Clinical Trials Register

Summary
EudraCT Number:	2008-008731-28
Sponsor's Protocol Code Number:	DPM-B-305
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-09-18
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2008-008731-28

A.3

Full title of the trial

A phase III multicenter, randomized, parallel, controlled, double blind study to investigate the safety and efficacy of inhaled mannitol over 12 months in the treatment of bronchiectasis.

A.4.1

Sponsor's protocol code number

DPM-B-305

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pharmaxis Ltd.
B.1.3.4	Country	Australia
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pharmaxis Limited
B.4.2	Country	Australia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharmaxis Pharmaceuticals Limited
B.5.2	Functional name of contact point	Amy Stuart
B.5.3	Address:
B.5.3.1	Street Address	The Priory, Stomp Road
B.5.3.2	Town/ city	Burnham, Bucks
B.5.3.3	Post code	SL1 7LW
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	amy.stuart@pharmaxis.co.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Inhaled mannitol
D.3.4	Pharmaceutical form	Inhalation powder, hard capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mannitol
D.3.9.1	CAS number	69658
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Inhaled mannitol
D.3.4	Pharmaceutical form	Inhalation powder, hard capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mannitol
D.3.9.1	CAS number	69658
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Bronchiectasis

E.1.1.1

Medical condition in easily understood language

Bronchiectasis is a chronic lung condition in which damage to the
airways causes abnormal dilation of one or more bronchi, leading to
pooling of mucus in affected areas

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10006445
E.1.2	Term	Bronchiectasis
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the difference in the rates of graded pulmonary exacerbations, in patients with bronchiectasis treated with inhaled mannitol compared to placebo control.

E.2.2

Secondary objectives of the trial

To evaluate the difference in:
-Quality of Life as measured by the St. Georges Respiratory Questionnaire (SGRQ).
-Antibiotic use prescribed for treated pulmonary exacerbations. Such antibiotic use parameters to be analyzed will include number of discrete courses; days on antibiotics; and time to antibiotic need.
-Sputum volume.
-Daytime sleepiness scores.
-Lung functions (FEV1, FVC, FEV1/FVC. FEF25-75 values).
-(Exploratory) to investigate the difference in the number of hospitalisations due to pulmonary exacerbations.
To evaluate the difference in other graded exacerbation parameters (time to first exacerbation and duration of exacerbation). To monitor the safety profile of inhaled mannitol compared to placebo control in subjects with bronchiectasis by investigating adverse events, airway reactivity, hematology, clinical chemistry, sputum microbiology and vital signs. To compare health status and utility scores (cost effectiveness).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Written informed consent.
Documented evidence of confirmed diagnosis of bronchiectasis.
Aged 18 to 85 years inclusive.
FEV1 >= 40% and <= 85% predicted and >= 1.0L.
Clinician documented history of at least 2 exacerbations requiring antibiotic treatment, in the 12 months prior to study, and at least 4 in 2 years prior to study.
SGRQ score >=30
24 hour sputum production >=10g
Chronic sputum production >= 15mL per day on majority of days in 3 months prior to study.
Ability to perform techniques necessary to measure lung function.

E.4

Principal exclusion criteria

Investigators, site personnel directly affiliated with the study, or immediate families. Bronchiectasis as a result of cystic fibrosis, focal endobronchial lesion or otherwise curable causes.
Terminally ill or listed for transplantation, end stage interstitial lung disease.
Use of hypertonic saline in the 14 days before, or use during study.
Any previous use of mannitol for more than one day.
Significant episode of haemoptysis (>60mL) in the 6 months prior to study.
Rescue antibiotics in the 4 weeks prior to study.
Any of the following in the 3 months prior to study: smoking; myocardial infarction;cerebral vascular accident; major ocular, abdominal, chest or brain surgery. Known cerebral, aortic or abdominal aneurysm.
Actively treated mycobacterium tuberculosis or non active infection requiring treatment.
Unstable ABPA requiring steroid therapy.
Active malignancy.
Breast feeding or pregnant or planning to become pregnant or using unreliable contraception.
Participation in another study.
Known intolerance to mannitol or B agonists.
Uncontrolled hypertension.
Any condition deemed by the Investigator to put the patient at risk or seriously confound the study result.
Previous screen failure for this study.

E.5 End points

E.5.1

Primary end point(s)

Pulmonary exacerbation rates (graded exacerbations).

E.5.1.1

Timepoint(s) of evaluation of this end point

This is a 52 week study and the primary end point will be measured
across the 52 weeks.

E.5.2

Secondary end point(s)

Efficacy
St George's Respiratory Questionnaire (SGRQ) scores
Courses of; days on; time to need for; oral, IV or inhaled antibiotics
prescribed for worsening respiratory
signs and symptoms related to a treated pulmonary exacerbation
Time to first graded exacerbation; duration of graded exacerbations
24 hour sputum volume
Change in daytime sleepiness scores
Change in FEV1, FVC, FEV1/FVC, FEF25-75 values
(Exploratory) Number of hospitalizations due to pulmonary
exacerbations
Safety
Adverse events
Airway reactivity following a mannitol tolerance test (MTT) (acute
decrease in FEV1 >20%)
Laboratory tests:
Complete blood count; electrolytes; creatinine and blood urea nitrogen;
and liver function tests
Qualitative sputum microbiology: disappearance or appearance of
pathogens
Vital signs and physical examination
Costs, Health Status, Utilities and Cost Effectiveness
Total costs incurred in intervention and placebo control groups
* Costs associated with inhaled mannitol
* Costs of antibiotic use and rescue medication
* Costs of hospitalizations and other secondary care services used
* Cost of primary and community care services used
Results from Health Utilities Index Questionnaire in intervention and
placebo control groups to derive:
* Health status
* Health related quality of life
* Utility scores
* Calculation of quality adjusted life years
Determination of cost-effectiveness ratios for intervention and placebo
control groups
* Sensitivity analysis, to assess extent to which variation in parameter
estimates affect cost effectiveness
ratios
* Analysis on the extent to which variation in parameters affects results
from the Health Utilities Index
Questionnaire

E.5.2.1

Timepoint(s) of evaluation of this end point

This is a 52 week study and the secondary end point will be measured
across the 52 weeks.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Placebo = sub-therapeutic control

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Chile

Germany

Netherlands

New Zealand

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last subject last visit

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-09-18.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

180

F.4.2.2

In the whole clinical trial

474

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The patient will continue with their normal treatment or care under
their current physician

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-11-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-02-28

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