based upon a modified Grizzle model for crossover design. Absolute and relative changes from baseline in percentage of predicted FEV1 and FVC will be analysed. The absolute change in percentage of predicted lung function (FEV1 and FVC) will be the primary focus. Changes in FEF25-75 will also be analysed.
• Safety data will be analysed descriptively (listings and summary tables).

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: The subject must:

1. Personally provide, or have a legal guardian provide written informed consent to participate in the trial, according to local regulations;
2. rhDNase and maintenance antibiotic use is allowed but treatment must have been established at least 3 months prior to screening. The subject must remain on rhDNase and / or maintenance antibiotics for the duration of the trial. The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial;
3. Have a confirmed diagnosis of cystic fibrosis (sweat test result greater than or equal to 60 mEq/L chloride and/or genotyping showing two identifiable mutations consistent with a diagnosis of cystic fibrosis);
4. Be aged greater than or equal to 6 years and < 18 years;
5. Have a percentage of predicted FEV1 of greater than or equal to 30% and less than or equal to 90% at Screening (Visit 0). Percentage of predicted FEV1 will be calculated using Wang for children aged < 8 years, and using NHanes III for those greater than or equal to 8 years; and
6. Be able to perform all the techniques necessary to measure lung function.

Exclusion Criteria: The subject must NOT:

1. Be using maintenance nebulised hypertonic saline;
2. Be considered "terminally ill"; eligible for lung transplantation, or have received a lung transplant previously;
3. Require home oxygen or assisted ventilation;
4. Have had an episode of massive haemoptysis defined as acute bleeding ≥240 ml in a 24-hour period and/or recurrent bleeding ≥100 ml/day over several days in the three-months prior to Screening (Visit 0);
5. Have a known intolerance to mannitol;
6. Be taking non-selective beta-blockers;
7. In the three months prior to Screening (Visit 0) have had a myocardial infarction; a cerebral vascular accident; major ocular, abdominal, chest or brain surgery;
8. Have a known cerebral, aortic or abdominal aneurysm;
9. Be currently participating in, or have participated in another investigative drug trial within four weeks of Screening (Visit 0);
10. Be pregnant or breastfeeding, or plan to become pregnant whilst in the trial;
11. For females of childbearing potential, be using an unreliable form of contraception, (at the discretion of the investigator);
12. Have any concomitant medical, psychiatric, or social condition that, in the Investigator's opinion, would put the subject at significant risk, may confound the results or may significantly interfere with the subject's participation in the trial; or
13. Have a "failed" or "incomplete" mannitol tolerance test (as described in Section 8.3.1.1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Inhaled Placebo; Eight-week treatment period with inhaled placebo b.d.	Drug: Inhaled Placebo; The PLacebo is non respirable mannitol due to the big size particle; Other Names: Control
Active Comparator: Inhaled Mannitol; Eight-week treatment period Inhaled Mannitol 400 mg b.d.	Drug: Inhaled Mannitol; Active treatment is inhaled mannitol with a particle size of 3-4 microns; Other Names: Mannitol; IDPM; Dry Powder Mannitol for Inhalation; Bronchitol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on lung function (FEV1)	To determine the effect of eight weeks of twice-daily treatment with inhaled dry powder mannitol on lung function (FEV1) in subjects with CF who are aged six to seventeen years.	The absolute change from each treatment period baseline to week 8 of each treatment period in percentage of predicted FEV1.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on FVC	To determine the effect of inhaled mannitol on FVC	The absolute change from each treatment period baseline to week 8 of each treatment period in percentage of predicted FVC.
Effect of inhaled mannitol on FEF25-75	To determine the effect of inhaled mannitol on FEF25-75 (exploratory endpoint)	The absolute change from each treatment period baseline to week 8 of each treatment period in percentage of predicted FEF25-75.
Assess safety	Assessment of safety will be made on the basis of reviewing changes in physical examination and using adverse event data.	From each treatment period baseline to week 8 of each treatment period.
Sputum weight	To evaluate the difference in treatment induced sputum weight in subjects treated with inhaled mannitol compared with placebo	The absolute change from each treatment period baseline to week 8 of each treatment period in sputum weight.

Collaborators and Investigators

• Sponsor: Pharmaxis
• Investigators: Principal Investigator: Christiane De Boeck, UZ Leuven, Belgium; Principal Investigator: Jeremy Hull, Dr, John Radcliffe Hospital, Oxford, UK; Principal Investigator: Anne Munck, Dr, Hôpital Robert Debré, France; Principal Investigator: Joachim Riethmuller, Dr, Universitats Kinderklinik Tubingen, Germany; Principal Investigator: Larry Lands, MD, 'Montreal Children's Hospital, Montreal, Canada; Principal Investigator: Alexander Möller, MD, University Childrens Hospital Zurich; Principal Investigator: Sonia Volpi, MD, Azienda Ospedaliera Universitaria Integrata Verona Italy; Principal Investigator: Harm Tiddens, MD, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: June 17, 2013
• First Submitted That Met QC Criteria: June 19, 2013
• First Posted (Estimate): June 21, 2013

Study Record Updates

• Last Update Posted (Estimate): October 14, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: FEV1; improving lung function; paediatric and adolescent
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: DPM-CF-204; 2012-002699-14 (EudraCT Number)