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

Primary Purpose

Cystic Fibrosis

Status

Completed

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

Inhaled Mannitol

Inhaled Placebo

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring improving lung function, paediatric and adolescent, FEV1

Eligibility Criteria

6 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria: The subject must:

Personally provide, or have a legal guardian provide written informed consent to participate in the trial, according to local regulations;
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;
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);
Be aged greater than or equal to 6 years and < 18 years;
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
Be able to perform all the techniques necessary to measure lung function.

Exclusion Criteria: The subject must NOT:

Be using maintenance nebulised hypertonic saline;
Be considered "terminally ill"; eligible for lung transplantation, or have received a lung transplant previously;
Require home oxygen or assisted ventilation;
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);
Have a known intolerance to mannitol;
Be taking non-selective beta-blockers;
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;
Have a known cerebral, aortic or abdominal aneurysm;
Be currently participating in, or have participated in another investigative drug trial within four weeks of Screening (Visit 0);
Be pregnant or breastfeeding, or plan to become pregnant whilst in the trial;
For females of childbearing potential, be using an unreliable form of contraception, (at the discretion of the investigator);
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
Have a "failed" or "incomplete" mannitol tolerance test (as described in Section 8.3.1.1).

Sites / Locations

John Radcliffe Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Inhaled Placebo

Inhaled Mannitol

Arm Description

Eight-week treatment period with inhaled placebo b.d.

Eight-week treatment period Inhaled Mannitol 400 mg b.d.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Effect on FVC

To determine the effect of inhaled mannitol on FVC

Effect of inhaled mannitol on FEF25-75

To determine the effect of inhaled mannitol on FEF25-75 (exploratory endpoint)

Assess safety

Assessment of safety will be made on the basis of reviewing changes in physical examination and using adverse event data.

Sputum weight

To evaluate the difference in treatment induced sputum weight in subjects treated with inhaled mannitol compared with placebo

Full Information

NCT ID

NCT01883531

First Posted

June 17, 2013

Last Updated

October 12, 2015

Sponsor

Pharmaxis

1. Study Identification

Unique Protocol Identification Number

NCT01883531

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2015

Overall Recruitment Status

Completed

Study Start Date

June 2013 (undefined)

Primary Completion Date

October 2015 (Actual)

Study Completion Date

October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pharmaxis

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis

Keywords

improving lung function, paediatric and adolescent, FEV1

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

95 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Inhaled Placebo

Arm Type

Placebo Comparator

Arm Description

Eight-week treatment period with inhaled placebo b.d.

Arm Title

Inhaled Mannitol

Arm Type

Active Comparator

Arm Description

Eight-week treatment period Inhaled Mannitol 400 mg b.d.

Intervention Type

Drug

Intervention Name(s)

Inhaled Mannitol

Other Intervention Name(s)

Mannitol, IDPM, Dry Powder Mannitol for Inhalation, Bronchitol

Intervention Description

Active treatment is inhaled mannitol with a particle size of 3-4 microns

Intervention Type

Drug

Intervention Name(s)

Inhaled Placebo

Other Intervention Name(s)

Control

Intervention Description

The PLacebo is non respirable mannitol due to the big size particle

Primary Outcome Measure Information:

Title

Effect on lung function (FEV1)

Description

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.

Time Frame

The absolute change from each treatment period baseline to week 8 of each treatment period in percentage of predicted FEV1.

Secondary Outcome Measure Information:

Title

Effect on FVC

Description

To determine the effect of inhaled mannitol on FVC

Time Frame

The absolute change from each treatment period baseline to week 8 of each treatment period in percentage of predicted FVC.

Title

Effect of inhaled mannitol on FEF25-75

Description

To determine the effect of inhaled mannitol on FEF25-75 (exploratory endpoint)

Time Frame

The absolute change from each treatment period baseline to week 8 of each treatment period in percentage of predicted FEF25-75.

Title

Assess safety

Description

Assessment of safety will be made on the basis of reviewing changes in physical examination and using adverse event data.

Time Frame

From each treatment period baseline to week 8 of each treatment period.

Title

Sputum weight

Description

To evaluate the difference in treatment induced sputum weight in subjects treated with inhaled mannitol compared with placebo

Time Frame

The absolute change from each treatment period baseline to week 8 of each treatment period in sputum weight.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: The subject must: Personally provide, or have a legal guardian provide written informed consent to participate in the trial, according to local regulations; 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; 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); Be aged greater than or equal to 6 years and < 18 years; 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 Be able to perform all the techniques necessary to measure lung function. Exclusion Criteria: The subject must NOT: Be using maintenance nebulised hypertonic saline; Be considered "terminally ill"; eligible for lung transplantation, or have received a lung transplant previously; Require home oxygen or assisted ventilation; 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); Have a known intolerance to mannitol; Be taking non-selective beta-blockers; 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; Have a known cerebral, aortic or abdominal aneurysm; Be currently participating in, or have participated in another investigative drug trial within four weeks of Screening (Visit 0); Be pregnant or breastfeeding, or plan to become pregnant whilst in the trial; For females of childbearing potential, be using an unreliable form of contraception, (at the discretion of the investigator); 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 Have a "failed" or "incomplete" mannitol tolerance test (as described in Section 8.3.1.1).

Overall Study Officials: