Long Term Administration of Inhaled Mannitol in Cystic Fibrosis - A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects
Phase: PHASE3
Conditions: Cystic Fibrosis
Sponsor: Syntara

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DPM-CF-303 Long Term Administration of Inhaled Mannitol in Cystic Fibrosis -  A Safety 
and Efficacy in Adult Cystic Fibrosis Subjects 
 
Protocol: v2.0 13 October 2014 
 
NCT02134353 
 

 
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SYNOPSIS 
Protocol Version & 
Date: 
V2.0 
13th October 2014 
Drug Name: 
Dry powder mannitol 
Trial Number: 
DPM-CF-303 
Phase: 
III 
Indication: 
Cystic fibrosis 
Trial Centers: 
Multicenter 
Title: 
Long Term Administration of Inhaled Mannitol in Cystic Fibrosis – 
A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects 
Sponsor: 
Pharmaxis Limited, 20 Rodborough Road, Frenchs Forest, NSW 
2086 Australia. Tel: +61 2 9454 7200 
Trial Duration 
28 weeks 
Number of Subjects 
350 to 440 
Trial Design 
Randomized, multicenter, double-blind, controlled, parallel group 
Primary 
Objective(s): 
To determine whether inhaled mannitol (400 mg b.i.d.) is superior to 
control (50 mg b.i.d.) for improving lung function as measured by 
mean change from baseline FEV1 (mL) over the 26-week treatment 
period in adult subjects with cystic fibrosis (CF). 
Secondary 
Objectives: 
There are hierarchical and non-hierarchical secondary objectives.  
Analysis of hierarchical secondary objectives will continue until a 
non-significant p-value (i.e. p > 0.05) is returned. 
Hierarchical secondary objectives 
1. 
To determine whether inhaled mannitol (400 mg b.i.d.) is 
superior to control for improving lung function as measured 
by mean change from baseline FVC (mL) over the 26-week 
treatment period in adult subjects with CF; 
2. 
To determine whether inhaled mannitol (400 mg b.i.d.) is 
superior to control in increasing the time to first pulmonary 
exacerbation over the 26-week treatment period in adult 
subjects with CF; 
3. 
To determine whether in adult subjects with CF, inhaled 
mannitol (400 mg b.i.d.) is superior to control for reducing 
the number of days on antibiotics due to pulmonary 
exacerbation (oral, inhaled or IV); 
4. 
To determine whether in adult subjects with CF, inhaled 
mannitol (400 mg b.i.d.) is superior to control for decreasing 
the number of days in hospital due to pulmonary 
exacerbation; and 
5. 
To determine whether inhaled mannitol (400 mg b.i.d.) 
decreases the rate of pulmonary exacerbations over the 26-
week treatment period compared to control in adult subjects 
with CF. 
 
 

 
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Non-hierarchical secondary objectives 
To determine whether in adult subjects with CF, inhaled mannitol 
(400 mg b.i.d.) is superior to control  
• for decreasing the incidence of exacerbations (i.e. the proportion 
of subjects with one or more exacerbation); 
• for improving ease of expectoration; and 
• for improving subject reported respiratory symptoms as measured 
by CFQ-R respiratory domain. 
Primary 
Endpoint(s): 
The primary endpoint is the mean change in FEV1 (mL) from 
baseline (Visit 1) over the 26-week treatment period (to Visit 4). 
Secondary 
Endpoints: 
• Mean change from baseline FVC (mL) over the 26-week 
treatment period; 
• Time to first pulmonary exacerbation over the 26-week treatment 
period; 
• Rate of pulmonary exacerbations over the 26-week treatment 
period; 
• Number of days in hospital due to pulmonary exacerbation; 
• The incidence of pulmonary exacerbations; 
• Number of days on antibiotics (oral, inhaled or IV) due to 
pulmonary exacerbation; 
• Ease of expectoration measured using a visual analogue scale; 
and 
• CFQ-R respiratory domain score. 
Hypothesis: 
We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the 
mean change from baseline FEV1 (mL) compared to control over the 
26-week treatment period in adult subjects with cystic fibrosis.  For 
the purposes of determining an appropriate sample size for statistical 
power while retaining trial feasibility in an orphan disease population 
the trial is powered to detect a difference of 80 mL, however any 
improvement in FEV1 could be considered clinically meaningful. 

 
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Trial 
Population: 
(Diagnosis for main criteria 
for inclusion) 
Subject Inclusion Criteria 
The subject must meet all of the following criteria: 
1. 
Have given written informed consent to participate in this trial 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 at least 18 years old; 
4. 
Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]); 
5. 
Be able to perform all the techniques necessary to measure lung function;  
6. 
Be adherent with maintenance therapies (antibiotics and/or rhDNase), if 
used, for at least 80% of the time in the two weeks prior to visit 1; and 
7. 
If rhDNase and/or maintenance antibiotic are being used treatment must 
have been established at least 1 month prior to screening (Visit 0).  The 
subject should remain on the rhDNase and / or maintenance antibiotics for 
the duration of the trial.  The subject should not commence treatment with 
rhDNase or maintenance antibiotics during the trial. 
Subject Exclusion Criteria 
The subject must NOT meet any of the following criteria: 
1. 
Be investigators, site personnel directly affiliated with this trial, 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 maintenance nebulized hypertonic saline in the 2 weeks prior to 
visit 1; 
5. 
Have had a significant episode of hemoptysis (> 60 mL) in the three 
months prior to Visit 0; 
6. 
Have had a myocardial infarction in the three months prior to Visit 0; 
7. 
Have had a cerebral vascular accident in the three months prior to Visit 0; 
8. 
Have had major ocular surgery in the three months prior to Visit 0; 
9. 
Have had major abdominal, chest or brain surgery in the three months 
prior to Visit 0; 
10. 
Have a known cerebral, aortic or abdominal aneurysm; 
11. 
Be breast feeding or pregnant, or plan to become pregnant while in the 
trial; 
12. 
Be using an unreliable form of contraception (female subjects at risk of 
pregnancy only); 
13. 
Be participating in another investigative drug trial, parallel to, or within 4 
weeks of screening (Visit 0); 
14. 
Have a known allergy to mannitol; 
15. 
Be using non-selective oral beta blockers; 
16. 
Have uncontrolled hypertension –i.e. 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 subject’s participation in the trial; or 
18. 
Have a failed or incomplete mannitol tolerance test (MTT) (as evaluated 
in Section 8.1.1.1). 

 
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Dosage and 
Administration: 
Mannitol (400 mg b.i.d.) or control (50 mg b.i.d.) 
Blinding: 
Double-blind 
Data Collection: 
Refer to the time and events schedule for a schedule of activities 
Efficacy 
Evaluations: 
Refer to the time and events schedule for a schedule of activities 
Safety Evaluations: 
Refer to the time and events schedule for a schedule of activities 
Statistical Methods: 
Sample size:  The minimum sample size is based on the assumption 
that the change from baseline in FEV1 on control is 0 mL and the 
change from baseline in FEV1 on mannitol is 80 mL.  A sample size 
of 350 (175 Mannitol : 175 Control) subjects will yield 90 % power 
at the 0.05 significance level to detect this difference between the 
treatment groups assuming a pooled standard deviation of 230 mL. 
Primary Endpoint: The mean absolute change from baseline FEV1 
(mL) over weeks 6, 14 and 26 will be compared between the two 
treatment groups with a restricted maximum likelihood (REML) 
based repeated measures approach.  
Secondary Endpoints: The mean absolute change in FVC, the 
changes from baseline in ease of expectoration and the CFQ-R 
respiratory domain score will be modeled as per the primary 
endpoint.  The time to first pulmonary exacerbation will be explored 
using Cox Proportional Hazards. Changes in rates of pulmonary 
exacerbations, antibiotic use and days in hospital will be explored 
using negative binomial models.  Analysis of incidence of pulmonary 
exacerbation will be completed using logistic regression. 
 

 
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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................... 2 
TIME AND EVENTS SCHEDULE ........................................................................................ 6 
TABLE OF CONTENTS ......................................................................................................... 8 
CONTACT LIST .................................................................................................................... 11 
ABBREVIATIONS ................................................................................................................ 12 
1 INTRODUCTION ............................................................................................................ 14 
1.1 Background ............................................................................................................... 14 
1.1.1 Findings from non-clinical trials ........................................................................ 15 
1.1.2 Findings from clinical trials ............................................................................... 15 
1.1.3 Pharmacokinetics................................................................................................ 16 
1.1.4 Efficacy .............................................................................................................. 16 
1.1.5 Safety .................................................................................................................. 17 
1.2 Rationale for trial....................................................................................................... 18 
2 TRIAL OBJECTIVES AND PURPOSE ......................................................................... 19 
2.1 Primary objective ...................................................................................................... 19 
2.2 Secondary objectives ................................................................................................. 19 
2.2.1 Hierarchical secondary objectives ...................................................................... 19 
2.2.2 Non-hierarchical secondary objectives .............................................................. 19 
2.3 Hypothesis ................................................................................................................. 19 
3 COMPLIANCE STATEMENT ....................................................................................... 20 
3.1 Variations to the protocol .......................................................................................... 20 
4 OVERVIEW OF TRIAL DESIGN .................................................................................. 20 
4.1 Trial design ................................................................................................................ 20 
4.2 Trial design rationale ................................................................................................. 21 
4.2.1 Primary endpoint ................................................................................................ 21 
4.2.2 Secondary endpoints........................................................................................... 21 
5 TRIAL POPULATION .................................................................................................... 22 
5.1 General considerations .............................................................................................. 22 
5.2 Subject inclusion criteria ........................................................................................... 22 
5.3 Subject exclusion criteria .......................................................................................... 22 
6 INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ................................................ 23 
6.1 Dosage and administration ........................................................................................ 23 
6.1.1 Treatment adherence .......................................................................................... 24 
6.1.2 Investigational medicinal product – formulation and manufacture.................... 24 
6.1.3 Labeling, packaging and storage ........................................................................ 24 

 
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6.1.4 Investigational medicinal product supply and accountability ............................ 26 
6.2 Pre-trial and concomitant medications ...................................................................... 26 
6.2.1 Pre-trial medication ............................................................................................ 27 
6.2.2 Concomitant medication..................................................................................... 27 
6.2.3 Concomitant medications that must be withheld prior to the trial visits ............ 27 
6.2.4 Prohibited medications and non-pharmacological treatments............................ 28 
7 INVESTIGATIONAL MEDICATION TREATMENT ALLOCATION ....................... 28 
8 TREATMENT EVALUATIONS..................................................................................... 28 
8.1 Visit procedures ......................................................................................................... 28 
8.1.1 Screening (Visit 0).............................................................................................. 29 
8.1.2 Double-blind treatment visits ............................................................................. 36 
8.2 Efficacy ..................................................................................................................... 41 
8.2.1 Efficacy evaluations ........................................................................................... 41 
8.3 Safety ......................................................................................................................... 45 
8.3.1 Safety evaluations............................................................................................... 45 
8.3.2 Criteria ................................................................................................................ 47 
8.3.3 Adverse event reporting ..................................................................................... 47 
8.3.4 Reporting procedures ......................................................................................... 50 
9 SUBJECT COMPLETION / DISCONTINUATION ...................................................... 52 
9.1 Completion ................................................................................................................ 52 
9.2 Trial treatment discontinuation ................................................................................. 52 
9.3 Trial withdrawal ........................................................................................................ 52 
10 STATISTICAL METHODS .......................................................................................... 53 
10.1 General considerations ............................................................................................ 53 
10.1.1 Sample size justification ................................................................................... 53 
10.1.2 Analysis sets ..................................................................................................... 54 
10.1.3 Missing data ..................................................................................................... 54 
10.1.4 Multiple comparisons ....................................................................................... 55 
10.1.5 Sample size re-estimation ................................................................................. 55 
10.1.6 Interim analysis ................................................................................................ 55 
10.1.7 Subject disposition ........................................................................................... 55 
10.1.8 Baseline demographic and clinical characteristics ........................................... 56 
10.2 Efficacy analysis...................................................................................................... 56 
10.2.1 Primary objective ............................................................................................. 56 
10.2.2 Primary endpoint .............................................................................................. 56 
10.2.3 Primary analysis ............................................................................................... 56 
10.2.4 Primary analysis – missing data ....................................................................... 56 
10.2.5 Primary sensitivity analyses ............................................................................. 57 

 
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10.2.6 Primary per protocol analysis ........................................................................... 58 
10.2.7 Secondary analyses........................................................................................... 58 
10.2.8 Hierarchical testing of key secondary objectives ............................................. 60 
10.2.9 Secondary analyses – missing data .................................................................. 60 
10.2.10 Key secondary sensitivity analyses ................................................................ 61 
10.2.11 Subgroup analyses .......................................................................................... 61 
11 ETHICAL ASPECTS ..................................................................................................... 61 
11.1 Informed consent ..................................................................................................... 61 
11.2 Heath authorities, independent ethics committees / institutional review boards .... 62 
11.3 Confidentiality regarding trial subjects ................................................................... 62 
11.4 Data safety monitoring board (DSMB) ................................................................... 62 
12 TRIAL MANAGEMENT & ADMINISTRATIVE REQUIREMENTS ....................... 62 
12.1 Protocol amendments .............................................................................................. 62 
12.2 Direct access to source data / documents ................................................................ 62 
12.3 Monitoring and quality assurance ........................................................................... 63 
12.3.1 Information to trial personnel ........................................................................... 63 
12.3.2 Trial monitoring ............................................................................................... 63 
12.3.3 Audit and inspection ......................................................................................... 63 
12.4 Protocol deviations .................................................................................................. 64 
13 DATA HANDLING AND RECORD KEEPING .......................................................... 64 
13.1 Source data .............................................................................................................. 64 
13.2 Case report form (CRF) ........................................................................................... 64 
13.3 Archiving of trial documentation ............................................................................ 65 
14 FINANCING AND INSURANCE ................................................................................ 65 
15 REPORTING AND PUBLICATION OF RESULTS .................................................... 65 
15.1 Authorship ............................................................................................................... 66 
16 REFERENCES ............................................................................................................... 67 
17 SIGNATURE PAGE ...................................................................................................... 68 
 
 
 
 
 
 
 

 
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CONTACT LIST 
A full trial contact list will be provided as a separate document. 
Changes in the names, addresses or telephone numbers of these contacts will in general not 
require a protocol amendment. A protocol amendment maybe required for contact 
information being referenced, for the addition or removal of the primary Principal 
Investigator, regulatory authorities documented notifications or updates. 
 
 

 
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ABBREVIATIONS 
ADR 
 
adverse drug reaction 
AE 
 
adverse event 
ATS/ERS 
American Thoracic Society / European Respiratory Society 
b.i.d. 
 
twice daily 
BOCF  
baseline observation carried forward 
BTPS 
 
body temperature and pressure, saturated 
CF 
 
cystic fibrosis 
CFTR 
 
cystic fibrosis transmembrane conductance regulator 
cGMP  
current Good Manufacturing Practice 
CRF 
 
case report form 
eCRF 
 
electronic case report form 
DSMB  
data safety monitoring board 
FAO 
 
Food and Agriculture Organization of the United Nations 
FDA 
 
US Food and Drug Administration 
FEF25-75  
forced expiratory fraction from 25% to 75% of vital capacity 
FEV1 
 
forced expiratory volume in one second 
FVC 
 
forced vital capacity 
GCP 
 
Good Clinical Practice 
HR 
 
hazard ratio 
HRCT  
high resolution computed tomography 
ICF 
 
informed consent form 
ICH 
 
International Conference on Harmonization 
ICMJE  
international committee of medical journal editors 
IEC 
 
Independent Ethics Committee 
IRB 
 
Institutional Review Board 
IMP 
 
investigational medicinal product 
IWRS 
 
interactive web response system 
ITT 
 
intent to treat 
IUDR 
 
imputation using dropout reason 
IV 
 
intravenous 
JECFA  
The joint FAO / WHO expert committee on food additives 
MDI 
 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
 
multiple imputation 
MMRM  
mixed-effect model repeated measures 
MTT 
 
mannitol tolerance test 
PEF 
 
peak expiratory flow 
PP 
 
per protocol 
REML  
restricted maximum likelihood 

 
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rhDNase 
Recombinant human deoxyribonuclease 
 
SABA  
Short-acting beta2 agonist 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SOP 
 
standard operating procedure 
SpO2 
 
blood oxygen saturation 
VAS 
 
visual analogue scale 
WHO 
 
World Health Organization 
WOCF  
worst observation carried forward 
 

 
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1 INTRODUCTION 
1.1 Background 
Cystic fibrosis (CF) is an autosomal recessive inherited disorder caused by mutations in the 
gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) [1].  It is 
characterized by fat and protein malabsorption, failure to thrive and pulmonary disease [2].  
Cystic fibrosis is a life-threatening and chronically debilitating disease that markedly impairs 
quality of life [1].  To date, there are more than 1,600 specific mutations in the CF gene that 
are known [3].  The incidence of CF varies by ethnic group, with the greatest incidence 
occurring in Caucasians (1:3,200).  Far less people of African or Asian descent have this 
disease (incidence between 1:15,000 and 1:31,000) [2].  Despite genetic counseling, the 
prevalence of CF is likely to increase as the median survival time for subjects with CF 
increases [2]. 
Chronic progressive lung disease is the main negative prognostic factor in CF subjects [3].  
Subjects have progressive cycles of infection and inflammation, ultimately leading to 
respiratory failure [2].  The lungs become colonized with bacteria, probably due to the 
presence of thick, inspissated mucus in the airways, which traps inhaled microbes [2]. 
Cystic fibrosis has no cure.  Current life expectancy is between 30 and 40 years [1], although 
life expectancy is related to phenotype, with those with severe phenotypes having reduced 
life expectancy.  The goal of therapy is to delay disease progression [1].  The goal of therapy 
with respect to pulmonary disease is to maintain or improve respiratory function, as assessed 
by forced expiratory volume in one second (FEV1) [1].  Slowing the decline of lung function 
occurs by clearing airways of mucus, by controlling respiratory infections and by improving 
and maintaining respiratory function [1].  Clearing mucus occurs using physical techniques, 
such as active cycle of breathing, positive pressure autogenic drainage and physical therapy.  
Currently available pharmacological treatments include therapy with mucolytic drugs to 
improve mucociliary clearance of lower-airway secretions and treat chronic obstructive 
pulmonary disease [1].  Mucus clearance can be increased using hypertonic saline solutions 
[1], while rhDNase is used as a mucolytic agent.  Inhaled mannitol is being developed as a 
therapeutic agent for the treatment of cystic fibrosis and other diseases characterized by 
difficult to clear, thickened respiratory mucus.  Inhaled mannitol has been shown to increase 
mucociliary clearance and cough clearance [4, 5]. The exact mechanisms responsible remain 
unclear, however, due to its osmotic activity a combination of factors including changes in 
the rheology of mucus favoring ciliary and cough clearance may be responsible [6-8].  
Osmotic agents may change the viscoelastic properties of mucus by reducing the number of 
entanglements that mucin polymers form.  While ionic agents may achieve this by shielding 
the fixed charges along the mucin macromolecules, non-ionic agents such as mannitol may 
achieve this by disrupting the hydrogen bonds between mucins [6, 9]. Osmotic agents also 
increase the amount of water in the airway lumen potentially normalizing the airway surface 
liquid layer. This increased hydration may contribute to an increase in the activity of cilia 
and transportability of mucus. Additionally, osmotic agents may increase clearance of mucus 
by stimulating mucus secretion. The effect of osmolarity on mucus secretion could be direct 
or indirect via release of mediators from epithelial and mast cells and neuropeptides from 
sensory nerves which are known to be secretagogues. Although an increase in mucus 
secretion is not seen to be a desirable effect, this stimulation of mucus secretion may help 
increase clearance of viscous and stagnated mucus.  

 
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Mannitol may benefit subjects by reducing the mucus load acutely, or it may have a 
prolonged beneficial effect on mucociliary clearance. As excessive mucus in the airways 
may result in some limitation of airflow, a reduction in the mucus load should improve 
airway function irrespective of age. 
While adult subjects (aged at least 18 years) have been studied in previous phase III clinical 
trials of inhaled mannitol that assessed improvements in lung function [10, 11], there are 
remaining uncertainties around the effect size of inhaled mannitol 400 mg b.i.d. in this 
population. 
Therefore the primary purpose of this trial is to assess the efficacy of inhaled mannitol 
compared with control in subjects with cystic fibrosis aged 18 years and above. 
1.1.1 Findings from non-clinical trials 
Information regarding the findings from Non-Clinical Studies is presented in the 
Investigator’s Brochure Section NONCLINICAL STUDIES.   
Mannitol is present naturally in plants, algae, fungi and some bacteria.  It is used extensively 
as a food additive.  It does not appear to be mutagenic, cytotoxic, carcinogenic or 
teratogenic.  One trial has shown increased incidence of adrenal medullary hyperplasia plus 
pheochromocytoma in rats.  However, these were not dose related and were considered 
unrelated to the administration of mannitol. 
When ingested, mannitol has a laxative effect when given in doses greater than 10 to 20 g.  
The accepted daily intake of mannitol set by the joint FAO / WHO expert committee on food 
additives (JECFA) is 50 mg/kg. It is unlikely however, that the inhalation of less than 1g of 
mannitol per day via inhalation would reach this level. 
In animals, mannitol is rapidly absorbed following inhalation (peaking within 1 hour of 
completion of the dose), with negligible serum levels detected after 24 hours. 
1.1.2 Findings from clinical trials 
Findings from clinical studies are discussed in detail in the Investigator’s Brochure, section 
EFFECTS IN HUMANS. 
 
 

 
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1.1.3 Pharmacokinetics 
Refer to the Investigator’s Brochure (see Sections 5.2, 5.3 and 6.1.2). 
1.1.4 Efficacy 
The DPM-CF-301 trial [10] assessed the safety and efficacy of inhaled mannitol 400 mg 
b.i.d. compared to control in subjects aged six years or more with a diagnosis of cystic 
fibrosis.  This was a multicenter, randomized, controlled, parallel arm, double-blind phase III 
trial over 26 weeks.  It was followed by an optional 26-week open-label extension of the trial 
during which all subjects received inhaled mannitol 400 mg b.i.d..  The treatment effect of 
mannitol was superior to that of control (p < 0.001, Table 1).  Changes in other measures of 
lung function (FVC and FEF25-75) were consistent with the improvements in FEV1. 
DPM-CF-302 [11] was essentially the same as DPM-CF-301 in design, with only minor 
differences in the inclusion / exclusion criteria.  In this trial, inhaled dry powder mannitol 
improved absolute change in FEV1 compared with control over six-month treatment period, 
although this failed to reach statistical significance (p = 0.059, Table 1).  However, there 
were significant improvements in the relative change in FEV1 when subjects were treated 
with mannitol were compared to control groups – a difference of 3.75% (p = 0.029). 
A pooled analysis of DPM-CF-301 and DPM-CF-302 studies found a mean absolute change 
from baseline in FEV1 for dry powder mannitol versus control over 6 months was 73.4 mL 
(p<0.001).  Overall the studies show that dry powder mannitol improves lung function by six 
weeks, and the improvement was sustained over 26 weeks. The increase in FEV1 at six 
weeks was highly correlated with the improvement over the 26-week treatment period. 
Table 1: Treatment effect from the CF-301 and CF-302 studies 
Lung function 
measure 
CF-301 
Mannitol 400 mg 
b.i.d. vs. control 
across 26-weeks 
CF-302 
Mannitol 400 mg 
b.i.d. vs. control 
across 26-weeks 
Absolute change in 
FEV1 (mL) 
94.5 
p<0.001 
54.1 
p=0.059 
Absolute change in 
FVC (mL) 
126 
p<0.001 
71.4 
p=0.022 
 
Significant improvements in FEV1 were observed in subjects aged 18 and above in post-hoc 
analyses of studies DPM-CF-301 and DPM-CF-302 (Table 2). 
 
 

 
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Table 2: Treatment effect in adults from the CF-301 and CF-302 studies 
Lung function measure 
CF-301 
Mannitol 400 mg 
b.i.d. vs. control 
across 26-weeks 
CF-302 
Mannitol 400 mg 
b.i.d. vs. control 
across 26-weeks 
Absolute change in FEV1 (mL) 
108.46 
p<0.001 
85.94 
 
p=0.038 
Absolute change in FVC (mL) 
138.71 
 
p<0.001 
113.77 
 
p=0.011 
1.1.5 Safety 
Detailed description on the safety of inhaled dry powder mannitol in subjects with cystic 
fibrosis can be found in the Investigator’s Brochure, section SAFETY IN BRONCHITOL 
CLINICAL TRIALS. 
A total of 672 subjects have received mannitol in all the completed mannitol CF studies.  
The most frequently reported adverse drug reactions (ADRs) were cough (9.23 %), condition 
aggravated (cystic fibrosis pulmonary exacerbation) (6.10 %) and hemoptysis (5.36 %).  
Cough was very common (> 1/10), condition aggravated and hemoptysis were common 
(frequency ≥ 1/100, < 1/10). 
Other common ADRs (frequency ≥ 1/100, < 1/10) were: pharyngolaryngeal pain, headache, 
wheezing, bronchospasm, productive cough, throat irritation, post-tussive vomiting and 
vomiting, chest discomfort, upper and lower respiratory tract infections, and bacteria 
identified in the sputum. 
Adverse events with a difference of at least 2 % between mannitol 400 mg b.i.d. and control 
in the combined Phase 3 data (DPM-CF-301 and DPM-CF-302) are listed in Table 3. 
 
 

 
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Table 3: Adverse events with a difference of at least 2 % between mannitol 400 mg b.i.d. and control in 
the combined Phase 3 data (DPM-CF-301 and DPM-CF-302) 
MedDRA System Organ Class/ Preferred Term 
Mannitol 400 
mg b.i.d. 
N=361  
n (%) 
Control  
N=239  
n (%) 
Gastrointestinal Disorders 
 
 
Diarrhea 
17 (4.7) 
6 (2.5) 
Vomiting 
22 (6.1) 
6 (2.5) 
General Disorders and Administration Site Conditions 
 
 
Condition aggravated 
133 (36.8) 
96 (40.2) 
Infections and Infestations 
 
 
Lower respiratory tract infection 
22 (6.1) 
24 (10.0) 
Nervous System Disorders 
 
 
Headache 
64 (17.7) 
50 (20.9) 
Reproductive System and Breast Disorders 
 
 
Dysmenorrhea 
8 (2.2) 
0 (0.0) 
Respiratory, Thoracic and Mediastinal Disorders 
 
 
Cough 
76 (21.1) 
40 (16.7) 
Hemoptysis 
34 (9.4) 
13 (5.4) 
Pharyngolaryngeal pain 
44 (12.2) 
18 (7.5) 
 
Post-hoc analysis of CF-301 and CF-302 studies found that the incidence of hemoptysis was 
similar in the mannitol 400 mg and control arms of these studies in adults, although this has 
not been tested prospectively.   
1.2 Rationale for trial 
Given the improvements in FEV1 observed in adult subjects the post-hoc analysis of DPM-
CF-301 and DPM-CF-302, this trial (DPM-CF-303) aims to provide prospective evidence of 
the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above. 
 
 

 
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2 TRIAL OBJECTIVES AND PURPOSE 
2.1 Primary objective 
To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control (50 mg b.i.d.) 
for improving lung function as measured by mean change from baseline FEV1 (mL) over the 
26-week treatment period in adult subjects with CF. 
2.2 Secondary objectives 
There are hierarchical and non-hierarchical secondary objectives.  Analysis of hierarchical 
secondary objectives will continue until a non-significant p-value (i.e. p > 0.05) is returned. 
2.2.1 Hierarchical secondary objectives 
1. To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for 
improving lung function as measured by mean change from baseline FVC (mL) over 
the 26-week treatment period in adult subjects with CF. 
2. To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in 
increasing the time to first pulmonary exacerbation over the 26-week treatment 
period in adult subjects with CF. 
3. To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is 
superior to control for reducing the number of days on antibiotics (oral, inhaled or 
IV) due to pulmonary exacerbation;  
4. To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is 
superior to control for decreasing the number of days in hospital due to pulmonary 
exacerbation; and 
5. To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of 
pulmonary exacerbations over the 26-week treatment period compared to control in 
adult subjects with CF. 
2.2.2 Non-hierarchical secondary objectives 
To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior 
to control  
• for decreasing the incidence of exacerbations (i.e. the proportion of subjects with one 
or more exacerbation); 
• for improving ease of expectoration; and 
• for improving subject reported respiratory symptoms as measured by CFQ-R 
respiratory domain. 
2.3 Hypothesis 
We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the mean change from 
baseline FEV1 (mL) compared to control over the 26-week treatment period in adult subjects 
with cystic fibrosis. Any improvement in FEV1 is considered clinically meaningful, 
however, this trial has set a threshold of 80 mL for the purposes of determining an 
appropriate sample size for statistical power while retaining trial feasibility in an orphan 
disease population. 

 
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3 COMPLIANCE STATEMENT 
The trial will be conducted in accordance with the protocol and the International Conference 
on Harmonization (ICH) and Good Clinical Practice (GCP) guidelines.  In addition, the trial 
will be conducted in compliance with all applicable laws and regulatory requirements 
relevant to the use of new therapeutic agents in each participating country.  Agreement of the 
Investigator(s) to conduct and administer this trial in accordance with the protocol and 
associated regulations will be documented in trial agreements with the Sponsor, and other 
forms as required by national authorities in the country where the trial center is located. 
The Investigator(s) is/are responsible for ensuring the privacy, safety and welfare of the 
subjects during and after the trial, and must ensure that fully functional resuscitation 
equipment and personnel trained in its proper use are immediately available in case of a 
medical emergency. The Investigator(s) must be familiar with the background and 
requirements of the trial and with the properties of the investigational medication as 
described in the Investigator's Brochure. 
The Principal Investigator at each center has the overall responsibility for the conduct and 
administration of the trial at their center, and for contact with trial center management, the 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB), and local 
authorities. 
3.1 Variations to the protocol 
No changes from the final approved (signed) protocol will be initiated by the Investigator 
without agreement by the Sponsor, and if required, the ethics committee’s prior written 
approval of favorable opinion of a written amendment, except when necessary to eliminate 
immediate hazards to the subjects. Changes that are considered only logistical or 
administrative, do not require prior ethics committee prior approval.  The Principal 
Investigator(s) and the Sponsor must sign any protocol amendment. 
4 OVERVIEW OF TRIAL DESIGN 
4.1 Trial design 
This is a double-blind, randomized, parallel arm, controlled, multicenter, and interventional 
clinical trial.  Potential subjects will sign the informed consent form (ICF) and be assessed 
for eligibility.  After satisfying all inclusion & exclusion criteria, subjects will be given a 
mannitol tolerance test (MTT). Those subjects that pass the MTT will be randomized to 
receive inhaled mannitol (400 mg b.i.d.) or control b.i.d. for a period of 26-weeks, in a 1:1 
fashion (See trial flowchart in Figure 1). Note: No tests should be performed before consent 
is obtained (also refer to the TIME AND EVENTS schedule). 
  

 
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5 TRIAL POPULATION 
5.1 General considerations 
Potential subjects must meet all the inclusion, but none of the exclusion criteria, as listed 
below. 
5.2 Subject inclusion criteria 
The subject must meet all of the following criteria: 
1. 
Have given written informed consent to participate in this trial 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 at least 18 years old; 
4. 
Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]);  
5. 
Be able to perform all the techniques necessary to measure lung function;  
6. 
Be adherent with maintenance therapies (antibiotics and/or rhDNase), if used, for at 
least 80% of the time in the two weeks prior to visit 1; and 
7. 
If rhDNase and/or maintenance antibiotic are being used treatment must have been 
established at least 1 month prior to screening (Visit 0).  The subject should remain 
on the rhDNase and / or maintenance antibiotics for the duration of the trial.  The 
subject should not commence treatment with rhDNase or maintenance antibiotics 
during the trial. 
5.3 Subject exclusion criteria 
The subject must NOT meet any of the following criteria: 
1. 
Be investigators, site personnel directly affiliated with this trial, 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 maintenance nebulized hypertonic saline including in the 2 weeks prior to 
visit 1; 
5. 
Have had a significant episode of hemoptysis (>60 mL) in the three months prior to 
Visit 0; 
6. 
Have had a myocardial infarction in the three months prior to Visit 0; 
7. 
Have had a cerebral vascular accident in the three months prior to Visit 0; 
8. 
Have had major ocular surgery in the three months prior to Visit 0; 
9. 
Have had major abdominal, chest or brain surgery in the three months prior to Visit 
0; 
10. 
Have a known cerebral, aortic or abdominal aneurysm; 
11. 
Be breast feeding or pregnant, or plan to become pregnant while in the trial; 
12. 
Be using an unreliable form of contraception (female subjects at risk of pregnancy 
only); 
13. 
Be participating in another investigative drug trial, parallel to, or within 4 weeks of 
visit 0; 
14. 
Have a known allergy to mannitol; 
15. 
Be using non-selective oral beta blockers; 
16. 
Have uncontrolled hypertension i.e. systolic BP > 190 and / or diastolic BP > 100; 

 
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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 subject’s participation in the trial; 
18. 
Have a failed or incomplete MTT (as evaluated in Section 8.1.1.1);  
6 INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
6.1  Dosage and administration 
This is a parallel trial, including 26 weeks of treatment with either inhaled mannitol (400 mg 
b.i.d.) or control (mannitol 50 mg b.i.d.).  The inhalation technique for control and mannitol 
is identical. 
WHEN TO START TREATMENT FOR SUBJECTS WITH A 
CURRENT PULMONARY EXACERBATION 
Subjects should be stable and clear of pulmonary exacerbations for at 
least two weeks prior to visit 1. If a subject has an exacerbation after Visit 
0 (screening), Visit 1 should occur 2 to 5 weeks from the end of the 
treatment for the exacerbation or the end of the adverse event, whichever is later.   
There is no requirement to stop the IMP if a subject has a pulmonary exacerbation during a 
treatment phase. Subject can receive additional treatment as required. 
The IMP is to be administered in a standardized manner (see Figure 2).  The Investigator is 
responsible for instructing the subject on the correct IMP inhalation technique, and on use of 
the bronchodilator (albuterol/salbutamol metered dose inhaler (MDI) or similar) 5 to 15 
minutes prior to the IMP administration.  To ensure a good IMP delivery technique, training 
kits containing empty capsules are available. 
The Investigator will prescribe the subject with a bronchodilator (albuterol /salbutamol 
metered dose inhaler [MDI] or similar) to be used as premedication prior to inhalation of the 
IMP.  This bronchodilator may also be used in the event of post-treatment chest tightness.  
Premedication (albuterol/salbutamol MDI or preferred alternative) should be recorded in the 
Subject Diary.  Use of any bronchodilator following IMP for post-treatment chest tightness 
should also be recorded in the Subject Diary. 
Subjects will take IMP twice a day, once in the morning and once in the evening.  The 
evening dose should be administered approximately 2 hours before sleep.   
The recommended order of treatment procedures is: 
1. bronchodilator; 
2. mannitol/control; 
3. physiotherapy / exercise*; 
4. rhDNase; 
5. inhaled antibiotics; then 
6. inhaled corticosteroids. 
The procedures 4, 5 and 6 may not be applicable to all subjects and the order of procedures 
3, 4, 5 and 6 listed above is a suggestion only but the order in which they are used should 
remain consistent throughout the study.  Bronchodilator must always precede 
mannitol/control.  

 
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*When possible, individual physiotherapy and exercise (if used as a substitute to 
physiotherapy) techniques and routines should be kept consistent throughout the study. 
Subjects should record in the Subject Diary the date of any missed doses of IMP. 
Each kit dispensed contains additional supply to account for the allowed visit windows. 
6.1.1 Treatment adherence 
Treatment adherence will be determined by returned medication count. If the subject has 
missed doses of their medication, then they should be counseled about the importance of 
compliance, and re-educated on investigational medication intake.  Any possible treatment 
discontinuation due to non-adherence should be discussed with the Sponsor’s Project 
Manager and Sponsor’s Medical Director. 
6.1.2 Investigational medicinal product – formulation and manufacture 
Bronchitol has a centralized European marketing authorization for use in Adult patients with 
cystic fibrosis. However it does not have a marketing authorization or is not available in 
every participating country therefore it is being treated as Investigational medicinal 
product.  Details on the investigational product can be found in the Investigator’s Brochure.  
Trial treatment (mannitol and control) will be provided as indistinguishable red capsules. 
6.1.3 Labeling, packaging and storage 
IMP is labeled according to local regulatory requirements. The mannitol dry powder is 
encapsulated in opaque capsules prior to blister packing in aluminum foil. Blisters are 
contained within cartons with a dry powder inhaler device(s). IMP blinding is maintained by 
the use of kit numbers enabling traceable labeling. 
IMP is to be stored at room temperature (59°F to 77°F or 15°C to 25°C), in a secure area 
with restricted access.  The site Investigator/Pharmacist is responsible for storage, 
temperature monitoring and maintaining accurate accountability records. 
Once the IMP has been dispensed to subjects, it must not be refrigerated, nor kept in humid 
conditions, such as in the bathroom.  IMP must be stored at room temperature, in a clean, 
dry, environment.  Capsules should only be removed from the foil packaging immediately 
prior to use. 
 
Important: Instruct your subjects the IMP can only be used with the 
inhaler provided. 
 
 

 
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6.1.4 Investigational medicinal product supply and accountability 
Pharmaxis will provide the participating sites with sufficient amount of IMP.   
The site Investigator must ensure that deliveries of investigational product from the Sponsor 
are correctly received by a responsible person (e.g., Pharmacist), that all receipts are 
recorded in writing, that the product is stored in a secure area under recommended and 
proper storage conditions, and that they are used in accordance with the protocol.  It is the 
responsibility of the Investigator to ensure that the integrity of the investigational medication 
is not jeopardized prior to dispensing.  The investigational medication must be dispensed as 
provided by the Sponsor with no further repackaging done at site.  
The site Pharmacist / Investigator(s) / legally qualified designee, as documented on the Site 
Signature / Delegation of Authority Log, will dispense/administer the investigational 
medication only to subjects enrolled in this trial following the procedures set out in Section 
6. The site Pharmacist / Investigator(s) is responsible for assuring the retrieval of all trial 
supplies from the subjects.  Unused investigational medication(s) (opened, unopened, or 
empty capsules) must be returned to the Sponsor or destroyed on site (if appropriate) after 
the investigational medication accountability has been completed and destruction has been 
authorized by the Sponsor. 
Trial drug accountability should be performed by counting the used (empty blisters) and 
unused trial drug remaining in blisters. 
The Investigator(s) must maintain accurate and adequate records including dates of receipt 
and return of IMP shipments, and batch numbers and quantities received/returned from/to 
Pharmaxis, as well as dates and amounts dispensed to/returned by trial subjects. Destruction 
of trial supplies should not be done without prior approval from the Sponsor.  Full 
accountability documentation (with witnessing) is required for all destroyed IMP at an 
investigator site. 
The Investigator / site Pharmacist will be required to provide the Monitor with access to the 
investigational medication and records for periodic review.  
Copies of the accountability records will be provided to the pharmacy monitor for inclusion 
in the trial master file. 
It is forbidden to use investigational medication for purposes other than defined in this 
protocol. 
6.2 Pre-trial and concomitant medications 
Any treatment that is considered necessary for the subject’s welfare may be given at the 
discretion of the Investigator.  Administration of all concomitant medications must be 
reported in the appropriate section of the CRF as noted below.  Generic names are to be 
recorded, along with the start and stop dates, dose, frequency, route and indication.  Trade 
names are acceptable for combination medications. 
 
 

 
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6.2.3.1 Rescue medications 
If a subject develops chest tightness or shortness of breath as a consequence of withholding 
bronchodilators or other respiratory medications on the morning of the due visit, they should 
take their usual bronchodilator and phone or attend the clinic for advice.  Where the health of 
the subject is in question, the subject should attend the clinic for assessment.  Note should be 
made of the event precipitating the use of rescue medication and the subsequent 
management.  If necessary the due visit should be rescheduled. 
6.2.4 Prohibited medications and non-pharmacological treatments 
The following medications are prohibited from Screening (Visit 0) and throughout the trial 
protocol period: 
• Maintenance treatment with nebulized hypertonic saline 
• Non-selective oral beta-blockers 
7 INVESTIGATIONAL MEDICATION TREATMENT ALLOCATION 
Subjects will be randomized following informed consent and satisfying all the inclusion and 
none of the exclusion criteria.  Subjects are randomized in a 1:1 ratio to receive either 
inhaled mannitol 400 mg b.i.d. or control (inhaled mannitol 50 mg b.i.d.) for a period of 26-
weeks. Randomization will be stratified by rhDNase use and country. 
The Pharmacist, Investigator or legally responsible designee will dispense the treatment 
allocated to the subject and record the randomized kit numbers in the dispensing log. 
The subject, the investigative staff and Sponsor will be blinded to the treatment allocation. 
Appropriate site staff will be provided with access to unblinding information. In the event of 
a medical emergency, and when management of a subject’s condition requires knowledge of 
the IMP, his/her randomization information may be obtained. Such emergencies should be 
discussed with the Sponsor in advance whenever possible prior to disclosure of the subject’s 
treatment allocation. An automatic email is sent to the designated trial team member as soon 
as the subject is unblinded. 
Any subject giving consent, but not fulfilling the criteria to participate in the trial will not be 
entered into the Case Report Form (CRF) with the exception of mannitol tolerance test 
(MTT) status.  Subjects giving consent but not entered into the CRF will be documented as 
screen failures.  Subjects who are administered the MTT should be entered onto the CRF 
irrespective of the MTT result; however, the subject’s trial identifier and date of birth will be 
detailed in the IWRS. 
 
8 TREATMENT EVALUATIONS 
8.1 Visit procedures 
This trial consists five trial visits and 9 telephone calls over a period of 28-weeks (see TIME 
AND EVENTS SCHEDULE). 
 

 
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8.1.1 Screening (Visit 0)  
Subjects will be screened for eligibility during the Screening phase.  Refer to the TIME 
AND EVENTS SCHEDULE for a complete list of procedures to be performed during the 
Screening visit. 
• Obtain written informed consent - this must be obtained before any trial related 
procedures, including medication-withholding requests, are undertaken. This may be 
done prior to V0; 
• Review inclusion / exclusion criteria; 
• Obtain demographic information:  
o date of birth; 
o height and weight (no shoes using a stadiometer); 
o race and gender; 
o age at diagnosis; 
o CFTR mutation  (if known)*; and 
o previous diagnosis of CF related bronchiectasis (yes, no, unknown)*. 
• Review medical history; 
• Review and record concomitant medications for the previous 3 months; 
• Perform physical examination, including but not limited to: 
o pulmonary function tests (FEV1, FVC, FEV1 % predicted  PEF, FEF25-75 ); 
o urine pregnancy test (for females of child-bearing potential); and 
o physical examination / vital signs (including chest sounds, weight, BP, HR, 
O2 saturation, temperature, respiratory rate). 
• 
Premedicate with four puffs of albuterol/salbutamol from a metered dose inhaler 
(MDI) (360-400µg)**; 
• Conduct mannitol tolerance test (MTT) (see section 8.1.1.1); 
• Collect 1 x sputum sample for qualitative microbiology (sent to local lab); 
alternatively, an oropharyngeal or cough swab is permitted. 
• Collect blood sample for hematology, electrolytes, urea, creatinine and liver function 
testing (collected following local laboratory procedures and sent to local lab); and 
• Issue subject diary and instruct the subject on how to complete it. 
* Enter this data only if known and confirmed evidence is available. 
** Bronchodilator is to be used approximately 5 -15 minutes prior to MTT. The default bronchodilator for this 
trial is 4 x puffs albuterol/salbutamol (360-400µg). However, the subject’s preferred alternative 
bronchodilator may be used as an alternative premedication. Please record premedication details. 
 
Re-screening of subjects may be considered upon approval by the Sponsor or delegate.  Re-
screening will not be considered for subjects who have had a ‘failed’ or ‘incomplete’ 
mannitol tolerance test. 
 
 

 
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8.1.1.1 Mannitol tolerance test (MTT) 
The MTT identifies subjects who have airway hyperresponsiveness in response to inhaled 
mannitol. Airway hyperresponsiveness is determined by measuring the degree of 
bronchoconstriction that occurs following sequential administrations of mannitol. 
As is standard in administering agents that have the potential to cause 
bronchoconstriction, a physician, appropriately trained, to treat acute 
bronchospasm, including the use of resuscitation equipment, must be available 
to respond to an emergency. 
As a minimum, the person conducting the MTT procedure must: 
• Be competent/trained, qualified and experienced in performing bronchial provocation 
tests; 
• Be familiar with safety and emergency procedures; 
• Know when to stop further testing; 
• Be proficient in the administration of inhaled bronchodilators and other rescue 
medications and equipment; and 
• Not be the same person who administers IMP in the clinic  
The following equipment must be available during the MTT procedure: 
• MTT kit with a dry powder inhaler; 
• Bronchodilator metered dose inhalers and spacers; 
• A spirometry system that meets ATS/ERS requirements; 
• Calculator and 60 second timer; 
• Pulse oximeter; 
• Adrenaline, atropine and oxygen; and 
• Resuscitation equipment. 

 
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MTT Assessment 
Failed MTT (i.e. “positive” MTT) when the 
subject’s: 
1. oxygen saturation falls to < 89 %.  
Record this as an adverse event; 
2. FEV1 falls ≥ 20% from baseline 
following cumulative doses of 120 mg or 
240 mg of mannitol; 
3. FEV1 falls ≥ 20% from baseline 
following a cumulative dose of 400 mg 
of mannitol, and does not return to within 
20% of baseline FEV1 within 15 minutes; 
or 
4. FEV1 falls ≥ 50% from baseline 
following a cumulative dose of 400 mg 
of mannitol. 
Passed MTT (i.e. “negative” MTT) occurs 
when: 
1. a cumulative dose of 400 mg mannitol 
has been administered and no positive 
criteria have been met (see above); or 
2. a cumulative dose of 400 mg mannitol 
has been administered and FEV1 falls ≥ 
20% but <50% from baseline but returns 
to within 20% of baseline FEV1 within 
15 minutes. 
An Incomplete (failed) test occurs when: 
1. Cough is highly distressing or vomiting 
occurs during the procedure.  Record this 
as an adverse event; or 
2. Any other medical event not listed above 
that leads to the test not being completed.  
Record this as an adverse event. 
 
 
Record times of all spirometry during MTT procedure. 
 
 
Bronchoconstriction may occur during the MTT.  If the subject shows clinical 
signs and symptoms of bronchoconstriction measure FEV1 and treat 

 
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accordingly.  If bronchoconstriction is severe or distressing, record as an adverse event. 

 
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Figure 3: The MTT procedure 
 

 
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8.1.1.2  Phone call 1 week after visit 0 (Week -1 ± 1 day) 
One week after the screening (Visit 0) visit of the trial, the Investigator or designate, will call 
the subject to: 
• collect information on any adverse events experienced (including pulmonary 
exacerbations or hemoptysis); 
• collect information on current concomitant medications; 
• confirm attendance to next clinic visit; 
• remind the subject to adhere to withholding periods; and 
• remind the subject to complete their subject diary. 
 
8.1.2 Double-blind treatment visits 
Refer to the TIME AND EVENTS SCHEDULE for a complete list of procedures to be 
performed during the double-blind treatment visits.  
8.1.2.1 Baseline (Visit 1) 
Visit 1 will occur 2 to 5 weeks post screening visit  
Prior to the visit, confirm medication-withholding periods have been adhered to 
(including 2-weeks wash out from hypertonic saline).  If not, the subject’s visit 
should be postponed. 
Confirm that the subject is not currently having a pulmonary exacerbation.  In 
the event of a pulmonary exacerbation, visit 1 should occur 2 to 5 weeks from the 
end of the treatment for the exacerbation or of the adverse event, whichever is later. 
The following procedures will be performed: 
• Review subject diary. 
• Randomize eligible subjects if compliance with maintenance therapies (antibiotic & 
rhDNase) is at least 80% in the two weeks prior to visit 1 using the Subject Diary.; 
• Review concomitant medications, and adverse events; (including pulmonary 
exacerbations or hemoptysis); 
• Complete ease of expectoration VAS and respiratory domain of the CFQ-R  
questionnaire; 
• Conduct physical examination (chest sounds, weight, BP, HR, O2 saturation, temperature, 
respiratory rate); 
• Perform pre-mannitol pulmonary function testing (FEV1, FVC, PEF, FEF25-75); 
• Assign IMP using IWRS; 
• Dispense IMP and bronchodilator according to randomization schedule; 
• Premedicate with four puffs of albuterol/salbutamol from a metered dose inhaler (MDI) 
(360-400µg), 5 to 15 minutes prior to each dose of IMP.  The subject’s preferred 
bronchodilator may be used as an alternative premedication. Care must be taken to ensure 
that a bronchodilator is used prior to ALL doses of IMP; 

 
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• Train the subjects on correct administration and inhalation of IMP, then administer initial 
dose of IMP (mannitol/control) according to ‘IMP Administration Procedure’ (see 
Section 6.1 figure 2) and randomization number; IMP administration should not be 
performed by the same person who administers the MTT. 
• Perform pulmonary function test 30 minutes post dose. If the subject has a measured fall 
in FEV1 >20% at 30 minutes post dose completion, no further study medication should 
be administered. The subject should be continued in the study on an intention to treat 
basis. Symptomatic bronchoconstriction should be managed as medically appropriate. 
The respiratory technician performing spirometry could be the same person who 
administers the IMP as long as they have not performed the MTT. 
• Access IWRS to complete the required visit information. 
 
8.1.2.2  Phone call 2 weeks after visit 1 (Week 2 ± 3 days) 
Two weeks after visit 1, the Investigator or designate, will telephone the subject to: 
• Collect information on any adverse events experienced (including pulmonary 
exacerbations or hemoptysis); 
• Collect information on current concomitant medications; 
• Remind the subject to adhere to withholding periods; 
• Discuss adherence to trial treatment; Is this subject continuing with the IMP treatment? If 
the answer is NO but the subject is continuing their participation in the trial, please 
schedule an IMP discontinuation visit (within 2 weeks after IMP discontinuation); 
• Remind the subject to return all trial drug (whether used or unused) at the next clinic 
visit; and 
• Remind the subject to complete all relevant sections of the subject diary and to bring the 
diary to each visit. 
 
8.1.2.3  Phone call 2 weeks before visit 2 (Week 4 ± 3 days) 
Two weeks before visit 2, the Investigator or designate, will call the subject to: 
• Collect information on any adverse events experienced (including pulmonary 
exacerbations or hemoptysis); 
• Collect information on current concomitant medications; 
• Confirm attendance to next clinic visit; 
• Remind the subject to adhere to withholding periods; 
• Discuss adherence to trial treatment; Is this subject continuing with the IMP treatment? If 
the answer is NO but the subject is continuing their participation in the trial, please 
schedule an IMP discontinuation visit (within 2 weeks after IMP discontinuation); 
• Remind the subject to return all trial drug (whether used or unused) at the next clinic visit; 
and 

 
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• Remind the subject to complete all sections of the subject diary and to bring the diary to 
each visit. 
8.1.2.4 Visit 2 
Visit 2 should occur on completion of 6 weeks trial treatment (± 7 days) 
 
 
Prior to the visit, confirm medication-withholding periods have been adhered to.  
If not, the subject’s visit should be postponed. 
 
 
The following procedures will be performed: 
• Review subject diary. 
• Review concomitant medications and adverse events (including pulmonary exacerbations 
or  hemoptysis); 
• Complete ease of expectoration VAS and respiratory domain of the CFQ-R  
questionnaire; 
• Conduct physical examination (chest sounds, weight, BP, HR, O2 saturation, temperature, 
respiratory rate); 
• Perform pre-mannitol pulmonary function testing (FEV1, FVC,  PEF, FEF25-75); 
• Dispense IMP and bronchodilator according to randomization schedule; 
• Premedicate with four puffs of albuterol/salbutamol from a metered dose inhaler (MDI) 
(360-400µg), 5 to 15 minutes prior to each dose of IMP.  The subject’s preferred 
bronchodilator may be used as an alternative premedication. Care must be taken to ensure 
that a bronchodilator is used prior to ALL doses of IMP; 
• Administer dose of IMP (mannitol/control) according to ‘IMP Administration Procedure’ 
(see Section 6.1 figure 2) and randomization number.  Check the subject’s inhalation 
technique and re-train if required; 
• Perform pulmonary function test 30 minutes post dose. If the subject has a measured fall 
in FEV1 >20% at 30 minutes post dose completion, no further study medication should 
be administered. The subject should be continued in the study on an intention to treat 
basis. Symptomatic bronchoconstriction should be managed as medically appropriate); 
• Conduct drug accountability; and 
• Access IWRS to complete the required visit information. 
 
 

 
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8.1.2.5  Phone call 2 weeks after visit 2 (Week 8 ± 3 days) 
Two weeks after visit 2, the Investigator or designate, will telephone the subject, and 
complete the procedures as per Section 8.1.2.2.  
8.1.2.6  Phone call 2 weeks before visit 3 (Week 12 ± 3 days) 
Two weeks before visit 3, the Investigator or designate will telephone the subject.  
Information collected will be as per Section 8.1.2.3. 
 
8.1.2.7 Visit 3 
Visit 3 should occur at the end of 14 weeks trial treatment (± 7 days) 
 
 
Prior to the visit, confirm medication-withholding periods have been adhered to.  
If not, the subject’s visit should be postponed. 
 
 
The following procedures will be performed: 
• Review subject diary. 
• Review concomitant medications and adverse events (including pulmonary exacerbations 
or hemoptysis); 
• Complete ease of expectoration VAS and respiratory domain of the CFQ-R questionnaire;  
• Conduct physical examination (chest sounds, weight, BP, HR, O2 saturation, temperature, 
respiratory rate); 
• Perform pre-mannitol pulmonary function testing (FEV1, FVC, PEF, FEF25-75); 
• Dispense IMP and bronchodilator according to randomization schedule; 
• Premedicate with four puffs of albuterol/salbutamol from a metered dose inhaler (MDI) 
(360-400µg), 5 to 15 minutes prior to each dose of IMP.  The subject’s preferred 
bronchodilator may be used as an alternative premedication. Care must be taken to ensure 
that a bronchodilator is used prior to ALL doses of IMP; 
• Administer dose of IMP (mannitol/control) according to ‘IMP Administration Procedure’ 
(see Section 6.1 figure 2) and randomization number.  Check the subject’s inhalation 
technique and re-train if required; 
• Perform pulmonary function test 30 minutes post dose. If the subject has a measured fall 
in FEV1 >20% at 30 minutes post dose completion, no further study medication should 
be administered. The subject should be continued in the study on an intention to treat 
basis. Symptomatic bronchoconstriction should be managed as medically appropriate. 
• Conduct drug accountability; and 
• Access IWRS to complete the required visit information. 

 
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8.1.2.8  Phone call 2 weeks after visit 3 (Week 16 ± 3 days) 
Two weeks after visit 3, the Investigator or designate will telephone the subject.  Information 
collected will be as per Section 8.1.2.2. 
8.1.2.9  Phone call 6 weeks before visit 4 (Week 20 ± 3 days) 
Six weeks before visit 4, the Investigator or designate will telephone the subject.  Information 
collected will be as per Section 8.1.2.3. 
8.1.2.10  Phone call 2 weeks before visit 4 (Week 24 ± 3 days) 
Two weeks before visit 4, the Investigator or designate will telephone the subject.  
Information collected will be as per Section 8.1.2.3. 
8.1.2.11 Visit 4 
Visit 4 should occur at the end of 26 weeks of trial treatment (-7 to +28 days) 
 
Prior to the visit, confirm medication-withholding periods have been adhered to.  
If not, the subject’s visit should be postponed. 
 
The following procedures will be performed: 
• Review and collect subject diary. 
• Review concomitant medications and adverse events  (including pulmonary exacerbations 
or hemoptysis); 
• Complete ease of expectoration VAS and respiratory domain of the CFQ-R questionnaire;  
• Conduct physical examination (chest sounds, weight, BP, HR, O2 saturation, temperature, 
respiratory rate); 
• Perform pre-mannitol pulmonary function testing (FEV1, FVC, , PEF, FEF25-75); 
• Premedicate with four puffs of albuterol/salbutamol from a metered dose inhaler (MDI) 
(360-400µg), 5 to 15 minutes prior to each dose of IMP.  The subject’s preferred 
bronchodilator may be used as an alternative premedication. Care must be taken to ensure 
that a bronchodilator is used prior to ALL doses of IMP; 
• Administer dose of IMP (mannitol/control) according to ‘IMP Administration Procedure’ 
(see Section 6.1 figure 2) and randomization group;  
• Perform pulmonary function test 30 minutes post dose. Symptomatic bronchoconstriction 
should be managed as medically appropriate;  
• Conduct drug accountability; and 
• Access IWRS to complete the required visit information. 
 
 

 
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8.1.2.12  Final phone call 1 week after visit 4 (Week 27 ± 1 day) 
One week after the final visit of the trial, the Investigator or designate, will call the subject to: 
• Collect information on any adverse events experienced (including pulmonary 
exacerbations or hemoptysis); and 
• Collect information on current concomitant medications; and 
• Discharge subject from trial. 
8.1.2.13 IMP discontinuation visit (within 2 weeks after IMP discontinuation) 
Within two weeks of discontinuation of IMP, subjects should undergo an IMP 
discontinuation visit.  At this visit, the following procedures will be performed: 
• Review subject diary; 
• Review concomitant medications and adverse events (including pulmonary exacerbations 
or hemoptysis); 
• Complete ease of expectoration VAS and respiratory domain of the CFQ-R questionnaire;  
• Conduct physical examination (chest sounds, weight, BP, HR, O2 saturation, temperature, 
respiratory rate); 
• Perform pulmonary function testing (FEV1, FVC,  PEF, FEF25-75); 
• Access IWRS to complete the required visit information. 
8.2 Efficacy 
8.2.1 Efficacy evaluations 
Efficacy evaluations are highlighted in the TIME AND EVENTS SCHEDULE. Briefly, these 
include: 
8.2.1.1 Pulmonary function tests (Spirometry) 
Perform all trial spirometry according to the American Thoracic Society / European 
Respiratory Society (ATS/ERS) criteria [12], using a standardized spirometer that meets 
ATS/ERS requirements and using a trained, experienced, qualified technician.  Pharmaxis or 
designee must approve all trial staff responsible for performing spirometry prior to the 
staff being delegated this task. 
Perform all lung function measures using the same spirometer throughout the trial.  Perform 
spirometry at the same time of day for each visit (± 1 to 2 hours where possible).  All visits 
should coincide with the trough treatment effect – that is, approximately 6 to 24 hours 
following the previous inhaled mannitol dose.  Subjects must refrain from smoking within 1 
hour of testing, consuming alcohol within 4 hours of testing, and performing vigorous 
exercise within 30 minutes of testing.  Concomitant medications must be withheld prior to 
spirometry according to Table 4. 
Complete spirometry after the physical exam, but prior to administration of any 
bronchodilator. 
Seat the subject for the procedure unless they are obese, in which case testing in the standing 
position is preferred. 

 
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Table 6: ATS/ERS Criteria for acceptable spirometry [12] 
ATS/ERS criterion 
Number of trials 
> 3 acceptable FVC maneuvers 
If more than eight attempts are made with the subject unable to perform a single 
acceptable maneuver, then discontinue testing. 
In some cases, testing can be continued after additional instruction and demonstration, 
where the subject’s clinical condition and tolerance allow. 
Acceptability 
1. Satisfactory “start of test” 
• 
No excessive hesitation or false start extrapolated volume; 
• 
Extrapolated volume < 5% of FVC or 0.150 L (whichever is greater); 
2. No coughing during the first second of the maneuver, or any other cough that the 
Trial Staff believe interferes with the measurement of accurate results; 
3. No early termination of expiration; 
4. No Valsalva maneuver (glottis closure) or hesitation during the maneuver that causes 
a cessation of airflow; 
5. No leak at the mouth; 
6. No obstructed mouthpiece; and 
7. No evidence of an extra breath being taken during the maneuver. 
A minimum exhalation time of ≥ 6 seconds or ≥ 3 seconds for children 
Repeatability 
After three acceptable spirograms have been obtained, apply the following tests: 
1. The two largest FVC must be within *0.150 L of each other; and  
2. The two largest FEV1 must be within *0.150 L of each other. 
If both are met, testing can be concluded, otherwise continue testing until both criteria 
are met or a total of eight tests have been performed or the subject cannot or should not 
continue. 
*For those with FVC of ≤1.0L, both these values are 0.100L. 
 
 
 

 
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“Hospital in the home” or an equivalent program; or attendance / observation in the 
emergency department is not considered to be a hospital admission. Medications 
administered as part of any elective procedure or hospital in the home process, are to be 
recorded as concomitant medications.  
8.2.1.5  Hospital admission  
At the time of hospital admission, the following information will be recorded in the CRF and 
on the SAE Form, if available: 
• physical examination and medical history; 
• signs and symptoms checklist; 
• sputum microbiology results; 
• spirometry; 
• number of days since last hospital admission; 
• results of laboratory tests; and 
• chest X ray reports. 
8.2.1.6 Hospital discharge 
In addition to information recorded as per hospital admission, at the time of hospital 
discharge for an SAE the following information must be obtained as close as possible to the 
discharge date, and recorded in the CRF and on a follow-up SAE Form: 
• medications during admission; and 
• Start and end dates of hospitalization. 
8.2.1.7 Ease of expectoration 
A visual analogue scale will be used to assess the subjects’ perceptions on ease of 
expectoration [14] while using IMP.  Subjects will be asked to record the ease of 
expectoration over the previous week using a 10-cm visual analogue scale (0 = very difficult; 
10 = very easy). 
8.3 Safety 
Safety assessments are highlighted in the TIME AND EVENTS SCHEDULE. 
8.3.1 Safety evaluations 
Any clinically significant change in safety evaluation will be recorded as an adverse event 
(AE) as detailed in Section 8.3.1.1. 
 
 

 
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8.3.1.1 Adverse events (AEs) 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational medicinal product(s) will be recorded on the Adverse Event 
page of the CRF.  Subjects will be questioned for the occurrence of any new or worsening 
signs or symptoms at each visit by the following methods: 
• Information volunteered by the subject; 
• Open ended and non-leading questions such as: Have you had any health problems 
since your last visit?; 
• Observation by the investigational team, other care providers or relatives; or 
• Medical Record and Subject Diary review. 
The appropriate clinical individual at the trial site provides assessment and treatment of any 
trial related medical emergencies involving trial subjects.  
Please refer to Section 8.3.3 for further details on AE reporting procedures.  
8.3.1.2 Clinical laboratory tests 
Sputum microbiology, and screening bloods (hematology, electrolytes, urea, creatinine and 
liver function tests) are the only laboratory tests required for this trial protocol.  Laboratory 
tests are performed and analyzed following the local laboratory’s standard procedures.  If any 
other routine clinical laboratory testing is performed and a clinically significant result is 
obtained, then this must be recorded as an AE (see Section 8.3.3).  
8.3.1.3 Vital signs 
Temperature, pulse, respiratory rate and blood pressure will be assessed according to the 
TIME AND EVENTS SCHEDULE. 
Temperature should be taken at the same site each visit (e.g. oral, tympanic, or axillary). 
Blood pressure will be assessed seated.  
8.3.1.4 Physical examination 
Physical examinations will be as per the TIME AND EVENTS SCHEDULE.  A physician 
should preferably conduct the physical examination, but where timing prohibits this, a 
suitably trained nurse may undertake this task.  The physician should be consulted if any 
abnormality in the examination is detected. 
8.3.1.5 Pregnancy testing 
Perform urine pregnancy tests at screening on all females of child-bearing potential. Subjects 
who are pregnant are excluded from the trial. Female subjects who are at risk of becoming 
pregnant are expected to prevent pregnancy occurring while on treatment by using effective 
birth control methods e.g. oral contraceptive, condom, IUD, injectable contraceptive, or 
diaphragm. Male subjects have no contraceptive restrictions. 
The Investigator will inform the Sponsor immediately of any case of pregnancy and collect 
information on any subject who becomes pregnant during the trial using the Pregnancy 
Report Form. Discontinue pregnant subjects from treatment but continue to follow-up for 

 
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scheduled safety assessments for the duration of the trial. Subjects will also be followed to 
determine the outcome of pregnancy.  See also section 8.3.4.3. 
8.3.2 Criteria 
An assessment of safety will be made on the basis of reviewing changes in physical 
examination, spirometry and using adverse event data. 
8.3.3 Adverse event reporting 
8.3.3.1 Definitions 
Adverse event  
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this product.  
An AE can therefore be any unfavorable or unintended sign (for example an abnormal 
laboratory finding), a symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to that product. 
Any worsening (e.g. clinically significant adverse change in frequency and/or intensity) of a 
pre-existing condition, which is temporally associated with the use of a medicinal product, is 
also considered an AE. Recurring symptoms associated with pre-existing conditions will not 
be considered AEs during the trial, unless they have a clinically significant increase in 
severity and/or frequency. 
 Hemoptysis is an event of special interest in this trial and should be reported as a 
separate Adverse Event every time it occurs, even if it is considered to be a 
component of a pulmonary exacerbation and/or if it is an ongoing / intermittent 
medical history condition. 
 
 
 

 
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Serious adverse event (SAEs) 
A serious adverse event (SAE) for this trial is defined as any unfavorable medical occurrence 
that at any dose:  
1) Results in death 
 
2) Is life-threatening 
NOTE: the term “life-threatening” refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event, which hypothetically 
might have caused death if it were more severe. 
3) Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: The following do not meet the definition of hospitalizations for SAE reporting 
purposes: 
• An Emergency Department visit that did not result in an admission to the 
hospital 
• Hospitalizations for social reasons 
• Planned hospitalizations for surgery or procedure planned prior to the 
subject’s entry into the trial, unless the subject experiences an additional AE 
that prolongs the pre-planned hospitalization. This pre-planned hospitalization 
must be documented in the subject’s CRF medical record page at screening 
(Visit 0). 
 
4) Results in persistent or significant disability or incapacity 
 
5) Is a congenital anomaly or birth defect 
 
6) Other important medical event 
NOTE: Appropriate medical judgment should be exercised for important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definitions above. These should usually be 
considered serious. 
 
 

 
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8.3.3.2 Causality assessment 
The Investigator will make a causality assessment according to his/her best judgment.  The 
following criteria can be used as a guidance to assess the causal relationship.  These are not 
definitive, but presented as examples. 
Definitely related: 
• There is evidence of exposure to the investigational medication or procedure 
• The temporal sequence of the AE onset relative to administration of the 
investigational medication or procedure is reasonable 
• The SAE is more likely explained by the investigational medication or procedure than 
by another cause 
• De-challenge (if performed) is positive 
• Re-challenge (if feasible and if performed) is positive 
• The AE shows a pattern consistent with previous knowledge of the investigational 
medication  or investigational medication   class 
Probably related: 
• There is evidence of exposure to the investigational medication or procedure 
• The temporal sequence of the AE onset relative to administration of the 
investigational medication or procedure is reasonable 
• The AE is more likely explained by the investigational medication or procedure rather 
than by another cause 
• De-challenge (if performed) is positive 
• Re-challenge (if performed) is positive or ambiguous 
Possibly related: 
• There is evidence of exposure to the investigational medication or a protocol 
procedure 
• The temporal sequence of the AE onset relative to administration of the 
investigational medication or procedure is reasonable 
• The AE could have been due to another equally likely cause 
• De-challenge (if performed) is negative or ambiguous 
• Re-challenge (if performed) is negative or ambiguous 
Probably not related: 

 
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• There is evidence of exposure to the investigational medication or protocol procedure 
• There is another more likely cause of the AE 
• De-challenge (if performed) is negative or ambiguous 
• Re-challenge (if performed) is negative or ambiguous 
Definitely not related: 
• The subject did not receive the investigational medication or undergone any protocol 
procedure  
• Temporal sequence of the AE onset relative to administration of the investigational 
medication or procedure is not reasonable  
• There is another obvious cause of the AE 
• De-challenge (if performed) is negative 
• Re-challenge (if performed) is negative 
8.3.3.3 Severity assessment 
Mild: the subject has an awareness of a sign or symptom, but it is easily tolerated and does 
not alter normal activity 
Moderate: the sign or symptom causes discomfort and/or interference with the subject’s 
usual activity 
Severe: the sign or symptom causes significant impairment of function or incapacitation, 
and/or the subject is unable to perform usual activities 
8.3.4 Reporting procedures 
8.3.4.1 All adverse events 
The Investigator will assess all AEs and record details of seriousness (see Section 8.3.3.1), 
severity (see Section 8.3.3.3), duration, action taken with the investigational medication, and 
relationship to the investigational medication (causality, see Section 8.3.3.2). The 
Investigator will also record details of de-challenge and re-challenge with the investigational 
medication. 
All adverse events that meet any of the serious criteria defined in Section 8.3.3.1 will be 
reported as SAEs. 
All AEs, whether serious or not, will be reported from signing of the informed consent form 
until 7 days after the last trial visit. 
All SAEs, including those spontaneously reported to the Investigator by the subject, must be 
reported using the SAE Form. 

 
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If a subject experiences an SAE any time after the 30 day post final trial visit follow-up 
period and the SAE is considered to be related to the investigational medication, the 
Investigator should report this to Pharmaxis immediately. 
All AEs, regardless of seriousness, severity or presumed causality must be recorded in the 
subject’s medical records and in the CRF.  AEs that occur in subjects who have screen failed 
and are not entered into the CRF will be captured on the AE Reporting Log in the 
Investigator Site File. All SAEs that occur in subjects who have screen failed will be reported 
from informed consent.  
The Sponsor is responsible for reporting AEs to the relevant regulatory authorities according 
to international and local regulations applicable to this trial.    
The Investigator is responsible for reporting AEs to the appropriate IEC that approved the 
protocol, as required and documented by the IEC. 
Pulmonary exacerbations are expected to occur as part of the disease but will be recorded as 
adverse events. Expedited reporting of serious exacerbations to Regulators and Ethics 
Committees will only be carried out if the exacerbation is considered to be related to trial 
drug and is clinically different to that normally expected in a particular subject (e.g. more 
severe). In such cases, the difference should be noted on the AE form.  
8.3.4.2 Serious adverse events 
The Principal Investigator or designee will report all SAEs immediately and in any 
situation no later than 24 hours after any member of the investigational team becomes 
aware of the event. 
The Investigator must make an assessment of causality (see Section 8.3.3.2) and severity (see 
Section 8.3.3.3) of all SAEs.  All actions taken and outcomes must also be recorded. 
The SAE Report Form should be completed and forwarded to:  
 
 
 
SAEs will be followed up until the event has resolved and the report is assessed as complete; 
or the subject is lost to follow-up.  In addition, an Investigator may be requested by 
Pharmaxis to provide or obtain specific additional follow-up information in an expedited 
fashion for the purposes of full safety assessment. 
All follow-up information should be reported as described above.  
 
 

 
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8.3.4.3 Pregnancy 
Pregnancy is not usually considered an SAE or an AE.    
If an Investigator becomes aware that a subject, or the sexual partner of a male subject, 
becomes pregnant while they are participating in the trial or within the 7-day post trial 
follow-up period they will notify Pharmaxis immediately.   
A Pregnancy Report Form should be completed and be forwarded to;  
 
 
 
Female subjects who become pregnant will be withdrawn from treatment but will continue to 
be followed up for scheduled safety assessments for the duration of the trial. 
All pregnancies should be followed to term and the outcome reported to Pharmaxis.  In the 
case of a pregnancy in the sexual partner of a male subject consent will be sought from the 
partner to obtain follow-up information. 
If a subject or baby experience any adverse event during the pregnancy or after birth this will 
be reported as described throughout Section 8.3. 
9 SUBJECT COMPLETION / DISCONTINUATION 
9.1 Completion 
A subject will be considered to have completed the trial if he or she has completed 
assessments up to visit 4. Subjects who prematurely discontinue investigational drug 
treatment during the trial and fail to present for the scheduled trial visits for any reason will 
not be considered to have completed the trial.  Subjects who discontinue from the IMP but 
continue to participate in the trial to the final assessment will be considered to have 
completed the trial. 
9.2 Trial treatment discontinuation 
All subjects who discontinue IMP treatment and remain in the trial will be requested to attend 
an IMP discontinuation visit within 2 weeks of the last dose.  A complete evaluation should 
be made at this visit. 
All efforts should be made to ensure that subjects who discontinue IMP treatment remain 
in the trial, and continue all other scheduled visits as per protocol. 
A subject will be discontinued from treatment if she becomes pregnant. 
9.3 Trial withdrawal 
A subject will be withdrawn from the trial for any of the following reasons: 
• Loss to follow-up; 
• Withdrawal of consent; 
• The subject’s attending physician requests that the subject be withdrawn from the 
trial; or 

 
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• The Investigator or the Sponsor, for any reason, stops the trial or stops the subject 
participating in the trial. 
Protocol deviations will not lead to automatic withdrawal unless they indicate a significant 
risk to the subject’s safety.  All protocol deviations must be discussed promptly with the 
Sponsor. 
All subjects who are withdrawing from the trial will attend their next scheduled visit.  This 
should be within two weeks of administration of the last dose of IMP.  A complete final 
evaluation at the time of the subject’s withdrawal should be made and an explanation be 
given as to why the subject is withdrawing or being withdrawn from the trial.  The reason and 
date of withdrawal must be noted on the CRF.  If the reason for withdrawal is an AE or a 
clinically significant laboratory test result, monitoring will continue until resolution or until 
an appropriate medical judgment concerning the cause or importance has been made.  The 
specific event or test result(s) must be recorded on the CRF.  
10 STATISTICAL METHODS 
10.1 General considerations 
A full description of the statistical methods planned for this trial can be found in the DPM-
CF-303 Statistical Analysis Plan (SAP).  
Efficacy analyses will be conducted using the intention to treat (ITT) analysis set (refer 
Section 10.1.2.1) as well as the per protocol (PP) analysis set (refer Section 10.1.2.2). Safety 
analyses will be conducted on the safety analysis set (refer Section 10.1.2.3). 
Significance tests will be performed assuming a two-sided 0.05 significance level; two-sided 
95% confidence intervals will also be computed.  
 
10.1.1 Sample size justification 
Enrolment will continue until at least 350 subjects have been randomized to treatment in a 
1:1 ratio. 
Assuming that the change from baseline in FEV1 on control is 0 mL and the change from 
baseline in FEV1 on mannitol is 80 mL, then a sample size of 350 (175 Mannitol : 175 
Control) subjects will yield 90 % power at the 0.05 significance level to detect this difference 
between the treatment groups assuming a pooled standard deviation of 230 mL. The sample 
size calculation is based on a t-test of the treatment contrast at week 26. While this approach 
is not completely concordant with the primary analysis which computes the mean change in 
FEV1 over all three post-baseline visits it can be considered a suitable method for estimating 
sample sizes for longitudinal analyses and is likely to be conservative. 
The estimated pooled standard deviation of 230 mL is based on the observed pooled standard 
deviation in the pooled adult DPM-CF-301 and DPM-CF-302 data from subjects who 
completed the studies. 
This minimum sample size is based upon the observed pooled standard deviation from both 
DPM-CF-301 and DPM-CF-302 studies in subjects with baseline FEV1 of more than 40% but 
less than 90%. However the observed standard deviations were different in these two 

 
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previous studies, and were highly influenced by a few outlying values.  In addition, the 
present trial (DPM-CF-303) will be conducted at different sites and in different countries to 
the previous studies.  Thus there is some uncertainty as to what the observed standard 
deviation is likely to be in this trial (DPM-CF-303). For these reasons a sample size re-
estimation is planned to be completed after at least 300 subjects have been recruited and will 
be based on all available 26-week data. This blinded sample size re-estimation will be based 
on the method of Kieser and Friede [15] which preserves the overall type 1 error rate. 
Therefore no adjustments to the overall significance level for the trial is required.  See 
Section 10.1.5 for more information. 
  
10.1.2 Analysis sets 
10.1.2.1 Intention to treat (ITT) analysis set 
The ITT analysis set (also known as the Full Analysis Set) will include all subjects who were 
randomized to treatment. Subjects will be analyzed according to the treatment group to which 
they were randomized. 
10.1.2.2 Per protocol (PP) analysis set 
The per protocol analysis set consists of all randomized subjects, who have: 
• Strictly met all the inclusion and exclusion criteria (i.e. will exclude those subjects 
who have been granted an exception to be included in the trial); 
• No major protocol deviations which would affect efficacy evaluations; 
• Taken trial drug for at least 60% of the 26-week treatment period; 
• A valid baseline FEV1 measure; and 
• At least two valid assessments of FEV1 following the baseline visit (Visit 0). 
The decision to include subjects in the per protocol dataset will be made prior to unblinding 
of the randomization schedule. For the per protocol analysis any non-valid assessments of 
FEV1 will be excluded from the analysis.  The validity of the FEV1 measurements will be 
assessed prior to unblinding. The subject must meet the requirement for a valid baseline and 
two valid post-baseline FEV1 assessments. 
10.1.2.3 Safety analysis set 
The safety analysis set will include all subjects who received at least one dose (or part 
thereof) of randomized trial treatment. Subjects will be analyzed in the treatment group based 
on the treatment they received. 
10.1.2.4 Mannitol Tolerance Test (MTT) analysis set 
The MTT set will include all subjects participating in the mannitol tolerance test prior to 
randomisation regardless of their subsequent randomisation status. It includes subjects who 
fail the MTT (MTT positive) or who have an incomplete procedure, along with those who 
pass the MTT (MTT negative).   
10.1.3 Missing data 
Where a subject has missing baseline data, where possible, the screening (Visit 0) value will 
be used.  

 
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10.1.8 Baseline demographic and clinical characteristics 
Baseline characteristics will be described using the safety population.  If required, these may 
also be produced for the intent to treat analysis set (ITT). Demographics, medical history and 
other baseline variables will be summarized as appropriate to the type of data. 
10.2 Efficacy analysis 
10.2.1 Primary objective 
To determine whether inhaled mannitol (400mg b.i.d.) is superior to control for improving 
lung function as measured by mean change from baseline FEV1 (mL) over the 26-week 
treatment period in adult subjects (18 years or older) with CF. 
10.2.2 Primary endpoint 
The primary endpoint is the mean change from baseline FEV1 (mL) measured at weeks 6, 14 
and 26. 
10.2.3 Primary analysis 
The mean absolute change from baseline FEV1 (mL) over weeks 6, 14 and 26 will be 
compared between the two treatment groups with a REML based repeated measures 
approach.  
Analyses will include the fixed, categorical effects of treatment, rhDNase use, country, visit, 
and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline 
percent predicted FEV1. An unstructured (co)variance structure will be used to model the 
within-subject errors. 
The planned primary efficacy model will take the form: 
 
Significance tests will be based on least-squares means using a two-sided 0.05 significance 
level.  Two-sided 95% confidence intervals will be computed. 
 
 
Change in % predicted FEV1, relative change in FEV1 (% change) and relative change in % 
predicted FEV1 will also be analyzed using the primary model. 
10.2.4 Primary analysis – missing data 
Subjects who discontinue drug treatment will remain in the trial and continue to provide all 
scheduled FEV1 measurements. While all efforts will be made to ensure subjects remain in 
the trial, the following planned imputation strategy will allow for an appropriate primary 
analysis in the presence of missing FEV1 data. 
Missing baseline (Visit 1) measurements for the primary efficacy variable (FEV1) will be 
imputed using screening (Visit 0) values, if available. 
Missing post-baseline measurements for the primary efficacy variable (FEV1) will be 
imputed utilizing an Imputation Using Dropout Reason (IUDR) methodology.  For subjects 
who discontinue due to safety, tolerability, lack of efficacy or were lost to follow-up, missing 
post-baseline FEV1 measures will be imputed using the baseline (Visit 1) FEV1 measurement 
(baseline observation carried forward [BOCF] procedure).  Missing FEV1 measurements as a 
Change from baseline FEV
1 = Baseline % predicted FEV
1 + Treatment + rhDNase + Visit + Country +
Treatment × Visit
(
)

 
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result of other causes of trial discontinuation (e.g. relocation, pregnancy) will not be 
explicitly imputed. 
Imputation of missing FEV1 measurements by means of BOCF is a reasonable assumption in 
the studies of adult subjects with cystic fibrosis, as these subjects who discontinue will no 
longer receive treatment and are thus likely to promptly return to their baseline lung function. 
Imputation by BOCF specifically inhibits any possible prolongation of an observed early 
treatment benefit implicitly conferred by a mixed model. 
A framework of imputation by BOCF in combination with the IUDR strategy seeks to 
specifically address the primary regulatory question of interest, that is to provide a reliable 
estimation of the treatment effect over 26 weeks as observed in all randomized subjects. 
10.2.5  Primary sensitivity analyses 
The following planned sensitivity analyses are intended to gain insights into how different 
analytical assumptions influence the results of the planned primary analysis.  Depending on 
the extent and pattern of withdrawals and “missingness” further sensitivity analyses in 
additional to those given below may be performed. If necessary, further details will be 
provided in the SAP. 
10.2.5.1 Primary sensitivity analysis #1:  
To elicit insights into the effect of imputation via the planned BOCF + IUDR framework the 
primary analyses will be repeated with no explicit imputation of missing post-baseline FEV1. 
10.2.5.2 Primary sensitivity analysis #2: 
To elicit insights into the effects of including data from subjects after cessation of trial 
treatment (by including these data, the effects of subsequent therapy are attributed to trial 
treatment), the primary analyses will be repeated excluding these data both with imputation 
of missing (and excluded) post-baseline FEV1 assessments and without explicit imputation. 
Data from IMP discontinuation visit or early withdrawal from the study that has been 
collected will be examined here also. 
10.2.5.3 Primary sensitivity analysis #3: 
Sensitivity of the primary result to choice of “across weeks 6 to 26” versus “at week 26” 
estimates of the treatment effect will be gauged by computing the least square mean 
difference at week 26 for the purposes of comparison. 
10.2.5.4 Primary sensitivity analysis #4:  
A potential disadvantage of employing a single imputation method such as BOCF is the risk 
of artificially attenuating the natural variability in the longitudinal data. To gauge the possible 
impact of this effect, a two-sample t-test at week 26 will be undertaken computing point 
estimates from the data with BOCF but computing variation only from subjects who 
completed the trial. Furthermore a non-parametric equivalent (e.g. Wilcoxon rank sum test) 
will be undertaken on the data with BOCF imputation. These results will be compared to the 
week 26 contrast computed by the primary efficacy model (Primary sensitivity analysis #2). 
10.2.5.5 Primary sensitivity analysis #5:  
The primary analysis will be repeated using the mean FEV1 measurement from screening 
(Visit 0) and baseline (instead of the baseline FEV1 measurement) in order to determine if the 
primary results are sensitive to any observed changes between screening and baseline in 
FEV1. 

 
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10.2.5.6 Primary sensitivity analysis #6 
Two responder analyses will be undertaken: 
1. A responder will be defined as those who have an increase from baseline FEV1 of 
greater than 100 mL (subjects who discontinued from the trial will be classified as 
non-responders). 
2. A non-responder will be defined as those who have a reduction from baseline FEV1 of 
more than 100 mL (subjects who discontinued from the trial will be classified as non-
responders). 
Proportions in each treatment group will be assessed for each definition and compared 
between treatment groups using logistic regression. 
10.2.5.7 Primary sensitivity analysis #7 
In addition to the responder analysis described above, a responder analysis will be undertaken 
where the cut-off for classification as a responder will be change from baseline FEV1 greater 
than: -300, -250, -200, -150, -100, -50, 0, 50, 100, 150, 200, 250 & 300mL respectively. 
These results will be plotted in a graphical summary for both treatment groups. These results 
can be scrutinized to ensure a consistent trend of treatment effect that is insensitive to any 
particular definition of response. 
10.2.5.8 Primary sensitivity analysis #8 
To explore the impact of patterns of “missingness” in the data, multiple imputation (MI) with 
penalties will be used. Missing data across the treatment period, namely week 6 to week 26, 
will be first imputed by MI (i.e. multiple times). Then the impact of various penalties will be 
explored including linking penalties to reason for “missingness” and increasing penalties for 
subjects with multiple missing data (as these subjects could be less likely benefit from the 
treatment). The imputed longitudinal data will be analyzed by mixed-effect model repeated 
measures (MMRM) model as above. 
10.2.5.9 Primary sensitivity analysis #9 
To explore the effect of different imputation methods, the primary analysis will be repeated 
using a worst observation carried forward (WOCF) + IUDR method rather than the BOCF + 
IUDR framework. 
10.2.6 Primary per protocol analysis 
The primary analysis is planned to estimate the treatment effect of being randomized to 
mannitol. In order to estimate the treatment effect of taking mannitol a per protocol analysis 
is planned. This entails re-fitting the primary efficacy model to the per-protocol analysis set. 
The results of this per protocol analysis will provide an extra robustness check on the main 
results from the ITT population. 
10.2.7 Secondary analyses  
Three key secondary objectives are ordered as follows and will be subjected to a hierarchical 
testing procedure outlined in Section 10.2.8 
10.2.7.1 Hierarchical secondary objectives 
Objective #1: To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control 
for improving lung function as measured by mean change from baseline FVC (mL) over the 
26-week treatment period in adult subjects with CF. 

 
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Analysis: The absolute change in FVC will be analyzed as per the primary analysis (i.e. 
REML based repeated measures approach using a model including the fixed, categorical 
effects of treatment, rhDNase use, country, visit, and treatment-by-visit interaction, as well 
as, the continuous, fixed covariate of baseline percent predicted FEV1). 
Objective #2: To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in 
increasing the time to first pulmonary exacerbation over the 26-week treatment period in 
adult subjects with CF. 
Analysis: The time (in days) from the date of first treatment to the date of the first pulmonary 
exacerbation (any grade) will be analyzed using the Cox’s Proportional Hazards model with 
time to first exacerbation as the outcome, and treatment, country, rhDNase use and historical 
exacerbation rate as factors.  The hazard ratio will be presented with 95% confidence limits.  
When a subject does not have an exacerbation during the trial period the subject will be 
censored at the date of their last participation in the trial. 
Objective #3: To determine whether in adult subjects with CF, inhaled mannitol (400 mg 
b.i.d.) is superior to control for reducing the number of days on antibiotics (oral, inhaled or 
IV) due to pulmonary exacerbation. 
Analysis: The number of days on antibiotics will be compared between treatment groups 
using a negative binomial model with the number of days on antibiotics recorded by each 
subject over the trial period as the outcome variable, and treatment group, country, rhDNase 
use and historical exacerbation rate as predictors.  An offset variable of the natural log of 
number of days in the trial will be used in the model to adjust for different lengths of follow-
up.  The rate ratio will be presented with 95% confidence limits. 
Objective #4: To determine whether in adult subjects with CF, inhaled mannitol (400 mg 
b.i.d.) is superior to control for decreasing the number of days in hospital due to pulmonary 
exacerbation. 
Analysis: The number of days in hospital (admissions only) due to pulmonary exacerbation 
will be compared between treatment groups using a negative binomial model with the 
number of days in hospital due to pulmonary exacerbation experienced by each subject over 
the trial period as the outcome variable, and treatment group, country, rhDNase use and 
historical exacerbation rate as predictors.  An offset variable of the natural log of number of 
days in the trial will be used in the model to adjust for different lengths of follow-up.  The 
rate ratio will be presented with 95% confidence limits. 
Objective #5: To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of 
pulmonary exacerbations over the 26-week treatment period compared to control in adult 
subjects with CF. 
Analysis: The rate of pulmonary exacerbations will be compared between treatment groups 
using a negative binomial model with the number of pulmonary exacerbations experienced by 
each individual over the trial period as the outcome variable, and treatment group, country 
and rhDNase use as predictors.  Historical exacerbation rate will be used as a covariate.  An 
offset variable of the natural log of number of days in the trial will be used in the model to 
adjust for different lengths of follow-up.  The rate ratio will be presented with 95% 
confidence limits. 
10.2.7.2 Non-hierarchical secondary objectives 
Objective #1:  To determine whether in adult subjects with CF, inhaled mannitol (400 mg 
b.i.d.) is superior to control for decreasing incidence of pulmonary exacerbations. 
Logistic regression will be used to estimate the treatment effect (odds ratio) on the proportion 

 
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of subjects with one or more exacerbations. Covariates of country, rhDNase use and 
historical exacerbation rate will be included in the logistic regression model. 
Objective #2: To determine whether in adult subjects with CF, inhaled mannitol (400 mg 
b.i.d.) is superior to control for improving ease of expectoration. 
Analysis: The change in VAS score from baseline will be analyzed in a similar manner to the 
primary endpoint.  The mean absolute change from baseline VAS score over weeks 6, 14 and 
26 will be compared between the two treatment groups with a REML based repeated 
measures approach. Analyses will include the fixed, categorical effects of treatment, rhDNase 
use, country, visit, and treatment-by-visit interaction, as well as the continuous, fixed 
covariates of baseline VAS score and baseline % predicted FEV1. An unstructured 
(co)variance structure will be used to model the within-subject errors. 
Objective #3: To determine whether in adult subjects with CF, inhaled mannitol (400 mg 
b.i.d.) is superior to control for improving respiratory symptoms measured by CFQ-R 
respiratory domain. 
Analysis: Component questions in the questionnaire will be appropriately transformed 
according to the scoring manual, so that the best response will be uniformly the highest score 
and the worst response will be uniformly the lowest score.  The mean absolute change from 
baseline in the CFQ-R respiratory domain score over weeks 6, 14 and 26 will be compared 
between the two treatment groups with a REML based repeated measures approach. Analyses 
will include the fixed, categorical effects of treatment, rhDNase use, country, visit, and 
treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline CFQ-R 
respiratory domain score and baseline % predicted FEV1. An unstructured (co)variance 
structure will be used to model the within-subject errors. 
The CFQ-R respiratory domain includes the question “Have you had to cough up mucus?” 
The scoring algorithm scores an affirmative answer to this question as a negative outcome for 
the subject, however, due to the mechanism of action of mannitol (i.e. inducing coughing up 
mucus) an affirmative answer here may not be a negative outcome and hence this question is 
inappropriate here. Therefore, the above analyses will be repeated on the CFQ-R respiratory 
domain score omitting this question.  
10.2.8 Hierarchical testing of key secondary objectives 
The hypotheses for the primary efficacy endpoint and the three key secondary efficacy 
endpoints will be formally tested utilizing a hierarchical testing approach to preserve the 
type-I error rate. Objectives will be tested in the order in which they are ranked in Section 2. 
10.2.9  Secondary analyses – missing data 
Change from baseline FVC:  
Missing post-baseline measurements will be handled as per the primary efficacy endpoint 
(FEV1). 
Time to first pulmonary exacerbation: 
Subjects who withdraw from the trial prior to experiencing an exacerbation will be censored 
at the date of the last participation in the trial.  
Pulmonary exacerbation rate:  
In the event a subject discontinues from the trial before week 14 with no observed instances 
of a pulmonary exacerbations the number of pulmonary exacerbations will be imputed using 
half the subject’s historical (previous 12 months) pulmonary exacerbation count (rounded 
upwards) and their treatment exposure time will be imputed as 26 weeks.  

 
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In the event a subject discontinues from the trial after week 14 with no observed instances of 
a pulmonary exacerbations the number of pulmonary exacerbations will be imputed using one 
quarter the subject’s historical (previous 12 months) pulmonary exacerbation count (rounded 
upwards) and their treatment exposure time will be imputed as 26 weeks. 
Number of days in hospital and number of days on antibiotics: 
Primary negative binominal analysis allows for different lengths of follow-up via offset 
variable. No further allowance for missing data will be made in these analyses. 
Pulmonary exacerbation incidence: 
No allowance for missing data will be made in this analysis.  
Ease of expectoration: 
Missing post-baseline measurements will be handled as per the primary efficacy endpoint 
(FEV1). 
CFQ-R respiratory domain score: 
Missing post-baseline measurements will be handled as per the primary efficacy endpoint 
(FEV1).  
10.2.10 Key secondary sensitivity analyses 
Change in absolute FVC from baseline:  
* Analysis will be repeated without imputation of missing data. 
Pulmonary exacerbation rate:  
* Analysis will be repeated without imputation of missing data. 
* A zero inflated negative binomial model will be fitted and compared to the specified 
negative binomial model. 
10.2.11 Subgroup analyses 
Limited subgroup analyses of relevant primary and secondary will be performed to assess 
consistency of response between those: 
• with and without rhDNase use; 
• with and without Pseudomonas aeruginosa infection; 
• with differing baseline percentage of predicted FEV1. 
11 ETHICAL ASPECTS 
The trial will be conducted in accordance with the International Conference on 
Harmonization (ICH) and Good Clinical Practice (GCP) guidelines.  In addition, the trial will 
be conducted in compliance with all applicable laws and regulatory/health authority(ies) 
requirements relevant to the use of new therapeutic agents in each participating country.  
11.1 Informed consent 
This trial will be conducted in compliance with the US federal FDA 21 CFR Part 50-
Protection of Human Subjects requirements.  Written informed consent will be obtained from 
each subject before any trial related procedures or assessments are performed and after the 
aims, methods, anticipated benefits, and potential hazards are explained.  Explanation will 
also be provided to the subjects that they are free to refuse participation in the trial and free to 
withdraw from the trial at any time without prejudice to future treatment. 

 
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The subject’s willingness to participate in the trial will be documented in writing on an 
informed consent form, which will be signed by the subject and the person obtaining the 
consent with the date and time of that signature indicated.  The Investigator(s) will keep the 
original informed consent forms and copies will be given to the subjects. In addition, the 
person conducting the informed consent discussion will document the process of obtaining 
consent in the subject’s medical record. 
Written and/or oral information about the trial in a language understandable by the subject 
will be given to all subjects.  The information provided must include a statement that this is a 
clinical research study/trial, the duration and an adequate explanation of the aims, methods, 
anticipated benefits, potential hazards, and insurance arrangements in force. 
11.2 Heath authorities, independent ethics committees / institutional review 
boards 
The Investigator(s) will ensure that the conduct of the trial conforms to ICH/GCP Guidelines 
and with national laws and regulations for clinical research.  
Before starting this trial, the protocol will be submitted to the national/local health authorities 
and to the IEC/IRB for evaluation.  As required, the trial will not start before the IEC/IRB 
and health authorities give approval or a favorable opinion. 
11.3 Confidentiality regarding trial subjects 
The Investigator(s) must assure that the privacy of the subjects, including their personal 
identity and all personal medical information, will be maintained at all times.  In CRFs and 
other documents submitted to the Sponsor, subjects will not be identified by their names, but 
by an identification code (e.g., subject or screen number).  
The Monitor, properly authorized persons on behalf of the Sponsor’s quality assurance unit, 
or competent authorities may scrutinize personal medical information for the purpose of 
verifying data recorded on the CRF.  Personal medical information will always be treated as 
confidential, according to local privacy regulations.  
11.4 Data safety monitoring board (DSMB) 
A DSMB will be established.  The constitution and duties of the DSMB will be documented 
in a DSMB charter, but the primary function will be to provide ongoing review of safety data. 
12 TRIAL 
MANAGEMENT 
& 
ADMINISTRATIVE 
REQUIREMENTS 
12.1 Protocol amendments 
 
12.2 Direct access to source data / documents 
The Monitor(s), Auditor(s), and Regulatory Inspector(s) will be given direct access to source 
data and documentation (e.g., medical records, laboratory reports, diagnostic imaging) for 
source data verification, provided that subject confidentiality is maintained in accordance 
with local requirements and privacy regulations. 

 
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12.3 Monitoring and quality assurance 
12.3.1 Information to trial personnel 
The Investigator(s) is responsible for ensuring that all trial personnel are qualified and trained 
for their designated roles and responsibilities. He/she shall provide information about the trial 
to all staff members directly involved in the trial or in any element of subject management, 
both before starting the practical performance of the trial and during the course of the trial 
(e.g., when new staff become involved). 
The Monitor(s) is responsible for initiating the site, for ensuring site compliance with the 
protocol and for closing out the site at the end of the trial.  Additional information available 
during the trial should be provided to the Investigator by the Sponsor on an ongoing basis. 
The Investigator is responsible for ensuring that the site staff are fully informed and 
appropriately trained. Specific training in relation to additional information should be 
supported and documented by the Monitor as required. (The Investigator must ensure and 
document that new staff members involved in the trial are fully informed and trained prior to 
completing any trial related tasks. The Monitor is responsible for ensuring that training has 
been completed to ensure trial compliance). 
12.3.2 Trial monitoring 
For this trial, the average monitoring frequency is expected to be once every five to ten 
weeks, but is subject to recruitment rates.  The Monitor(s) or Sponsor representative is 
responsible for ensuring that the trial is conducted according to the protocol, Standard 
Operating Procedures (SOPs) and in compliance with GCP. 
The Monitor(s) is the primary link between the Sponsor and the Investigator.  The main 
responsibilities of the Monitor(s) is to visit the Investigator before, during, and after the trial 
to ensure adherence to the protocol, and to assure that all data are correctly and completely 
recorded and reported and that informed consent is obtained and recorded for all subjects 
before their participation in the trial. 
The Monitor(s) will contact and visit the Investigator at regular intervals throughout the trial.  
The Monitor(s) will be allowed access to check and verify the various records (CRFs and 
other pertinent data records) relating to the trial to verify adherence to the protocol and to 
ensure the completeness, consistency, and accuracy of the data being recorded. 
As part of the supervision of the trial progress other Sponsor personnel may, on request, 
accompany the Monitor(s) on visits to the trial center.  The Investigator and assisting staff 
must agree to cooperate with the Monitor(s) to resolve any problems, errors, or possible 
misunderstandings concerning any data discrepancies detected in the course of these 
monitoring visits. 
12.3.3 Audit and inspection 
According to ICH / GCP Guidelines, the Sponsor may audit the investigational site to 
compare raw data, source data, and associated records with the interim (if applicable) or final 
report of the trial to assure that data have been accurately reported and the trial was 
conducted in compliance with the protocol, SOPs, GCPs and applicable regulatory 
requirements.  The Sponsor’s worldwide Clinical Quality Assurance department is 
responsible for the auditing of the trial.  Auditing may be contracted to an external body. 

 
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The Investigator(s) must accept that regulatory authorities may conduct an inspection to 
verify compliance of the trial with the protocol, GCPs and applicable regulatory 
requirements. 
12.4 Protocol deviations 
The protocol must be read thoroughly and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety, and well-being 
of the subject requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the 
Investigator as a sub-Investigator.  
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone. This allows for an early joint decision to be made as to whether or not the subject 
should continue in the trial. The Investigator, the Sponsor, and the Medical Monitor will 
document this decision. 
13 DATA HANDLING AND RECORD KEEPING 
13.1 Source data 
The Investigator is required to prepare and maintain adequate and accurate case histories (i.e., 
medical records) designed to record all observations and other data pertinent to the trial for 
each trial subject.  The medical records must contain adequate information to allow for 
verification of subject identity throughout the trial.  
Any data recorded directly on the CRF, as agreed to by the Sponsor for which no other 
written or electronic record will be maintained in the subject’s medical record, will be 
considered source data (e.g., results of physical examinations, vital signs testing, or the drug 
administration procedure).  The agreement between the Investigator and the Sponsor, 
including the type of parameters allowed to be entered directly on the CRFs, must be 
documented in the subject’s source documentation. 
The CRF and the subject’s medical records pertinent to the trial will be reviewed by the 
Pharmaxis’ designated Monitor, auditors and possibly by representatives from the IRB/IEC 
and regulatory bodies such as the US Food and Drug Administration (FDA) to the extent 
permitted by regulations. 
The Investigator is required to retain a subject identification code list to allow unambiguous 
identification of each subject included in the trial. This list should contain the subject’s full 
name, date of birth, dates of participation and identification number as per country 
regulations. The Investigator must agree to supply all details to the Sponsor auditor(s) and/or 
regulatory authorities, ensuring the data are held confidentially at the Investigator’s center 
after completion of the trial. A note will be made in the hospital or clinical medical records, if 
appropriate, that the subject is participating in a clinical trial. 
13.2 Case report form (CRF) 
In this trial, the CRF will be an electronic CRF (eCRF). The Investigator or the designated 
site person must complete the CRF and supporting documentation for each subject within a 
timely manner of the visit occurring. 

 
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The Monitor(s) and Data Manager(s) will review the completed data for accuracy, 
completeness and consistency with source documentation.  The Monitor or Data Manager 
will submit requests for correction/clarification of data (e.g., queries) to the Investigator or 
designee when inconsistencies are identified during monitoring and source data verification 
or during the edit check process.  
All corrections and alterations to CRF data must be made by the Investigator or by the 
designated site personnel in a timely manner and according to the instructions provided.  
Completed CRFs should then be reviewed and signed by the Principal Investigator or 
designated site personnel.  All persons, their roles and responsibilities delegated by the 
Investigator participating in the trial must be indicated on the delegation of authority log.  
A full audit trail detailing corrections and alternations made to the CRF will be maintained. 
13.3 Archiving of trial documentation 
Trial data and other essential documents must be retained for a period of at least 15 years for 
adult trials; at least 25 years for trials involving children; or at least 2 years after the last 
approval of a marketing application, and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  It is the responsibility 
of the Sponsor to inform the Investigator(s)/institution(s) when these documents need no 
longer be retained.  The original record of the CRFs will be archived by the Sponsor for the 
lifetime of the product.  No trial document or image will be destroyed without prior written 
agreement between the Sponsor and the Investigator(s).  Should the Investigator(s) wish to 
assign the trial records to another party or move them to another location, advance written 
notice will be given to the Sponsor. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
15 REPORTING AND PUBLICATION OF RESULTS 
The Sponsor is responsible for publically registering this trial on the National Library of 
Medicine’s website (http://clinicaltrials.gov) within 21 days of initiating enrolment.  
All information, including but not limited to information regarding dry powder mannitol or 
the Sponsor’s operations supplied by the Sponsor to the Investigator and not previously 
published, along with any data generated as a result of this trial, are considered confidential 
and remain the sole property of the Sponsor.  The Investigator agrees to maintain this 
information in confidence, and will use the information only to perform the trial. 

 
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The Sponsor is responsible for preparing a clinical trial report, in cooperation with the 
Investigator(s).  The Sponsor and the Principal/Coordinating Investigator will sign the final 
report. 
The Sponsor shall have the right to publish data and information without approval from the 
Investigator.  If an Investigator wishes to publish information from the trial, a copy of the 
manuscript must be provided to the Sponsor for review at least 60 days before submission for 
publication or presentation.  Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials.  If requested by the Sponsor in writing, the Investigator will 
withhold such publication for up to an additional 60 days to allow for filing of a patent 
application.  The Sponsor will not mandate modifications to scientific content and does not 
have the right to suppress information.  The Investigator will recognize the integrity of a 
multicenter trial by not publishing data derived from the individual site until the combined 
results from the completed trial have been published in full, within 12 months after 
conclusion, abandonment, or termination of the trial at all sites, or the Sponsor confirms there 
will be no multicenter trial publication.  Authorship of publications resulting from this trial 
will be based on the guidelines on authorship, such as those described in the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals, which state that the named 
authors must have made a significant contribution to the design of the trial or analysis and 
interpretation of the data, provided critical review of the paper, and given final approval of 
the final version. 
15.1 Authorship 
The publications should acknowledge the contribution of investigators jointly as the CF-303 
Trial Investigators and, where journal and space permit, the names of all investigators will be 
listed in the acknowledgement section. 
For the primary publication and any secondary analyses of the data set, the Principal / 
Coordinating Investigator plus the three highest recruiters who also fulfill the authorship 
criteria as outlined in the international committee of medical journal editors (ICMJE) 
guidelines will be named as authors on behalf of the CF-303 Trial Investigators.  Sponsor 
personnel who also fulfill the ICMJE’s criteria for authorship will also be offered authorship. 
 
 

 
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16 REFERENCES 
1. 
Committee for Medicinal Products for Human Use (CHMP), Guideline on the clinical 
development of medicinal products for the treatment of cystic fibrosis. 
EMEA/CHMP/EWP/9147/2008-corr, 2009, European Medicines Agency. 
2. 
Strausbaugh, S.D. and P.B. Davis, Cystic fibrosis: a review of epidemiology and 
pathobiology. Clin Chest Med, 2007. 28(2): p. 279-88. 
3. 
Salvatore, D., et al., An overview of international literature from cystic fibrosis 
registries. Part 3. Disease incidence, genotype/phenotype correlation, microbiology, 
pregnancy, clinical complications, lung transplantation, and miscellanea. J Cyst 
Fibros, 2011. 10(2): p. 71-85. 
4. 
Daviskas, E., et al., Inhalation of dry powder mannitol increases mucociliary 
clearance. Eur Respir J, 1997. 10(11): p. 2449-2454. 
5. 
Robinson, M., et al., The effect of inhaled mannitol on bronchial mucus clearance in 
cystic fibrosis patients: a pilot study. Eur Respir J, 1999. 14(3): p. 678-85. 
6. 
King, M., Mucoactive therapy: What the future holds for patients with cystic fibrosis. 
Pediatric Pulmonology, 1997. 24(Suppl 14): p. 122-123. 
7. 
Daviskas, E. and S.D. Anderson, Hyperosmolar agents and clearance of mucus in the 
diseased airway. J Aerosol Med, 2006. 19(1): p. 100-9. 
8. 
Daviskas, E., et al., Inhaled mannitol for the treatment of mucociliary dysfunction in 
patients with bronchiectasis: effect on lung function, health status and sputum. 
Respirology, 2005. 10(1): p. 46-56. 
9. 
Feng, W., et al., Improved clearability of cystic fibrosis sputum with dextran 
treatment in vitro. Am J Respir Crit Care Med, 1998. 157(3 Pt 1): p. 710-714. 
10. 
Bilton, D., et al., Inhaled dry powder mannitol in cystic fibrosis: an efficacy and 
safety study. Eur Respir J, 2011. 38(5): p. 1071-1080. 
11. 
Aitken, M.L., et al., Long-term inhaled dry powder mannitol in cystic fibrosis: an 
international randomized study. Am J Respir Crit Care Med, 2012. 185(6): p. 645-52. 
12. 
Miller, M.R., et al., Standardisation of spirometry. Eur Respir J, 2005. 26(2): p. 319-
38. 
13. 
Fuchs, H.J., et al., Effect of aerosolized recombinant human DNase on exacerbations 
of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. 
The Pulmozyme Study Group. N Engl J Med, 1994. 331(10): p. 637-42. 
14. 
Dwyer, T.J., et al., Effects of exercise on respiratory flow and sputum properties in 
patients with cystic fibrosis. Chest, 2011. 139(4): p. 870-7. 
15. 
Kieser, M. and T. Friede, Simple procedures for blinded sample size adjustment that 
do not affect the type I error rate. Stat Med, 2003. 22(23): p. 3571-81. 
16. 
Hankinson, J.L., J.R. Odencrantz, and K.B. Fedan, Spirometric reference values from 
a sample of the general U.S. population. Am J Respir Crit Care Med, 1999. 159(1): p. 
179-87. 
 
 
 
 
 
 

 
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17 SIGNATURE PAGE 
Protocol 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol and 
in accordance with the International Conference on Harmonization (ICH) and Good Clinical Practice 
(GCP).  I agree to report all information or data in accordance with the protocol, and in particular, I 
agree to report any serious adverse events.  I will accept the monitors’, auditors’, and regulatory 
inspectors’ oversight of the trial.  I will abide by the publication plan set forth in the Investigator 
Agreement with Pharmaxis.  I will promptly submit the protocol to the applicable ethical review 
board. 
Clinical Site:  
Site Number: 
Site Principal Investigator: 
_____________________________  _______________________________ 
Print Name  
 
 
 
Title 
_____________________________  _______________________________ 
Signature 
 
 
 
 
Date 
 
Accepted for the Sponsor – Pharmaxis Ltd 
_____________________________  _______________________________ 
Print Name  
 
 
 
Title 
_____________________________  _______________________________ 
Signature 
 
 
 
 
Date 
 
Accepted for the Sponsor’s Representative (if applicable________________) 
 
 
 
 
 
 
 
 
(Organization name) 
_____________________________  _______________________________ 
Print Name  
 
 
 
Title 
_____________________________  _______________________________ 
Signature 
 
 
 
 
Date 
 

 
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h 2014; 
 
 
 

 
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