Clinical trial NCT01946711
Conditions: Rhinosinusitis Chronic Polyposis
Keywords: CRS polyposis
Sponsor: Pari Pharma GmbH
Start date: 2013-08-28; Completion date: 2021-06-21
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study should create data for the selection of a clinically relevant primary endpoint to assess the efficacy and safety of Buparid/PARI SINUS as compared to Budes Nasal Spray in the therapy of chronic rhinosinusitis (CRS) with polyposis nasi in adult patients. Ideally, the selected parameter should allow a correlation between an objective methodology and the clinical outcome of the study patients.

Detailed description:

Arms: arm 1: Buparid 1 mg budesonide/2 ml nebuliser solution arm 2: Budes® Nasal Spray 50 µg budesonide/pump
Interventions: intervention 1: Budesonide intervention 2: Budesonide
Intervention descriptions: intervention 1: Inhalation intervention 2: Nasal spray

Protocol documents:
Prot_000.pdf: 
Final Clinical Trial Protocol 12082.101 ± Amendment 1 ± Protocol Version 2.0, 2015-02-10                  
CONFIDENTIAL 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
A randomised, open, controlled pilot study to investigate the efficacy and 
safety of Buparid/PARI SINUS versus Budes® Nasal Spray in the therapy 
of Chronic Rhinosinusitis (CRS) with polyposis nasi in adult patients 
Clinical Trial No.: 12082.101 
EudraCT No.: 2013-002414-12 
Protocol Amendment 1
Protocol Version 2 
Date: 10 February 2015 
Sponsor: PARI Pharma GmbH
 
Lochhamer Schlag 21
 
82166 Graefelfing  
 
Germany 
Confidentiality Statement 
This confident document is the property of PARI Pharma GmbH and it is provided for the use 
of the Investigator and other designated personnel solely in connection with the conduct of the 
study described herein. No information contained herein may be disclosed, except as 
necessary to obtain consent from the persons who are considering participation in the study, 
without prior written approval of PARI Pharma GmbH. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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Signature Page 3 
Title: A randomised, open, controlled pilot study to investigate the efficacy and safety of 
Buparid/PARI SINUS versus Budes® Nasal Spray in the therapy of Chronic 
Rhinosinusitis (CRS) with polyposis nasi in adult patients 
Investigator’s Signature: 
I have read the protocol and the protocol appendices. I understand the contents and intend to 
comply fully with all requirements and the applicable current local and international 
regulations and guidelines. No changes will be made without formal authorisation by PARI 
Pharma GmbH in the form of a protocol amendment. 
The Investigator is responsible for performing the study in accordance with this protocol, 
Directive 2001/20/EC, UK, FDA regulations, and any applicable local regulatory regulations 
where applicable, the International Conference on Harmonization (ICH) and Good Clinical 
Practice (GCP), and for collecting, recording, and reporting the data accurately and properly. 
Agreement of the Investigator to conduct and administer this study in accordance with the 
protocol will be documented in a separate study agreement with the Sponsor, and other forms 
as required by Competent Authorities in the country where the study centre is located. 
The Investigator is responsible for ensuring the privacy, health, and welfare of the patients 
during and after the study, 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 must be familiar with the background to and requirements of the study and 
with the properties of the study drug as described in the Investigator's Brochure, summary of 
product characteristics (SmPC) or package insert. 
The Principal Investigator at each centre has the overall responsibility for the conduct and 
administration of the study at that centre, and for contacts with study centre management, the 
Ethics Committee (EC), and with the Competent Authority (CA). 
______________ 
 
 
__________________________ 
Date 
 
 
 
 
[Signature] 
 
 
 
 
 
 
 
 


 
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2.
PROTOCOL SYNOPSIS 
Study Title: 
A randomised, open, controlled pilot study to investigate the 
efficacy and safety of Buparid/PARI SINUS versus Budes® Nasal 
Spray in the therapy of Chronic Rhinosinusitis (CRS) with 
polyposis nasi in adult patients
Sponsor:
PARI Pharma GmbH 
Lochhamer Schlag 21 
82166 Graefelfing 
Germany 
Protocol Number: 
12082.101 
EudraCT Number:
2013-002414-12 
Product: 
Buparid 1 mg/2 ml nebuliser solution
Study Phase:
Pilot study 
Protocol Amendment 1 
10 February 2015 
Original Protocol Date: 
01 July 2013 
Study Centres/Countries:
3 centres in Germany: 
Ludwig-Maximilians-University Munich; 
Georg-August-University Göttingen 
Johannes Gutenberg-Universität Mainz
Planned Study Period
(First Patient In ± Last 
Patient Out):
Start: April 2014 (FPI) 
Enrolment period: 18 months 
Duration of therapy: 2 months 
Control visits at Month 3 and Month 6 after start of therapy 
(follow-up) 
Duration of study: 24 months (LPO: Approx. August 2016) 
Planned number of 
subjects: 
A total of approximately 20 (2 x 10) evaluable patients are 
assumed to be sufficient to create enough data for the selection of 
an appropriate primary endpoint for a confirmatory study 
intending to demonstrate therapeutic benefit and to evaluate the 
adverse effect profile of Buparid/PARI SINUS in comparison to
Budes Nasal Spray. 


 
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Objective: 
The objective of this study is to create data for the selection of a 
clinically relevant primary endpoint to assess the efficacy and 
safety of Buparid/PARI SINUS as compared to Budes Nasal 
Spray in the therapy of chronic rhinosinusitis (CRS) with 
polyposis nasi in adult patients. Ideally, the selected parameter 
should allow a correlation between an objective methodology and 
the clinical outcome of the study patients. 
Study Design: 
This is a randomised, open, controlled pilot study in the therapy 
of CSR with polyposis nasi in adult patients. 
Inclusion Criteria: 
1.
Patient with confirmed diagnosis of chronic rhinosinusitis 
(CRS), i.e. inflammation of nasal mucosa and paranasal 
sinus, with polyposis nasi grade I-III (according to Rasp et 
al. 2000). Diagnosis is based on history of symptoms (nasal 
obstruction, running nose, postnasal drip, facial pain and 
hyposmia with a duration of > 3 months (according to 
EPOS3) and on MRT-imaging using the Lund-Mackey 
Score) 
2.
Patient with a PNIF (positive nasal inspiratory flow) of > 7 
l/min separated for left and right side of the nose 
3.
Patient¶s written informed consent obtained prior to any 
screening or study-specific procedure 
4.
Male or female,  18 years of age 
5.
Patient is able to undergo nasal therapy without restrictions 
6.
Capable to correctly use the PARI SINUS device (closing of 
the soft palate) in accordance with the package insert 
7.
Capable of understanding the purpose and risk of the clinical 
trial 
8.
Female patients with childbearing potential must have a 
negative 
urine pregnancy 
test prior to first IMP 
administration. Both women and men must agree to use a 
medically acceptable method of contraception throughout 
the IMP treatment period and for 3 months after IMP 
discontinuation. 
9.
Patient is able to participate in the study according to 
Investigator¶s opinion 
10. Patient has completed correctly the diary during the Wash-in 
Phase 
Exclusion Criteria: 
1.
Patients with cystic fibrosis 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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2.
Patients with CSR without polyposis nasi 
3.
Patients with polyposis nasi grade IV (according to Rasp et 
al. 2000) 
4.
Patients 
with 
prior 
sinonasal 
surgery 
(exemption: 
polypectomy) 
5.
Patients with primary ciliaritis 
6.
Pregnant or breastfeeding women 
7.
Patients with suspected active upper airway infection 
8.
Unlikely to comply with visits, inhalation procedures or 
other measurements scheduled in the protocol 
9.
Receipt of an investigational drug as part of a clinical trial 
within 4 weeks prior to first administration of IMP 
10. Any co-existing medical condition that in the Investigator¶s 
judgement will substantially increase the risk associated with 
the patient¶s participation in the clinical trial 
11. Psychiatric disorders or altered mental status precluding 
understanding of the informed consent process and/or 
completion of the necessary procedures 
12. Drug or alcohol abuse 
13. End-stage malignancies 
14. Known hypersensitivity to Budesonide 
15. Patients with oral steroid therapy within the last 4 weeks 
16. Patients with frequent epistaxis (> 2 per month) 
Investigational Medical 
Product: 
A) Buparid 1 mg/2 ml nebuliser solution (PARI Pharma 
GmbH); API: Budesonide 
B) Budes® Nasal Spray 50 µg/pump (Hexal AG); API: 
Budesonide 
Mode of 
Administration/Dosing 
Schedule: 
A) In patients allocated to receive Buparid, the drug will be 
administered by a once daily inhalation (in the evening) 
using the PARI SINUS nebuliser. At every study visit, one 
inhalation cycle will be monitored by the clinical trial centre 
personnel. 
B) In patients allocated to receive Budes Nasal Spray, the drug 
will be administered with 2 pumps per nostril twice daily (in 
the morning and the evening). 
Treatment Regimen: 
Following screening and consenting, all participants regardless of 
treatment allocation will receive Budes Nasal Spray 50 µg (2 


 
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pumps/nostril BID) in a 2-week Wash-in Phase before starting 
the IMP-treatment to prevent a bias of study results due to former 
individualised therapies. 
After passing the Wash-in Phase and completing the diary 
correctly patients will be randomly assigned to one of the 
following treatments: 
Treatment arm A (Buparid/PARI SINUS): 
Buparid 1 mg/2 ml once daily for 8 weeks (2 months), resulting 
in a daily delivered dose of 280 µg Buparid. 
Treatment arm B (Budes Nasal Spray): 
Budes Nasal Spray (50 µg/pump) 2 pumps per nostril twice daily 
for 8 weeks (2 months), resulting in a daily delivered dose of 400 
µg. 
Endpoints: 
Efficacy (at Visit 1, 2, 3 and 4): 
Health-specific quality of life 
Nasal obstruction 
Inflammation of nasal mucosa and paranasal sinus 
Expansion of polyposis nasi 
Nasal inflammation 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
At Follow-up Visit 5 and 6: 
Health-specific quality of life 
Requirement of surgery 
Customer satisfaction regarding the PARI SINUS device 
Safety (during the whole study period): 
Treatment-emergent adverse events (AEs) 
Assessment of Efficacy: 
Health-specific quality of life (at Visit 1, 2, 3, 4, 5 and 6): 
SNOT 22 (Sino-Nasal Outcome Test 22) 
Nasal obstruction (at Visit 1, 2, 3 and 4): 
Rhinonanometry (PNIF, positive nasal inspiratory flow) 
Inflammation of the nasal mucosa and paranasal sinus (at Visit 2 
and Visit 4): 
Magnetic Resonance Imaging 
o
Thickness of mucosa 
o
Lund-Mackay-Score 


 
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Expansion of polyposis nasi (at Visit 2 and Visit 4): 
Endoscopy (classification according to Rasp et al. 2000) 
Nasal inflammation (at Visit 1, 2, 3 and 4): 
ECP (Eosinophil Cationic Protein) 
Tryptase 
Symptoms of rhinosinusitis (at Visit 1, 2, 3 and 4): 
Nasal obstruction 
Rhinorrhoea 
Loss of smell/taste 
Facial pressure pain 
by means of VAS (Visual Analogue Scale) 
Loss of taste/Loss of smell (at Visit 1, 2, 3 and 4): 
Taste strips 
Sniffing sticks 
Assessment of Safety: 
The following safety parameters will be assessed at each clinical 
visit: 
Treatment-emergent adverse events (AEs) 
Statistical 
Considerations: 
An exploratory statistical analysis will be performed. The 
treatment groups will be characterized using methods of 
descriptive data analysis. Treatment group comparisons will be 
based mainly on 95% confidence intervals for differences 
between mean values or rates. 
 
 


 
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Study Visit Schedule 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Week -2 
Week 0 
Week 4 
Week 8 
Week 12 
Week 24 
Informed consent 
X 
 
 
 
 
 
In-/Exclusion criteria 
X 
 
 
 
 
 
Urine pregnancy test1 
X 
 
 
 
 
 
Demographics2 
X 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
IMP administration 
X4 
X 
X 
 
 
 
Inhalation compliance5 
 
 
X 
X 
 
 
Health-specific Quality of Life 
X 
X 
X 
X 
X 
X 
Nasal obstruction 
X 
X 
X 
X 
 
 
Inflammation of nasal mucosa and paranasal sinus 
 
X 
 
X 
 
 
Expansion of polyposis nasi 
 
X 
 
X 
 
 
Nasal inflammation 
X 
X 
X 
X 
 
 
Symptoms of rhinosinusitis 
X 
X 
X 
X 
 
 
Loss of taste/Loss of smell 
X 
X 
X 
X 
 
 
Requirement of surgery 
 
 
 
 
X 
X 
Customer satisfaction6 
 
 
 
 
X 
(X) 
Concomitant treatment7 
X 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X8 
X 
X 
X 
X 
X 
1 Only in women of childbearing potential 
2 Year of birth, gender, race, height, weight, nicotine and alcohol consumption 
3 Underlying condition, antibacterial/-viral/-fungal therapy 
4 Budes Nasal Spray for Wash-in 
5 Collection of used Buparid ampoules/Budes Nasal Sprays 
6 Only in patients randomized to Buparid/PARI Sinus treatment 
7 Name of drug, dosage, duration 
8 Baseline signs and symptoms 
(X) If not performed on previous visit 


 
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3.
TABLE OF CONTENTS 
Page No. 
1.
SIGNATURE PAGES ................................................................................................................................ 2
2.
PROTOCOL SYNOPSIS ........................................................................................................................... 5
3.
TABLE OF CONTENTS ......................................................................................................................... 11
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................ 14
5.
INTRODUCTION .................................................................................................................................... 16
5.1
Chronic Rhinosinusitis (CRS) with Polyposis nasi (NP) ................................................................. 16
5.2
Budesonide ...................................................................................................................................... 17
5.3
PARI SINUS ± Pulsating Aerosol Delivery System ........................................................................ 18
6.
BACKGROUND INFORMATION ........................................................................................................ 19
6.1
Name and Description of Investigational Medicinal Product .......................................................... 19
6.2
Findings from Non-clinical and Clinical Studies ............................................................................. 20
6.2.1
Non-clinical Studies ........................................................................................................... 20
6.2.2
Clinical Studies .................................................................................................................. 21
6.3
Known and Potential Risks and Benefits to Human Patients ........................................................... 21
6.4
Selection of Drugs and Doses .......................................................................................................... 24
6.5
Population Studied ........................................................................................................................... 26
7.
TRIAL OBJECTIVES AND PURPOSE ................................................................................................ 27
8.
TRIAL DESIGN ....................................................................................................................................... 28
8.1
Endpoints ......................................................................................................................................... 28
8.2
Trial Design ..................................................................................................................................... 28
8.2.1
Trial Overview ................................................................................................................... 29
8.2.2
Study Flowchart ................................................................................................................. 30
8.3
Randomisation and Stratification ..................................................................................................... 30
8.3.1
Blinding .............................................................................................................................. 31
8.4
Investigational Medicinal Product Treatment, Dosage and Administration .................................... 31
8.4.1
Formulation of Buparid ...................................................................................................... 31
8.4.2
Treatment and Dosage ........................................................................................................ 31
8.4.3
Administration .................................................................................................................... 31
8.5
Investigational Medicinal Product Packaging, Labelling and Storage ............................................. 33
8.5.1
Packaging ........................................................................................................................... 33
8.5.2
Storage ............................................................................................................................... 34
8.6
Inhalation Device Packaging ........................................................................................................... 34
8.7
Duration of Patient Participation ..................................................................................................... 34
8.8
Stopping Rules and Discontinuation Criteria ................................................................................... 35
8.8.1
Study Level ........................................................................................................................ 35
8.8.2
Centre Level ....................................................................................................................... 35
8.8.3
Patient Level ....................................................................................................................... 35
8.9
Investigational Medicinal Product Supply and Accountability ........................................................ 35
9.
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................................... 36
9.1
Patient Inclusion Criteria ................................................................................................................. 36
9.2
Patient Exclusion Criteria ................................................................................................................ 36
9.3
Withdrawal Criteria and Procedures, Interruption or Discontinuation of Study .............................. 37
9.4
Completion of Study and Loss to Follow-up ................................................................................... 38
10.
TREATMENT OF SUBJECTS ............................................................................................................... 39
10.1 Buparid/PARI SINUS ...................................................................................................................... 39
10.2 Budes Nasal Spray ........................................................................................................................... 39
10.3 Concurrent Treatment or Medication ............................................................................................... 40
10.4 Procedures for Monitoring Patient Compliance ............................................................................... 40
11.
ASSESSMENT OF EFFICACY .............................................................................................................. 41
11.1 Efficacy Parameters ......................................................................................................................... 41


 
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11.2 Methods and Timing of Efficacy Assessments and Procedures ...................................................... 41
11.2.1
Health-specific quality of life (at Weeks -2, 0, 4, 8, 12 and 24) ......................................... 41
11.2.2
Nasal obstruction (at Weeks -2, 0, 4 and 8) ........................................................................ 41
11.2.3
Inflammation of the nasal mucosa and paranasal sinus (at Weeks 0 and 8) ....................... 41
11.2.4
Expansion of polyposis nasi (at Weeks 0 and 8) ................................................................ 42
11.2.5
Nasal inflammation (at Weeks -2, 0, 4 and 8) .................................................................... 42
11.2.6
Symptoms of rhinosinusitis (at Weeks -2, 0, 4 and 8) ........................................................ 42
11.2.7
Loss of taste/Loss of smell (at Weeks -2, 0, 4 and 8) ......................................................... 43
12.
ASSESSMENT OF SAFETY .................................................................................................................. 44
12.1 Safety Parameters ............................................................................................................................ 44
12.2 Methods and Timing of Safety Assessments and Procedures .......................................................... 44
12.2.1
Pregnancy Test ................................................................................................................... 44
12.2.2
Adverse Events ................................................................................................................... 44
12.2.3
Monitoring of Adverse Events ........................................................................................... 48
13.
VISIT SCHEDULE .................................................................................................................................. 49
13.1 Study Visits ...................................................................................................................................... 49
13.2 Screening and Baseline Visit 1 (Week -2) ....................................................................................... 49
13.3 Visits 2 (Week 0) ............................................................................................................................. 50
13.4 Visits 3 (Week 4) ............................................................................................................................. 50
13.5 Visit 4 (Week 8) ............................................................................................................................... 51
13.6 Visits 5 (Week 12) ........................................................................................................................... 51
13.7 Visit 6 (Week 24) ............................................................................................................................. 51
14.
STATISTICS ............................................................................................................................................ 52
14.1 Statistical Concept ........................................................................................................................... 52
14.2 Sample Size Considerations ............................................................................................................. 52
14.3 Missing Data .................................................................................................................................... 52
14.4 Analyses of Patient Populations....................................................................................................... 53
14.5 Statistical and Analytical Methods .................................................................................................. 53
14.6 Baseline Comparability .................................................................................................................... 53
14.7 Analysis of Efficacy ........................................................................................................................ 54
14.8 Analysis of Safety ............................................................................................................................ 54
15.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 55
16.
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 56
16.1 Amendments and Protocol Violations ............................................................................................. 56
16.2 Information to Study Personnel ....................................................................................................... 56
16.3 Clinical Trial Monitoring ................................................................................................................. 56
16.4 Audit and Inspection ........................................................................................................................ 57
17.
ETHICAL AND REGULATORY ASPECTS ........................................................................................ 58
17.1 Responsibilities of the Investigator .................................................................................................. 58
17.2 Patient Information .......................................................................................................................... 58
17.3 Patient Informed Consent ................................................................................................................ 58
17.4 Subject Insurance ............................................................................................................................. 59
17.5 Ethics ............................................................................................................................................... 59
17.6 Notification to Competent Authorities (CA) and Ethics Committees (EC) ..................................... 60
17.6.1
Commencement of the Trial ............................................................................................... 60
17.6.2
Ending of the Trial ............................................................................................................. 60
17.6.3
Notification to Local Authorities ....................................................................................... 60
17.6.4
Protocol Amendment .......................................................................................................... 60
17.7 Confidentiality Regarding Study Patients ........................................................................................ 61
18.
DATA HANDLING AND RECORD KEEPING ................................................................................... 62
18.1 Source Documents and Data¶s Recorded on the Case Report Form ................................................ 62
18.2 Case Report Forms .......................................................................................................................... 62
18.3 Case Report Form (CRF) Handling ................................................................................................. 63
18.4 Source Data and Patient Files .......................................................................................................... 63
18.5 Investigator File and Archiving ....................................................................................................... 64


 
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18.6 Monitoring, Quality Assurance, and Inspection by Authorities ....................................................... 64
18.7 Completing, Signing, and Archiving CRFs ..................................................................................... 65
18.8 Data Management and Data Control ................................................................................................ 65
19.
FINANCING AND INSURANCE ........................................................................................................... 66
20.
REPORTING AND PUBLICATION OF RESULTS ............................................................................ 67
21.
ARCHIVING AND DATA RETENTION .............................................................................................. 68
22.
REFERENCES ......................................................................................................................................... 69
23.
APPENDIX I – CORE INFORMED CONSENT FORM ..................................................................... 71
24.
APPENDIX II – ACCEPTABLE METHODS OF CONTRACEPTION ............................................ 73


 
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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
 
Adverse Event 
ADR  
Adverse Drug Reaction 
API 
 
Active Product Ingredient 
AR 
 
Adverse Reaction 
BID 
 
Bis In Die; twice daily 
BSF 
 
Blow/Fill/Seal 
CA 
 
Competent Authority 
CRF 
 
Case Report Form 
CRS 
 
Chronic Rhinosinusitis 
CT 
 
Computer Tomography 
CTC  
Common Toxicity Criteri 
CYP 
 
Cytochrome P450 
DTPA  
Diethylene Triamine Pentaacetic Acid 
EC 
 
Ethics Committee 
ECG  
Electrocardiogram 
ECP 
 
Eosinophil Cationic Protein 
EOS 
 
End Of Study 
EPOS  
European Position Paper on Rhinosinusitis and Nasal Polyps 
FL 
 
Frontal Sinus Left 
FPI 
 
First Patient In 
FR 
 
Frontal Sinus Right 
GCP 
 
Good Clinical Practice 
hPa 
 
Hecto Pascal 
Hz 
 
Hertz 
ICH 
 
International Conference on Harmonization 
ID 
 
Identification 
IMP 
 
Investigational Medicinal Product (study drug) 
LPO 
 
Last Patient Out 
mbar  
Millibar 
MeDRA 
Medical Dictionary for Regulatory Activities 
ML 
 
Maxillary Sinus Left 
MMAD 
Mass Median Aerodynamic Diameter 
MR 
 
Maxillary Sinus Right 
MRI 
 
Magnetic Resonance Imaging 
MRT  
Magnetic Resonance Tomography 
N 
 
Number 
PNIF  
Positive Nasal Inspiratory Flow 
PP 
 
Per Protocol Analysis 
QD 
 
Quorum Die; once daily 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SAS 
 
Statistical Analysis Software 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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SD 
 
Standard Deviation 
SmPC  
Summary of Product Characteristics 
SNOT22 
Sino-Nasal Outcome Test 22 
SOP 
 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
V 
 
Volt 
VAS  
Visual Analogue Scale 
WHO  
World Health Organization 
 


 
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5.
INTRODUCTION
5.1
Chronic Rhinosinusitis (CRS) with Polyposis nasi (NP) 
Nasal polyps are a manifestation of chronic inflammation of the mucosa throughout the nose 
and sinuses from a group of disorders which all lead to swelling and overgrowth of the nasal 
mucosa (Mygind 2000). Polyps generally arise from the mucosa surrounding the middle 
meatus and often cause nasal blockage and restricted airflow. 
Chronic rhinosinusitis (CRS) is defined as the presence of two or more symptoms, one of 
which should be either nasal blockage/obstruction/congestion or nasal discharge 
(anterior/posterior nasal drip), with or without facial pain/pressure OR reduction or loss of 
smell. These symptoms need to be present for 12 weeks or more. Chronic rhinosinusitis is 
further classified as with polyps (CRSwNP) or without polyps (CRSsNP) based on the 
presence or absence of polyps, on endoscopic view, in the middle meatus (the area between 
the middle and inferior turbinates into which the maxillary, anterior ethmoid and frontal 
sinuses drain). This definition accepts that there is a spectrum of disease in CRS which 
includes polypoid change in the sinuses but which is not evident in the middle meatus and 
excludes those in the CRSwNP group. 
Chronic rhinosinusitis (CRS) is one of the most commonly diagnosed chronic illnesses 
affecting approx. 10-15% of the European population (van Cauwenberge 2000; Fokkens 
2007). It is the common understanding that inflammation of the nasal mucosa (i.e., rhinitis) 
due to bacterial or viral infections, allergies, or exposure to inhaled irritants leads to acute 
sinusitis. Chronic inflammation of the nasal mucosa results in mucosal swelling, increased 
mucus secretion, loss of cilia, airway obstruction and blocked sinus drainage. Under these 
conditions, bacteria and viruses that are normally removed from the nasal cavity and sinuses 
by drainage of secretions may proliferate. This blockage of mucus drainage from the sinuses 
and reduced ventilation creates an environment for chronic rhinosinusitis (Clement 1997, 
Baraniuk 2005). Impaired mucociliary clearance in patients with primary ciliary dyskinesia 
may also cause chronic sinusitis (Armengot 1994, Min 1995). 
CRS is a common problem that results in significant impairment of quality of life. Associated 
symptoms drive a patient to seek medical opinion. Although the definition of chronic 
rhinosiusitis is based on the occurrence and duration of symptoms, many clinicians use 
computer tomography (CT) scans to confirm the presence of disease, assess severity, and aid 
management decisions. It is often assumed that patients¶ symptoms correlate to ³objective´ 
scores of disease severity. However, the relationship between radiologic findings and 
symptoms at presentation in sinusitis remains controversial. The predictive value of radiologic 
scores in terms of symptomatic improvement after surgical intervention is also unknown. If 
radiologic finding do not correlate with either pretreatment symptoms or the outcome of 
treatment, it may be wrong to base treatment decisions on findings that do not reflect the 
patient¶s symptom load (Hopkins 2007). 
Sinonasal polyposis is a chronic disorder with a major effect on the quality of life of affected 
individuals. The management options for sinonasal polyposis are medical treatment, surgery, 
or a combined approach. It is a common practice to use systemic or topical corticosteroids as 
the first therapeutic choice, followed by surgery for resistant or recurrent cases. There is good 


 
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evidence, in the form randomized controlled trials, to support the use of topical nasal 
corticosteroids (Jankowski 2001, Penttila 2000). Short courses of systemic corticosteroids are 
also widely used in clinical practice to provide rapid relief of symptoms, followed by the use 
of long-term topical corticosteroids (Nores 2002, Nores 2003). 
The exact mechanisms that cause nasal polyps are largely unknown, possibly because a 
single, unified cause for the underlying inflammatory process may not exist (Benninger 
2003). It is more likely that many factors contribute to mucosal inflammation and that nasal 
polyps are a common result of a diverse group of disorders. Several theories have been 
suggested. No clear evidence exists for an allergic origin, although there is an established 
association with asthma and aspirin sensitivity (Slavin 2002). Nasal polyps are also seen in 
cystic fibrosis, Churg-Strauss syndrome and primary ciliary dyskinesia (Kartagener¶s 
syndrome) (Mygind 2000). 
Various outcome measures have been used to analyse the results of intervention in this patient 
population (Piccirillo 1995). Most of these are questionnaire-based visual analogue scores of 
symptoms and quality of life. Intranasal polyps can be visualized by means of nasendoscopy, 
and sinonasal polyp tissue can be shown be using imaging methods, such as computed 
tomography (CT) and magnetic resonance imaging (MRI); these approaches offer more 
objective methods of measuring treatment response. Many previous studies have shown a 
poor relationship between symptoms and objective measurement of pathology (Bhattacharyya 
1997, Stewart 1999, Wabnitz 2005). 
Due to the fact that the nose is an efficient filter for inhaled aerosol particles and the paranasal 
sinuses being virtually not ventilated there is limited success in the topical drug delivery to 
the nose and the paranasal sinuses when using nasal sprays. Despite the fact that the sinuses 
are poorly-ventilated hollow organs, in vivo and in vitro studies have shown that nebulized 
rugs can be deposited into the paranasal sinuses, although at very low concentrations (Sato 
1981; Möller 2008). Therefore, the primary option of treatment of CRS is surgery, often in 
combination with topical and systemic medical treatment. An efficient topical therapy may 
allow treating upper respiratory diseases more effectively, prevent sinus surgery or at least 
extend the time span for sinus surgery. This hypothesis is supported by clinical data upon 
nasal administration of Dornase alpha (Pulmozyme) vial pulsating aerosol delivery (PARI 
SINUS) in cystic fibrosis patients (Mainz 2008). 
The objective of this pilot study is to create data for the selection of a clinically relevant 
primary endpoint to assess the efficacy and safety of corticosteroidal treatment using 
Buparid/PARI SINUS as compared to Budes Nasal Spray in the therapy of CRS with 
polyposis nasi in adult patients. Ideally, the selected parameter should allow a correlation 
between an objective methodology and the clinical outcome of the study patients. 
5.2
Budesonide
It is accepted that inflammation is the key pathological process of CRS. Budesonide is a 
glucocorticosteroid with strong local corticosteroidal effect and exerts anti-inflammatory, 
anti-allergic, anti-exudative and anti-oedematous activity, with a lower incidence and severity 
of adverse effects than those seen with oral corticosteroids. Due to these characteristics the 
following effects can be achieved: 


 
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Inhibition of the formation, retention and release of mediators from mast cells, 
basophils and macrophages 
Reduction of the hyper-responsiveness of the epithelia to exogenous stimuli 
Reduction of the cholinergic stimuli, thus resulting in a decrease of secret production 
Proofing of the epithelial and endothelial membrane 
Reduction of inflammatory symptoms (oedema, cellular infiltration) 
The anti-inflammatory actions, such as inhibition of inflammatory mediator release and 
inhibition of cytokine-mediated immune response are probably the most important. 
5.3
PARI SINUS – Pulsating Aerosol Delivery System 
A pulsating aerosol is generated using the PARI Sinus system (PARI GmbH, Starnberg, 
Germany). It is based on a PARI BOY N aerosol drug delivery device. The compressor has an 
integrated pressure wave generator driven by the same motor. The pressure wave has a 45 Hz 
frequency with amplitude of 25 mbar. It is attached via a tubing connector to the vent opening 
of a PARI LC SPRINT Junior jet nebulizer in order to superimpose the pressure wave on the 
aerosol flow. The mass median aerodynamic diameter (MMAD) of the aerosol generated by 
the PARI LC SPRINT Junior jet nebulizer is 3.2 µm with a geometric standard deviation of 
2.6. The rate of mass output is 0.2 ml/min. For aerosol delivery to the nose the nebulizer is 
coupled to the right nostril and the left nostril vial a flow resistor to output tubing. During 
delivery the subject closes his soft palate, which directs the aerosol to the output nostril and 
prevents aerosol penetration to the lung. 


 
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6.
BACKGROUND INFORMATION 
6.1
Name and Description of Investigational Medicinal Product 
Buparid (budesonide) is a potent, non-halogenated glucocorticosteroid which, when 
administered by inhalation, possesses a high local anti-inflammatory action, with a lower 
incidence and severity of adverse effects than those seen with oral corticosteroids. Buparid 
has negligible mineralocorticoid activity. Buparid belongs to the Pharmacotherapeutic group: 
Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B 
A02. Chemically, Buparid is (11 ,16 )-16,17- (Butylidenebis(oxy))-11,21-dihydroxypregna-
1,4-diene-3,20-dione (CAS number 51333-22-3). Budesonide is present as the two epimers 
designated (22R) and (22S) which do not interconvert. 
The empirical formula is C25H34O6 and its molecular weight is 430.5. The structural formula 
is depicted in Figure 2 below. 
Figure 2 Chemical Structure of Budesonide -22R and -22S epimer 
 
Buparid-(22R), Buparid-(22S) 
Buparid is a sterile suspension obtained using the known excipients disodium edetate, sodium 
chloride, polysorbate 80 (Tween 80), citric acid anhydrous, sodium citrate and water for 
injections. The suspension is white and homogeneous with a pH between 4.0 to 5.0 and a 
relative density of 1.005 g/ml. Buparid is available as 0.125mg/ml, 0.250mg/ml and 0.5mg/ml 
strengths. 
Buparid is contained in unit dose containers of low density polyethylene without additives, 
slightly opaque and thermally sealed, obtained from polyethylene granules by Blow/Fill/Seal 
(BFS) technology. The nominal volume of these unit dose containers is 2.00 ml. 20 labelled 
unit dose containers, divided in 4 strips of 5 containers, are contained in PET/Al/PE pouches 
(1 strip in each pouch) and then in a suitable lithographed box, together with the leaflet. 
 


 
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6.2
Findings from Non-clinical and Clinical Studies 
6.2.1
Non-clinical Studies 
The active ingredient budesonide is widely used in a number of dosage forms including: 
inhalational powder, inhalational suspension, nasal suspension, rectal foam, and oral capsules. 
The primary pharmacology, toxicology, clinical pharmacology and clinical efficacy of 
budesonide has been established since 1980 and the pre-clinical and clinical data and has been 
reviewed by multiple competent agencies. 
6.2.1.1
Sino-nasal Deposition of inhalable drugs using the PARI SINUS nebuliser – 
Technical Data 
PARI SINUS compressor 
230 V/50 Hz 
Pressure 
 
 
 
1,400 hPa 
Flow  
 
 
 
6 l/min 
Pressure amplitude of bolus  
211 hPa 
Frequency of bolus 
 
 
44.5 Hz 
 
PARI LC-SPRINT SINUS nebuliser 
MMD  
3.6 µm 
Jetflow 
4.6 l/min 
The nebuliser output rate is approx. 200 mg/min, ie. within 8 min (= effective therapy 
duration time without breaks) 1.600 mg aerosol are delivered to the patient. This corresponds 
to approx. 1.6 ml inhalation medium. 
6.2.1.2
Pharmacokinetic Properties 
Absorption 
In adults the systemic availability of budesonide following administration of budesonide 
nebuliser suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 
70% of the dose delivered to the patients. A minor fraction of the systemically available drug 
comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 
min after start of nebulisation is approximately 4 nmol/l after a single dose of 2 mg. 
Distribution 
Budesonide has a volume of distribution of approximately 3 l/kg. Plasma protein binding 
averages 85 - 90%. 
Biotransformation 
Budesonide undergoes an extensive degree (  90%) of biotransformation on first passage 
through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid 
activity of the major metabolites, 6ß-hydroxybudesonide and 16a-hydroxyprednisolone, is 
less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by 
CYP3A, a subfamily of cytochrome P450. 


 
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Elimination 
The metabolites of budesonide are excreted as such or in conjugated form mainly via the 
kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high 
systemic clearance (approximately 1.2 l/min) in healthy adults, and the terminal half-life of 
budesonide after iv dosing averages 2-3 hours. 
6.2.1.3
Toxicology
The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the 
reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide). 
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide 
are less severe or similar to those observed after administration of other glucocorticosteroids, e.g. 
decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex. 
An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be 
verified in a repeat study, in which the incidence of gliomas did not differ between any of the 
groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control 
groups. 
Liver changes (primary hepatocellular neoplasms) found in male rats in the original 
carcinogenicity study were noted again in the repeat study with budesonide as well as with the 
reference glucocorticosteroids. These effects are most probably related to a receptor effect and 
thus represent a class-effect. 
Available clinical experience shows that there are no indications that budesonide or other 
glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man. 
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce 
malformations (cleft palate, skeletal malformations). However these animal experimental results 
do not appear to be relevant in humans at the recommended doses. 
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in 
increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent 
changes in glucocorticoid receptor density, neurotransmitter turnover and behavior at exposures 
below the teratogenic dose range.
6.2.2
Clinical Studies 
Not applicable. This is the first study with Buparid/PARI Sinus in this indication. 
6.3
Known and Potential Risks and Benefits to Human Patients 
Potential Risks: 
Special caution is necessary in patients with active or quiescent pulmonary tuberculosis and in 
patients with fungal or viral infections in the airways. 
During transfer from oral therapy to Buparid, a generally lower systemic corticosteroid action 
will be experienced, which may result in the appearance of allergic or arthritic symptoms such 
as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these 
conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare 
cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these 
cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary. 


 
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Patients, who have required high dose emergency corticosteroid therapy or prolonged 
treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of 
impaired adrenal function. These patients may exhibit signs and symptoms of adrenal 
insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment 
should be considered during periods of stress or elective surgery. 
Systemic effects may occur with any inhaled corticosteroids, particularly at high doses 
prescribed for long periods. These effects are much less likely to occur with inhalation 
treatment than with oral corticosteroids. Possible systemic effects include Cushing's 
syndrome, Cushingoid features, adrenal suppression, growth retardation in children and 
adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of 
psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, 
anxiety, depression or aggression (particularly in children). 
Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection 
may require treatment with appropriate antifungal therapy and in some patients 
discontinuation of treatment may be necessary. 
Adverse drug reactions in Table 6.3-1 are listed according to system organ classes in 
MedDRA. Within each system organ class, the adverse drug reactions are ranked by 
frequency, with the most frequent reactions first. In addition, the corresponding frequency 
category using the following convention (CIOMS III) is also provided for each adverse drug 
reaction: 
Very common ( 1/10); Common ( 1/100 to <1/10); Uncommon ( 1/1,000 to <1/100); Rare 
( 1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the 
available data). 
The likelihood of adverse events may be related to the age, renal function and condition of the 
patient. 


 
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Table 6.3-1: Adverse Drug Reactions 
Adverse Reactions 
Frequency category 
Infections and infestations 
Oropharyngeal candidiasis
Common
Respiratory, thoracic and mediastinal disorders 
Cough 
Hoarseness 
Throat irritation 
Bronchospasm 
Dysphonia 
 
Common 
Common 
Common 
Rare 
Rare 
Immune system disorders 
Immediate 
and 
delayed 
hypersensitivity 
reactions 
including rash, contact dermatitis, urticaria, angioedema 
and anaphylactic reaction
 
Rare 
Endocrine disorders 
Signs and symptoms of systemic corticosteroid effects, 
including adrenal suppression and growth retardation
 
Rare 
 
Psychiatric disorders 
Psychomotor hyperactivity 
Sleep disorders  
Anxiety 
Depression 
Aggression 
Behaviour changes (predominantly in children)
Rare 
Rare 
Rare 
Rare 
Rare 
Rare 
Skin and subcutaneous tissue disorders 
Bruising
 
Rare 
Eye disorders 
Glaucoma 
Cataract 
 
Not known 
Not known 
 
Potential Benefits: 
The conception of the SINUS technology is based on a more efficient drug deposition as 
compared to nasal spray delivery. Because of pulsation the drug is pressed through the 
congested ostia and allows penetration to the desired locus of action. The demonstrated 
residence time of pulsating aerosols should allow increasing the convenience of therapy by 
reduction of a twice-daily to a once-daily application. 
Given the correctness of these assumptions, the pulsating aerosol therapy might prevent or at 
least postpone a surgical intervention. 
 
 


 
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6.4
Selection of Drugs and Doses 
Table 6.4-1: Selection of Drugs and Doses 
Drug 
Delivered
Dose/ 
Treatment 
(µg) 
QD (µg) 
Daily 
Dose (µg) 
BID (µg) 
Daily Dose 
(µg) 
Buparid 
(1 mg/2 ml) 
280 
1 x 280 
280 
2 x 280 
560 
Pulmicort 
Topinasal 
64 µg 
64 / Pump 
2 pumps/nostril 
= 
4 x 64 
256 
2 x 1 pump/nostril 
= 
4 x 64 
256 
Budes Nasal Spray 
50 µg 
50 / Pump 
4 pumps/nostril 
= 
8 x 50 
400 
2 x 2 pumps/nostril 
= 
8 x 50 
400 
The rationale for the selection of a once-daily treatment of Buparid/SINUS and a twice-daily 
treatment with Budes Nasal Spray is that despite the lower daily dose administered via the 
former system a sufficient drug amount is deposited via a more efficient delivery system, 
resulting in at least comparable efficacy. 
There are two mayor differences between the SINUS nebulizer and nasal sprays: 
First, the droplet size is 3 µm for the SINUS and 50 µm for nasal pump sprays. As the nose is 
a very efficient particle filter, especially for particles larger than 10 µm, the aerosol mist of a 
nasal spray deposits at 100% in the anterior nose, mainly at the nasal vestibule and at the 
inferior turbinates. Very small droplets, as produced by the SINUS, can penetrate into the 
posterior regions of the nose and are only partly deposited there. 
The second major difference is that the nasal spray is applied during one inhalation 
manoeuvre to the nose, while the SINUS aerosol is applied with a pulsating air flow. The flow 
fluctuations at 45 Hz cause a ventilation of the sinus cavities in the nose, as shown in Figure 
6.4-1 below. The small droplets generated by the SINUS are capable to follow the induced 
airflow to the paranasal sinuses and deposit there. 
 
Figure 6.4-1: Anterior nasal 81mKr-gas gamma imaging without (w/o, A) and with (w, B and C) pulsating 
airflow. The nebulizer, coupled to the right nostril, and the exhaust tubing, coupled to the left nostril, is shown. 
Regions of interest of the nasal cavity (A) and of the right and left maxillary and frontal sinuses (MR, FR, FL, 
and ML) are shown (C) [from Möller et al. 2010]. 


 
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These differences in droplet size and air flow result in very different deposition patterns of 
nasal sprays versus SINUS as illustrated in Figure 6.4-2. While nasal sprays deposit mainly at 
the anterior nose, the SINUS delivers also aerosol to the upper posterior regions of the nose as 
well as to the maxillary, sphenoid and ethmoid sinuses. These different deposition patterns 
also result in different clearance times of the deposited particles from the nose. 
 
Figure 6.4-2: 99mTc-DTPA activity distribution image of a pump spray (A) vs. pulsating aerosol delivery (B) in 
lateral and anterior view without a nasal shield (Fig. 1, 2) and with a nasal shield (from Möller et al 2009). 
 
The 50% nasal retention was five times faster for nasal pump sprays than for pulsating aerosol 
in healthy volunteers (Table 6.4-1). 
 


 
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Table 6.4-1: Results of retention using nasal pump sprays and pulsation aerosol delivery 
(from Möller et al. 2010). 
 
Nasal Pump Spray 
Pulsating Aerosol 
50% Nasal retention 
14 ± 3.4 min 
72 ± 30 min 
24 h Nasal retention 
2.4 ± 1.8 % 
7.6 ± 1.3 % 
6 h cumulative dose 
0.33 ± 0.11 h 
1.98 ± 0.23 h 
The prolonged residence time of pulsating aerosols might allow a once daily treatment 
(Figure 6.4-3). 
 
Figure 6.4-3: 99mTc-DTPA nasal retention during six hours in a volunteer after delivery using a nasal 
pump spray or the pulsation aerosol device (from Möller et al. 2010). 
 
6.5
Population Studied 
Adult patients with confirmed diagnosis of chronic rhinosinusitis (CRS), i.e. inflammation of 
nasal mucosa and paranasal sinus, with polyposis nasi grade I-II (according to Rasp et al. 
2000). 


 
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7.
TRIAL OBJECTIVES AND PURPOSE 
The objective of this study is to create data for the selection of a clinically relevant primary 
endpoint to assess the efficacy and safety of Buparid/PARI SINUS as compared to Budes 
Nasal Spray in the therapy of chronic rhinosinusitis (CRS) with polyposis nasi in adult 
patients. Ideally, the selected parameter should allow a correlation between an objective 
methodology and the clinical outcome of the study patients. 
 
 
 
 


 
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8.
TRIAL DESIGN 
This is a randomised, open, controlled pilot study in the therapy of CSR with polyposis nasi in 
adult patients. 
 
8.1
Endpoints
Efficacy (at Visit 1, 2, 3 and 4): 
Health-specific quality of life 
Nasal obstruction 
Inflammation of nasal mucosa and paranasal sinus 
Expansion of polyposis nasi 
Nasal inflammation 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
At Follow-up Visit 5 and 6: 
Health-specific quality of life 
Requirement of surgery 
Customer satisfaction regarding the PARI SINUS device 
Safety (during the whole study period): 
Treatment-emergent adverse events (AEs) 
 
8.2
Trial Design 
This is a randomised, open, controlled pilot study to investigate the efficiency of drug 
delivery using the PARI SINUS device versus nasal spray in the therapy of CSR with 
polyposis nasi in adult patients. The study will be conducted in 3 centres in Germany. Patients 
will be allocated to receive either 1 mg/2 ml Buparid therapy once daily or the recommended 
twice daily doses of Budes Nasal Spray. Patients will be monitored at regular intervals during 
6 months for efficacy parameters and for all safety evaluations. 
 


 
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8.2.1
Trial Overview 
Study Visit Schedule 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Week -2 
Week 0 
Week 4 
Week 8 
Week 12 
Week 24 
Informed consent 
X 
 
 
 
 
 
In-/Exclusion criteria 
X 
 
 
 
 
 
Urine pregnancy test1 
X 
 
 
 
 
 
Demographics2 
X 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
IMP administration 
X4 
X 
X 
 
 
 
Inhalation compliance5 
 
 
X 
X 
 
 
Health-specific Quality of Life 
X 
X 
X 
X 
X 
X 
Nasal obstruction 
X 
X 
X 
X 
 
 
Inflammation of nasal mucosa and paranasal sinus 
 
X 
 
X 
 
 
Expansion of polyposis nasi 
 
X 
 
X 
 
 
Nasal inflammation 
X 
X 
X 
X 
 
 
Symptoms of rhinosinusitis 
X 
X 
X 
X 
 
 
Loss of taste/Loss of smell 
X 
X 
X 
X 
 
 
Requirement of surgery 
 
 
 
 
X 
X 
Customer satisfaction6 
 
 
 
 
X 
(X) 
Concomitant treatment7 
X 
X 
X 
X 
X 
X 
Adverse Events (AEs) 
X8 
X 
X 
X 
X 
X 
1 Only in women of childbearing potential 
2 Year of birth, gender, race, height, weight, nicotine and alcohol consumption 
3 Underlying condition, antibacterial/-viral/-fungal therapy 
4 Budes Nasal Spray for Wash-in 
5 Collection of used Buparid ampoules/Budes Nasal Sprays 
6 Only in patients randomized to Buparid/PARI Sinus treatment 
7 Name of drug, dosage, duration 
8 Baseline signs and symptoms 
(X) If not performed on previous visit 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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8.2.2
Study Flowchart 
 
CRS + PN
N = 20
Budes
Nasal Spray
N = 10
Buparid/
PARI SINUS
N = 10
Wash-In
Treatment Period
WEEK                 -2                  0                                        4                                        8                       
12                                     24
VISIT                    1                  2                                        3                                        4                       
5                                       6
Control Period
 
 
8.3
Randomisation and Stratification 
Patients will be screened by the Investigators to assess eligibility for entry into the study. A 
master log will be maintained for all screened patients. When a patient arrives in the clinic for 
the Visit 1, the Investigator will confirm that the patient meets all eligibility criteria. 
After clinical inclusion and exclusion criteria have been fully evaluated and the Wash-in 
phase has been completed, twenty patients will be prospectively randomized in a 1:1-ratio 
among the two treatments and control groups by block randomization. Randomization will be 
performed by an electronically generated algorithm. The randomization code of each patient 
will be provided to the Principal Investigator via closed and blinded envelops. Each patient 
will be assigned a number as part of the randomization process. The number assigned to a 
patient will become that patient¶s unique treatment number throughout the study and cannot 
be re-assigned to another patient. 
No treatment will be assigned to a patient before it has been ascertained that the patient has 
met all inclusion and no exclusion criteria and that the patient or her/his legal representative 
has given written informed consent. 
If the informed consent from the patient is obtained but the patient does not fulfil the criteria 
to participate in the study, the patient will not receive a randomisation number; however, data 
collected at screening may be recorded in the patient¶s source data and on the subject 
identification log. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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A stratification into subgroups is not planned due to the limited patient number of this pilot 
study. 
8.3.1
Blinding
Not applicable; this is an open-labelled study. 
8.4
Investigational Medicinal Product Treatment, Dosage and Administration 
8.4.1
Formulation of Buparid 
Buparid is a sterile suspension obtained using the known excipients disodium edetate, sodium 
chloride, polysorbate 80 (Tween 80), citric acid anhydrous, sodium citrate and water for 
injections. The suspension is white and homogeneous with a pH between 4.0 to 5.0 and a 
relative density of 1.005 g/ml. Buparid is available as 0.125 mg/ml, 0.250 mg/ml and 0.5 
mg/ml strengths. 
Buparid is contained in unit dose containers of low density polyethylene without additives, 
slightly opaque and thermally sealed, obtained from polyethylene granules by Blow/Fill/Seal 
(BFS) technology. The nominal volume of these unit dose containers is 2.00 ml. 20 labelled 
unit dose containers, divided in 4 strips of 5 containers, are contained in PET/Al/PE pouches 
(1 strip in each pouch) and then in a suitable lithographed box, together with the leaflet. 
The IMP (Buparid/PARI SINUS and Budes® Nasal Spray 50µg/pump) will be supplied by: 
PARI Pharma GmbH 
Lochhamer Schlag 21 
82166 Graefelfing 
Germany 
 
8.4.2
Treatment and Dosage 
Following screening and consenting, all participants regardless of treatment allocation will 
receive Budes Nasal Spray 50 µg (2 pumps/nostril BID) in a 2-week Wash-in Phase before 
starting the IMP-treatment to prevent a bias of study results due to former individualised 
therapies. 
After passing the Wash-in Phase and completing the diary correctly patients will be randomly 
assigned to one of the following treatments: 
Treatment arm A (Buparid/PARI SINUS): 
Buparid 1 mg/2 ml once daily for 8 weeks (2 months), resulting in a daily delivered dose of 
280 µg Buparid. 
Treatment arm B (Budes Nasal Spray): 
Budes Nasal Spray (50 µg/pump) 2 pumps per nostril twice daily for 8 weeks (2 months), 
resulting in a daily delivered dose of 400 µg. 
8.4.3
Administration 
All IMP inhalation with the PARI SINUS nebuliser during the scheduled visits MUST be 
self-administered by the patient under trial centre personnel supervision. 


 
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Instructions for administration should be followed as described on the inside leaflet of the 
medication package. 
Instructions for using Buparid ampoules 
1.
Break off the required number of ampoule(s) from the strip. Leave the rest in the 
foil envelope. 
2.
Shake the ampoule(s) gently. 
3.
Hold upright. Open the ampoule by twisting off the top of the ampoule(s). 
4.
Pour the quantity of medication prescribed by your doctor into the medication 
funnel. 
5.
Throw away the empty ampoule(s). Close the cap of the nebuliser. 
6.
Connect the face mask or mouthpiece to the nebuliser according to the nebuliser 
instructions. 
7.
Connect the nebuliser handset to the compressor. 
8.
Switch on the compressor. Using the face mask or mouthpiece, breathe in the mist 
calmly and deeply while sitting or standing in an upright position. If you are using a 
face mask, make sure that the mask fits tightly. 
9.
You will know when you have inhaled all of the medicine because the fine mist will 
stop coming out of your mask or mouthpiece. 
10.
How long it takes to nebulise all the medicine depends on the type of equipment you 
use. It will also depend on the amount of medicine you use. 
11.
Several drops of medication will remain in the nebuliser after inhalation. 
12.
Rinse your mouth with water. Spit out the water. Do not swallow it. If you have 
used a face mask, wash your face as well. 
13.
After each use, you must wash the nebuliser medication reservoir and mouthpiece 
(or face mask).  
 


 
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8.5
Investigational Medicinal Product Packaging, Labelling and Storage 
8.5.1
Packaging
8.5.1.1
Buparid
Buparid will be provided as 20 labelled unit dose ampoules (1 mg/2 ml each), divided in 4 
strips of 5 ampoules in pouches (1 strip in each pouch) and then in an outer packaging box. 
Pouches with 5 ampoules of IMP 
PARI Pharma GmbH, Lochhamer Schlag 21, 82166 Graefelfing, Germany, Tel.: +49 
(0)89 742846-10 
Batch: XXXXX: Protocol-No. 12082.101 
Site No.: 1 or 2, PI: Dr. XXXXXXX 
Subject No.: XX 
Dose: 1 mg/2 ml 
Route of administration: Inhalation 
FOR CLINICAL TRIAL USE ONLY 
 
Outer Packaging Containing 20 IMP ampoules 
Sponsor: PARI Pharma GmbH, Lochhamer Schlag 21, 82166 Graefelfing, Germany, Tel.: 
+49 (0)89 742846-10 
20 ampoules of investigational medical product 
Batch: XXXXX: Protocol-No. 12082.101 
Site No.: 1 or 2, PI: Dr. XXXXXXX 
Subject No.: XX 
Box No.: XX 
Route of administration: Inhalation 
Do not store above 30°C, do not freeze, protect from light 
Expiry Date: dd/mm/yyyy 
³Keep out of reach of children´ 
FOR CLINICAL TRIAL USE ONLY 
 
 


 
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8.5.1.2
Budes Nasal Spray 
Budes Nasal Spray 50 µg/pump will be provided in packages of 1 nasal spray á 10 ml 
suspension for 200 single doses. 
Budes Nasal Spray 
PARI Pharma GmbH, Lochhamer Schlag 21, 82166 Graefelfing, Germany, Tel.: +49 
(0)89 742846-10 
Batch: XXXXX: Protocol-No. 12082.101 
Site No.: 1 or 2, PI: Dr. XXXXXXX 
Subject No.: XX 
 
Outer Packaging Containing 1 Nasal Spray 
Sponsor: PARI Pharma GmbH, Lochhamer Schlag 21, 82166 Graefelfing, Germany, Tel.: 
+49 (0)89 742846-10 
1 Nasal Spray 
Batch: XXXXX: Protocol-No. 12082.101 
Site No.: 1 or 2, PI: Dr. XXXXXXX 
Subject No.: XX 
Box No.: XX 
Route of administration: Nasal spray 
Do not store above 25°C, do not freeze 
Expiry Date: dd/mm/yyyy 
8.5.2
Storage
Keep the ampoules in an upright position. 
Do not freeze the ampoules. 
Do not store the ampoules above 30°C. 
Store the ampoules in the original packaging. 
Store the ampoules in the foil envelope to protect them from light.
8.6
Inhalation Device Packaging 
The device package consists of the PARI SINUS Compressor (230V/50Hz), the PARI LC 
SPRINT SINUS nebuliser (incl. nose plug and nasal joining piece), the SINUS Instruction for 
Use and the SINUS Flyer ³Use & Hygiene´. 
8.7
Duration of Patient Participation 
Each patient will receive once or twice daily IMP treatment for 8 weeks (2 months). During 
study participation, 6 visits at the clinical trial centre are scheduled (see Study Flow Chart). 


 
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8.8
Stopping Rules and Discontinuation Criteria 
8.8.1
Study Level 
The study will be considered complete when 20 randomised patients have completed the 
study. The Sponsor may terminate the study before regular completion if the safety of any 
patient is a concern or a significant delay in patient recruitment occurs or for administrative 
reasons. 
8.8.2
Centre Level 
The Sponsor may close a centre, if 12 weeks after centre initiation no patient has been 
enrolled or if the enrolment rate is significantly reduced. All centres will be closed when the 
study is considered complete (see Section 8.8.1 for details). 
8.8.3
Patient Level 
A patient will be considered to have completed the study after having passed the second 
control visit at Week 24 after starting treatment with IMP. 
Patients will be removed from the study for the following reasons: 
Subjects may discontinue participation in the study at any time. 
The Principal Investigator may withdraw a subject at any time if it is in the best 
interest of the patient based upon clinical assessments or if the subject fails to comply 
with the protocol. 
If the study participant fails to take experimental medication or the patient fails to return for 
clinical follow-up the subject will be reached by telephone or a letter will be sent requesting a 
mandatory clinic visit and the reason for non-compliance shall be documented. 
 
8.9
Investigational Medicinal Product Supply and Accountability 
Each Investigator is responsible for ensuring that deliveries of IMP ampoules and boxes, 
PARI SINUS devices and other study materials from the Sponsor are correctly received and 
recorded, that these are handled and stored safely and properly, and that they are used in 
accordance with this protocol. 
Unused IMP ampoules (opened, unopened, or empty), boxes and PARI SINUS devices must 
be returned to the Sponsor, if appropriate, after the study and overall drug accountability has 
been completed. A list of IMP, PARI SINUS devices and other materials received, used, 
returned, or destroyed must be prepared and signed by the Principal Investigator; any 
discrepancies must be accounted for. 


 
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9.
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1
Patient Inclusion Criteria 
Patients are included in the study if all of the following criteria are met: 
1.
Patient with confirmed diagnosis of chronic rhinosinusitis (CRS), i.e. inflammation of 
nasal mucosa and paranasal sinus, with polyposis nasi grade I-III (according to Rasp et 
al. 2000). Diagnosis is based on history of symptoms (nasal obstruction, running nose, 
postnasal drip, facial pain and hyposmia with a duration of > 3 months (according to 
EPOS3) and on MRT-imaging using the Lund-Mackey Score) 
2.
Patient with a PNIF (positive nasal inspiratory flow) of > 7 l/min separated for left and 
right side of the nose 
3.
Patient¶s written informed consent obtained prior to any screening or study-specific 
procedure 
4.
Male or female,  18 years of age 
5.
Patient is able to undergo nasal therapy without restrictions 
6.
Capable to correctly use the PARI SINUS device (closing of the soft palate) in 
accordance with the package insert 
7.
Capable of understanding the purpose and risk of the clinical trial 
8.
Female patients with childbearing potential must have a negative urine pregnancy test 
prior to first IMP administration. Both women and men must agree to use a medically 
acceptable method of contraception throughout the IMP treatment period and for 3 
months after IMP discontinuation. 
9.
Patient is able to participate in the study according to Investigator¶s opinion 
10. Patient has completed correctly the diary during the Wash-in Phase 
9.2
Patient Exclusion Criteria 
Patients are excluded from participating in this study if one or more of the following criteria 
are met: 
1.
Patients with cystic fibrosis 
2.
Patients with CSR without polyposis nasi 
3.
Patients with polyposis nasi grade IV (according to Rasp et al. 2000) 
4.
Patients with prior sinonasal surgery (exemption: polypectomy) 
5.
Patients with primary ciliaritis 
6.
Pregnant or breastfeeding women 
7.
Patients with suspected active upper airway infection 
8.
Unlikely to comply with visits, inhalation procedures or other measurements scheduled 
in the protocol 


 
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9.
Receipt of an investigational drug as part of a clinical trial within 4 weeks prior to first 
administration of IMP 
10.
Any co-existing medical condition that in the Investigator¶s judgement will 
substantially increase the risk associated with the patient¶s participation in the clinical 
trial 
11.
Psychiatric disorders or altered mental status precluding understanding of the informed 
consent process and/or completion of the necessary procedures 
12.
Drug or alcohol abuse 
13.
End-stage malignancies 
14.
Known hypersensitivity to Budesonide 
15.
Patients with oral steroid therapy within the last 4 weeks 
16.
Patients with frequent epistaxis (> 2 per month) 
9.3
Withdrawal Criteria and Procedures, Interruption or Discontinuation of Study 
The patient is free to withdraw from the study for any reason and at any time without giving a 
reason for doing so and without penalty or prejudice. The Investigator is also free to terminate 
a patient¶s involvement in the study at any time if the patient¶s clinical condition warrants it. 
In order to support the Investigator in his/her decision to withdraw a patient, it is 
recommended to use the standard common toxicity criteria (CTC), version 3.0 as the basis for 
evaluation. If a grade 3 or 4 toxicity occurs to the patient, the Investigator should consider 
withdrawing the patient from the IMP therapy.  
It is also possible that the Sponsor or the Competent Authorities request termination of the 
study if there are concerns about conduct or safety. 
Patients who withdraw voluntarily, or who are discontinued from the study prior to Visit 6 
(end of study visit, Week 24) should have all final study visit procedures performed if 
possible (see Section 13.14). 
All patients withdrawn from the study will be followed-up for AEs and SAEs for further 2 
weeks or 4 weeks, respectively. Any patient with ongoing SAE(s) will be followed-up until 
recovery or stabilisation of the SAE(s). 
Reasons for withdrawal are: 
Revoke of informed consent by the patient or patient¶s legal representative 
Investigational treatment or the study procedures present an unacceptable medical risk to 
the patient 
Patient fails to comply with protocol procedures 
The reasons for withdrawal should be recorded in the CRF. 
In the event of patient withdrawal the Investigator must complete the provided screening and 
enrolment log stating the reason and date of withdrawal. 


 
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Patients who have consented to participate but who are withdrawn for any reason before 
randomisation will be replaced until the scheduled number of randomised patients has been 
achieved. Randomised patients who do not complete the study as scheduled for any reason 
and at any time will not be replaced. 
9.4
Completion of Study and Loss to Follow-up 
Patients will be considered to have completed the study if they were followed-up through 
Study Visit 6 (Study Week 24). It should be specified on the CRF whether or not the patient 
completed the study follow-up procedures through Study Week 24. 
A patient will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the 
patient¶s status at Visit 6 (Study Week 24). The Investigator should document attempts to re-
establish contact with any missing patient throughout the study period. If contact with a 
missing patient is established, follow-up should resume according to the protocol. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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10.
TREATMENT OF SUBJECTS 
10.1
Buparid/PARI SINUS 
Following screening and consenting, all participants regardless of treatment allocation will 
receive Budes Nasal Spray 50 µg (2 pumps/nostril BID) in a 2-week Wash-in Phase before 
starting the IMP-treatment to prevent a bias of study results due to former individualised 
therapies. 
After passing the Wash-in Phase and completing the diary correctly patients randomised to 
receive Buparid/PARI Sinus will be treated as follows: 
Buparid 1 mg/2 ml once daily for 8 weeks (2 months), resulting in a daily delivered dose of 
280 µg. 
The patients will be observed for a total of 6 months. 
 
10.2
Budes Nasal Spray 
Following screening and consenting, all participants regardless of treatment allocation will 
receive Budes Nasal Spray 50 µg (2 pumps/nostril BID) in a 2-week Wash-in Phase before 
starting the IMP-treatment to prevent a bias of study results due to former individualised 
therapies. 
After passing the Wash-in Phase and completing the diary correctly patients randomised to 
receive Budes Nasal Spray will be treated as follows: 
Budes Nasal Spray (50 µg/pump) 2 pumps per nostril twice daily for 8 weeks (2 months), 
resulting in a daily delivered dose of 400 µg. 
 
The patients will be observed for a total of 6 months. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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10.3
Concurrent Treatment or Medication 
Apart from the randomly allocated study medication, no other specific therapies for the 
treatment of CRS with polyposis nasi are prescribed during the study period (exception: nasal 
irrigations in a timely distance from IMP administration). 
However, any other treatment required during study period and prior to first IMP 
administration will be recorded in the CRF until last study visit (Visit 6). 
All other concurrent treatment or medication, including all procedural medication given 
before, during, and after the examination, will be recorded in the CRF. The trade name, and 
dosage should be documented. All treatment and medication will be encoded according to 
MedDRA in its current version. 
During the whole study, the use of systemic corticosteroids is prohibited. 
A patient may receive medications to treat AEs as deemed necessary by the Investigator or the 
patient¶s physician. 
10.4
Procedures for Monitoring Patient Compliance 
At each visit, the patient¶s compliance to the inhalation procedure (Section 8.4.3) will be 
monitored by the clinical trial centre personnel by supervising one inhalation cycle. A patient 
will be regarded as compliant if no more than 20% of inhalations of IMP treatment according 
to protocol are missed. The patients have to hand out used Buparid ampoules and Budes Nasal 
Sprays at each study visit in order to allow for drug accountability. 
Any time the patient has not the ability to inhale, due to e.g. AEs will not be considered in the 
compliance calculation. The reason for non-compliance shall be documented accordingly in 
the CRF. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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11.
ASSESSMENT OF EFFICACY 
11.1
Efficacy Parameters 
Parameters to determine efficacy of the corticosteroidal treatment include: 
Health-specific quality of life 
Nasal obstruction 
Inflammation of nasal mucosa and paranasal sinus 
Expansion of polyposis nasi 
Nasal inflammation 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
Requirement of surgery 
Customer satisfaction regarding the PARI SINUS device, if applicable 
 
11.2
Methods and Timing of Efficacy Assessments and Procedures 
11.2.1 Health-specific quality of life (at Weeks -2, 0, 4, 8, 12 and 24) 
Assessments will be done on all study visits (Visit 1 through Visit 6) using the Sino-Nasal 
outcome Test 22 (SNOT 22). 
11.2.2 Nasal obstruction (at Weeks -2, 0, 4 and 8) 
Nasal obstruction will be assessed using the method of rhinonanometry by measuring the 
positive nasal inspiratory flow (PNIF). Assessment will be done prior to Wash-in Phase (at 
Visit 1), prior to commencement of study medication (at Visit 2), during treatment (at Visit 3) 
and after end of treatment (at Visit 4). At each assessment the subject has to inhale maximally 
through the nose three times and the highest value will be recorded. 
11.2.3 Inflammation of the nasal mucosa and paranasal sinus (at Weeks 0 and 8) 
Inflammation of the nasal mucosa and paranasal sinus will be assessed be determination of 
the thickness of the mucosa using Magnetic Resonance Imaging (MRI) at Visits 2 and 4. The 
results will be interpreted using the Lund-Mackay-Score: 
Table 11.2-1: Lund-Mackay staging system 
Paranasal sinuses 
Right 
Left 
Maxillary (0, 1, 2) 
 
 
Anterior Ethmoid (0, 1, 2) 
 
 
Posterior Ethmoid (0, 1, 2) 
 
 
Sphenoid (0, 1, 2) 
 
 
Frontal (0, 1, 2) 
 
 
Ostiomeatal complex (0*, 2*) 
 
 
Total points to each side 
 
 
0 = no abnormalities; 1 = partial opacification; 2 = total opacification; 0* = not occluded; 2* = occluded 


 
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11.2.4 Expansion of polyposis nasi (at Weeks 0 and 8) 
Expansion of polyposis nasi will be assessed endoscopically at Visits 2 and 4. The results will 
be interpreted using the classification according to Rasp et al. 2000. 
Fig. 11.2-1: Classification according to Rasp et al. 2000. 
 
 
 
 
11.2.5 Nasal inflammation (at Weeks -2, 0, 4 and 8) 
Nasal inflammation will be assessed by determination of the Eosinophil Cationic Protein 
(ECP) and tryptase in nasal discharge at Visits 1, 2, 3 and 4. The samples will be analysed in 
the local laboratory of the study site. 
11.2.6 Symptoms of rhinosinusitis (at Weeks -2, 0, 4 and 8) 
Symptoms of rhinosinusitis will be documented at Visits 1, 2, 3, and 4. Parameters to be 
assessed include: 
Nasal obstruction (see 11.2.2) 
Rhinorrhoea 
Loss of smell/taste (see 11.2.7) 
Facial pressure pain (by means of a Visual Analogue Scale (VAS) 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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Visual Analogue Scale: 
Each subject will be asked to indicate the answer to the question ³How troublesome 
are your symptoms of rhinosinusitis?´ on a 10 cm visual analogue scale (Not 
troublesome 
 Most troublesome imaginable). 
11.2.7 Loss of taste/Loss of smell (at Weeks -2, 0, 4 and 8) 
Loss of taste will be assessed using taste strips at Visits 1, 2, 3 and 4. Loss of smell will be 
assessed using sniffing sticks at Visits 1, 2, 3 and 4. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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12.
ASSESSMENT OF SAFETY 
12.1
Safety Parameters 
The following safety parameters will be assessed: 
Treatment-emergent adverse events (AEs) 
 
12.2
Methods and Timing of Safety Assessments and Procedures 
12.2.1 Pregnancy Test 
Pregnancy tests will be obtained in women of childbearing potential only. A urine pregnancy 
test will be obtained prior to first IMP administration. 
12.2.2 Adverse Events 
12.2.2.1 Definitions
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH Guidelines for Good Clinical Practice, May 1996). 
This includes worsening of a pre-existing condition or increase in frequency of a pre-existing 
condition. An adverse event is considered serious if it meets any of the serious criteria listed 
below. To ensure no confusion or misunderstanding of the difference between the terms 
³serious´ and ³severe´, which are not synonymous, the following clarification is provided: 
The term ³severe´ is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
³serious´, which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient¶s life or functioning. Seriousness (not severity) serves a 
guide for defining regulatory reporting obligations. 
The official definition also extends to AEs occurring under placebo or in a reference group 
receiving drug or non-drug therapy. 
A baseline recording of any symptoms of illness will be performed before administration of 
the IMP. Only symptoms that increase in severity after study drug administration or new 
symptoms of illness will be recorded as AE in the CRF. 
Each patient will be closely observed and questioned for AEs during the study procedures and 
throughout the study period with non-leading questions (e.g. how do you feel?). The patients 
will be instructed to report to the study staff immediately any symptoms and/or signs which 
occur between the scheduled observation times. 


 
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All AEs reported by the patient or observed by the Investigator or hospital personnel will be 
reported in the CRF. The following information regarding each adverse event will be 
obtained: date and time of onset and resolution (duration), serious or non-serious (as defined 
below), severity, treatment required, outcome, relationship to study drug, and if the AE 
caused withdrawal from the study. 
In addition to the Investigator's own description of the AE, each AE event will be coded 
according to the MedDRA code list in its current version. The verbatim term will be recorded 
in the CRF. 
Adverse Reaction (AR) 
Adverse drug reactions (ADRs) are all noxious and unintended responses to a medicinal 
product related to any dose that a causal relationship between the medicinal product and an 
adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. An 
unexpected ADR is any adverse reaction not identified in nature or intensity in the current 
Summary of Product Characteristics (SmPC). 
Serious Adverse Events (SAEs) 
A SAE is defined as any untoward medical occurrence that at any dose: 
results in death, 
is life-threatening (immediate risk of death at the time of the event) 
requires inpatient hospitalisation or prolongation of existing hospitalisation, 
results in persistent or significant disability/incapacity, or 
is a congenital anomaly/birth defect 
Other: Medical and scientific judgement should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious. 
12.2.2.2 Relationship to Study Drug 
An AE will be considered as AR, if a causal relationship to the administration of IMP cannot 
be excluded, e.g. if the relationship is possible, probable or very likely according to the 
following definitions: 
Not related: An AE that is not related to the use of the investigational product 
Doubtful: An AE for which an alternative explanation is more likely - e.g. concomitant 
drug(s), concomitant disease(s), and/or the relationship in time suggests that a causal 
relationship is unlikely 
Possible: An AE that might be due to the use of the investigational product. An 
alternative explanation e.g. concomitant drug(s), concomitant disease(s), - is 
inconclusive. The relationship in time is reasonable; therefore the causal relationship 
cannot be excluded 


 
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Probable: An AE that might be due to the use of the investigational product. The 
relationship in time is suggestive (e.g. confirmed by dechallenge). An alternative 
explanation is less likely - e.g. concomitant drug(s), concomitant disease(s) 
Very likely: An AE that is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation - e.g. concomitant drug(s), concomitant 
disease(s). The relationship in time is very suggestive (e.g. it is confirmed by dechallenge 
and rechallenge) 
12.2.2.3 Maximum Intensity 
The severity of all adverse events will be evaluated as mild, moderate or severe using the 
following definitions: 
Mild: The event is easily tolerated 
Moderate: The event interferes with normal activity 
Severe*: The event is incapacitating (causes inability to perform usual activity or work) 
* There is a distinction between a severe adverse event and a serious adverse event; a severe 
reaction is not a serious adverse event unless it meets one of the criteria for serious events (see 
Section 12.3.1). 
12.2.2.4 Serious Adverse Event (SAE) Reporting 
Any serious adverse events occurring 
between the first clinical trial procedure and within 4 weeks after the completion of the 
EOS visit, whether or not considered related to the study drugs; 
or 
at any time after completion of the last follow-up and coming to the attention of the 
Investigator, if it is judged as related to the patient¶s participation in the study 
must be reported to the Sponsor's SAE Safety Officer within 24 h, as follows: 
Report all SAEs within 24 h of discovery of the event to the Safety Officer (indicated 
below) by telephone or fax 
Complete a supplemental SAE Form and send it to the Sponsor's Safety Officer within 24 
h after the discovery of the event 
Follow-up the SAE until the outcome is determined, providing periodic updates to the 
Safety Officer as requested 
Record the SAE in the patient's CRF on the AE page 
Provide any additional information if requested 
The Safety Officer must be notified by telephone when a document has been sent by fax. If 
limited information on the event is initially available, follow-up reports will be required. Each 
SAE should be reported to the EC and the local health authorities by the Principal 
Investigator, according to local regulations. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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SAE Safety Officer  
 
         Fax: 
+32 (0)15 29 93 38 
 
Dr. Rafaël Smetss 
 
SGS Life Science Services  
         Phone: +32 (0)15 29 93 94 
 
Mechelen Noord zone L 
 
Intercity Businesspark 
 
         E-mail: be.life.SAEprocessing@sgs.com 
 
Generaal De Wittelaan 19A bus 5 
 
2800 Mechelen 
 
Belgium 
 
12.2.2.5 Other Events to be Treated as Serious Adverse Event (SAE) 
Exposure to drug during pregnancy/lactation: 
In principle, pregnancy and the lactation period are exclusion criteria. In the event of a 
pregnancy occurring during the course of the study, the patient must be withdrawn from all 
IMP treatment immediately. The Investigator should report pregnancy cases occurring during 
the clinical trial to SGS Life Science Services Medical Affairs immediately using the SAE 
form. PARI Pharma GmbH must be notified without delay. Pregnancy cases will be followed-
up during the entire course of the pregnancy and postpartum period using SGS Life Science 
Services Drug Exposure during Pregnancy ± Pregnancy Form A and End of Pregnancy ± 
Pregnancy Form B. Parental and neonatal outcomes must be recorded even if they are 
completely normal and without AEs. The SAE reporting procedure should be followed, even 
though pregnancy is not considered a SAE. No ³serious criterion´ should be checked. The 
SAE report form is solely used to ensure expedited reporting. 
 
12.2.2.6 Investigational medicinal product (IMP) overdosing 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol. For the purposes of this study, any dose of aerosolised IMP 
administered to a patient that exceeds the dose foreseen in the protocol by more than 50% 
over 4 weeks should be reported as an overdose. It must be reported as an SAE, irrespective 
of outcome and even if toxic effects were not observed. 
 
12.2.2.7 Events Not Regarded as Adverse Events/Serious Adverse Events 
The following events will be not regarded as AEs/SAEs: 
Pre-scheduled (before any trial-related activity) hospitalisations/surgeries/interventions 
Trial endpoint-related worsening; these will be assessed as treatment success or failure 
during trial endpoint analysis 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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The Sponsor¶s responsibilities in regards to reporting SAEs and Suspected Unexpected 
Serious Adverse Drug Reactions (SUSARs) are in accordance with European Directive 
2001/20/EC. 
12.2.3 Monitoring of Adverse Events 
Any patient experiencing AEs, whether ascribed to the IMP or not, will be followed closely 
until the outcome is determined in addition to the EOS visit to assess adverse events. All AEs 
must be documented in the patient's medical record. The occurrence of AEs and SAEs will be 
monitored until 2 and 4 weeks after the EOS visit, respectively. Any patient with ongoing 
SAEs will be followed up until recovery or stabilisation of the SAE. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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13.
VISIT SCHEDULE 
All investigations and activities are listed in the flowchart and trial overview (Section 8.2) of 
the clinical trial protocol. Further details on the methodology of these investigations and 
activities are described in detail in Sections 8.1 through 8.2. The Investigator should adhere to 
the visit and procedure schedule as closely as possible. 
All patients assigned a randomisation number and who receive any IMP treatment will be 
followed according to the protocol regardless of the number of IMP received, unless consent 
for follow-up is withdrawn. The Sponsor must be notified of all deviations from the protocol 
visit schedule or evaluations and these visits/evaluations, if applicable, must be rescheduled or 
performed at the closest possible time to the original schedule. 
Patients will be instructed to call study personnel to report any abnormalities, including any 
hospitalisations or doctor visit, during the interval between study visits and to come to the 
study site if medical evaluation is needed and urgency of the situation permits. For emergency 
and other unscheduled visits to a medical facility other than the study site, medical records of 
the visit should be obtained by the Investigator. 
If a patient prematurely discontinues from the study for any reason, e.g. the patient withdraws 
consent for further participation in the study, the Sponsor will request that the evaluation 
listed under "Final Visit (EOS) for Patients who Prematurely Discontinue from the Study" 
(see Section 13.14) be completed prior to discontinuation. 
13.1
Study Visits 
A schedule of screening and study visit procedures is presented in section 8.2.1 (trial 
overview), followed by a detailed description of each visit. 
 
13.2
Screening and Baseline Visit 1 (Week -2) 
The Investigator must assess the following procedures: 
Written informed consent must be obtained from each patient or patient¶s representative 
according to local law prior to entering the clinical trial. The patient MUST give his/her 
original signature with date and time on the patient information/consent form. 
It should be marked in the hospital files that the patient is participating in a clinical study, 
including patient's ID, demographic data, date of inclusion and number of study. 
After the Investigator has obtained written informed consent from the patient, the following 
assessments will be made: 
Evaluate eligibility for the study per the inclusion/exclusion criteria 
Pregnancy tests will be obtained in women of childbearing potential only. A urine 
pregnancy test will be obtained at screening. 
Demographics: year of birth, gender, race, date of body measurements, height, weight, 
nicotine and alcohol consumption 
Medical history: underlying condition, antiviral/antifungal/antibacterial therapy 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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AEs (baseline signs and symptoms) 
Other concomitant treatment: name of drug, dosage, duration 
Health-specific quality of life 
Nasal obstruction 
Nasal inflammation 
Administration of Budes Nasal Spray for Wash-in 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
13.3
Visits 2 (Week 0) 
The Investigator must assess the following: 
Health-specific quality of life 
Nasal obstruction 
Inflammation of nasal mucosa and paranasal sinus 
Expansion of polyposis nasi 
Nasal inflammation 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
IMP administration 
AEs 
Other concomitant treatment: name of drug, dosage, duration 
13.4
Visits 3 (Week 4) 
The Investigator must assess the following: 
Health-specific quality of life 
Nasal obstruction 
Nasal inflammation 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
IMP administration 
Inhalation compliance 
AEs 
Other concomitant treatment: name of drug, dosage, duration 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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13.5
Visit 4 (Week 8) 
The Investigator must assess the following: 
Health-specific quality of life 
Nasal obstruction 
Inflammation of nasal mucosa and paranasal sinus 
Expansion of polyposis nasi 
Nasal inflammation 
Symptoms of rhinosinusitis 
Loss of taste/Loss of smell 
Inhalation compliance 
AEs 
Other concomitant treatment: name of drug, dosage, duration 
13.6
Visits 5 (Week 12) 
The Investigator must assess the following: 
Health-specific quality of life 
Requirement of surgery 
Customer satisfaction regarding the PARI SINUS device, if applicable 
AEs 
Other concomitant treatment: name of drug, dosage, duration 
13.7
Visit 6 (Week 24) 
The Investigator must assess the following: 
Health-specific quality of life 
Requirement of surgery 
Customer satisfaction regarding the PARI SINUS device, if applicable 
AEs 
Other concomitant treatment: name of drug, dosage, duration 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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14.
STATISTICS 
14.1
Statistical Concept 
This is the first study using the drug/device combination Buparid/PARI SINUS for treatment 
of CRS with polyposis nasi. It is therefore intended to be a proof-of-concept study with the 
aim of exploring the therapeutic potential of the novel drug/device combination in this 
indication as well as of assessing several efficacy outcome measures for their suitability to 
discriminate between different treatments in order to enable the selection of an appropriate 
primary endpoint for a confirmatory study intending to demonstrate therapeutic benefit. 
In accordance with the exploratory objectives of the trial the statistical concept will be purely 
descriptive, and treatment group comparisons will be based primarily on confidence intervals, 
particularly as the study will not be powered for a confirmatory proof of a clinically 
meaningful effect. 
Technical details of data analysis and presentation of the results will be provided in a 
Statistical Analysis Plan (SAP) that will be finalized before the execution of any analyses that 
will provide efficacy or tolerability results broken down by treatment. 
14.2
Sample Size Considerations 
Due to the current lack of availability of data required for the design of a confirmatory clinical 
trial, this pilot trial is intended to create sufficient data for a formal calculation of sample size 
and statistical hypotheses in a clinical investigation at a later phase of drug development 
(phase III). 
In this pilot study the determination of the sample size is primarily based on feasibility rather 
than on statistical reasons. It is intended to randomize a total of 20 patients. Ten patients will 
be randomized into the Buparid/PARI SINUS arm and 10 into the Budes Nasal Spray arm. 
When the sample size in each group is 10 patients, a two-sided 95% confidence interval for 
the difference between the treatment groups¶ mean values will extend 
0.88 standard 
deviation units from the point estimate.  
14.3
Missing Data 
The investigators should take every effort to assure complete data. Of note, patients 
withdrawn from treatment prematurely for any reason should be attempted to be followed up 
until the scheduled end of the observational period unless they withdraw their informed 
consent or further participation in the follow-up presents an intolerable medical risk. 
The data will be presented in an µobserved cases¶ analysis in which no imputation for missing 
values will be applied. In addition, in case of outcome measures assessed more than once 
during the course of the trial, analyses will be prepared in which the last valid post-baseline 
observation will be carried forward. In patients withdrawn from the trial for lack of efficacy 
or for lack of tolerability before the first post-baseline assessment, baseline values will be 
carried forward. Other missing data imputation techniques may be defined in the context of 
explorative analyses as needed. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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14.4
Analyses of Patient Populations 
Safety analysis set (SAS) 
The SAS is defined as all patients randomized who receive the investigational treatment at 
least once. 
Full analysis set (FAS) 
The FAS is defined as all patients randomized who receive the investigational treatment at 
least once, and who provide any post baseline data for treatment efficacy. 
A Data Review Meeting may decide to exclude patients from the FAS in cases of very severe 
protocol violations seriously interfering with the assessment of treatment efficacy (e. g., 
patients not suffering from the condition under investigation). 
Per protocol set (PPS) 
The PPS is defined as all patients included in the FAS 
who complete randomized treatment as scheduled, or who are withdrawn from treatment 
prematurely for lack of efficacy or for lack of tolerability, and 
for whom no major protocol deviations interfering with the assessment of treatment 
efficacy are observed. 
Eligibility for the analysis data sets will be determined in a Data Review Meeting held after 
closing the database but before performing any analyses broken down by treatment group. 
Protocol violations will be classified as µmajor¶ when a significant influence on the 
assessment of treatment efficacy cannot be excluded. Comprehensive justification for the 
classification of a protocol violation as µmajor¶ will be given in the Statistical Analysis Plan 
(SAP) as well as in the integrated clinical study report. 
With due regard to the principles if Intention to Treat the analysis of treatment efficacy will 
be performed in the FAS. Additional efficacy analyses will be performed in the PPS to 
provide sensitivity analyses which assess the efficacy of the investigational products in the 
absence of important protocol deviations. Any data referring to safety and tolerability will be 
analysed in the SAS. 
14.5
Statistical and Analytical Methods 
Continuous/quantitative data will be summarized in accordance with their applicable level of 
measurement, by specifying summary statistics such as number of eligible and valid cases, 
mean, standard deviation (SD), median, minimum and maximum. For categorical / qualitative 
data group frequencies and percentages for categories will be specified. Generally, 
percentages will be based on the total number of patients in the applicable analysis population 
as well as on the number of valid cases. 
14.6
Baseline Comparability 
Demographic data for age, height and weight will be summarized using descriptive statistics 
as noted above. Subject randomization, duration of treatment, subject disposition, drug 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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compliance and protocol violations and reason will be described. 
Prior medications within 2 weeks before Wash-in as well as any concomitant medication, 
relevant previous and any ongoing concurrent diseases will be coded according to medical 
standard dictionaries (WHO-DD and MedDRA) and will be summarized by treatment group. 
14.7
Analysis of Efficacy 
Treatment efficacy will be analysed by performing treatment group comparisons for the 
efficacy outcome measures identified in Section 11. For outcome measures assessed at and 
after baseline, absolute and relative differences to the baseline value will be calculated. 
Since the study¶s sample size has not been determined based on power considerations (see 
Section 14.2), and the concept of the trial is exploratory in nature (Section 14.1), p-value-
based comparisons are not of primary importance. The estimation of the treatment effects to 
be expected in a confirmatory trial for the different outcome measures will be based on 
determining 95% confidence intervals for the differences between the treatment groups¶ mean 
values, medians, or rates. 
14.8
Analysis of Safety 
Safety data will be collected for all subjects from study inclusion until Week 24 (end of 
follow-up). The analysis of safety will be based on adverse events (as defined in Section 
12.2.2) that are reported by the patients spontaneously or upon elicitation, which will be 
performed during all visits starting at baseline. 
Adverse events will be MedDRA coded and will be summarized by severity and relationship 
to the investigational treatment administered. 
The number of events as well as the number of patients with events will be presented by 
MedDRA Preferred Terms and System Organ Classes for the following endpoints: 
all adverse events; 
all potentially related adverse events, i.e., events for which a causal relationship with 
the investigational treatment is considered to be possible, probable or very likely; 
all serious adverse events; 
serious, potentially related adverse events 
Moreover, incidence densities of adverse events will be determined for each of the definitions 
above. The rates of potentially treatment related AEs will be compared between the study 
groups by computing risk ratios and their confidence intervals. 
Note: Only treatment emergent AEs (commencing after exposure to study medication, i.e. 
during the Wash-in and Treatment phase) will be included in the AE summaries. Non-
treatment emergent events (starting prior to exposure to study medication) will be included in 
the patient listings and not included in the above summaries. 
 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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15.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents and data 
records include but are not limited to: hospital records, clinical and office charts, laboratory 
notes, memoranda, patients¶ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilms or magnetic 
media, X-rays, patient files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
 
Case report forms, all copies of test results, and study-related regulatory documents [e.g., 
Informed 
Consents, 
Ethics 
Committee 
(EC)/Institutional 
Review 
Board 
(IBR) 
approvals/correspondence, etc.] must be available at all times for regulatory agency inspection 
and review by the Sponsor or its designee. During the periodic site monitoring visits, the 
source documents will be verified against data entered onto the CRF in order to assure that all 
data is accurately and completely reflected on the patient¶s CRF. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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16.
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1
Amendments and Protocol Violations 
No changes from the final approved (signed) protocol will be initiated without the EC¶s prior 
written approval or favourable opinion of a written amendment, except when necessary to 
eliminate immediate hazards to the patients or when the change involves only logistics or 
administration. The Principal Investigator(s) at the clinical trial site and the Sponsor sign the 
protocol amendment. 
The Principal Investigator is responsible for submitting any and all protocol deviations, 
violations or non-compliance issues that occur during the course of the study. 
Major protocol deviations and violations - will be documented and submitted to the 
ECs no later than 7 days of discovering them. If the deviation has potential to affect 
patient safety it must be reported immediately. 
Minor protocol deviations and non-compliance ± These deviations should be 
documented in the study file and will be reported to the EC according to local 
requirements. 
16.2
Information to Study Personnel 
The Investigator(s) is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the 
practical performance of the study and during the course of the study (e.g., when new staff 
become involved). 
The monitor(s) is responsible for explaining the protocol to all staff assisting the Investigator 
and for ensuring their compliance with the protocol. Additional information available during 
the study should be given as agreed upon, either by the Investigator(s) or the monitor (s), and 
always when new staff becomes involved in the study. 
16.3
Clinical Trial Monitoring 
A monitor from PARI Pharma GmbH or designee will contact and visit the Investigator 
intermittently during the trial. Each clinical site will be monitored within 2 weeks of 
randomisation of its first patient. The average monitoring frequency is expected to be one visit 
per month but this may be adjusted for the actual recruitment rate or for communication 
purposes, depending on the enrolment rate and outstanding issues or queries at the site. The 
monitor(s) or representative is responsible for ensuring that the study is conducted according 
to SOPs to ensure compliance with ICH-GCP. 
The monitor(s) is the primary link between the Sponsor and the Investigator. The main 
responsibilities of the monitor(s) are to visit the Investigator before, during, and after the 
study 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 
patients before their participation in the study. 
The monitor(s) will contact and visit the Investigator at regular intervals throughout the study. 
The monitor(s) will be allowed to check and verify the various records (CRFs and other 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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pertinent data records) relating to the study 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 study progress other Sponsor personnel may, upon request, 
accompany the monitor(s) on visits to the study centre. The Investigator and assisting staff 
must agree to co-operate with the monitor(s) to resolve any problems, errors, or possible 
misunderstandings concerning the data detected in the course of these monitoring visits. 
During the monitoring visit, the following items must be accessible for review: 
Source documents, including informed consent forms, for all screened patients 
Investigator Site File (100% source data verification will be conducted) 
CRFs for all patients 
Drug accountability logs 
Drug supply and clinical supply cabinets 
Storage of lab samples 
All study staff will also need to make themselves available for review of monitoring 
issues 
16.4
Audit and Inspection 
According to ICH Guidelines on GCP, the Sponsor or their legal representatives may audit 
the investigational site to compare raw data, source data, and associated records with the 
interim or final report of the study to assure that data have been accurately reported. The 
Sponsor's quality assurance unit, independent of the Clinical Research and Development 
Department, is responsible for auditing the study. 
The Investigator(s) must accept that regulatory authorities may conduct an inspection to 
verify compliance of the study with GCP. 
In addition, regulatory bodies and their discretion may conduct inspection. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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17.
ETHICAL AND REGULATORY ASPECTS 
The protocol will be reviewed and approved by the EC of each participation centre prior to 
study initiation. 
Serious adverse events regardless of causality will be reported to the Sponsor within 24 h and 
to the EC, and the Investigator will keep the EC informed as to the progress of the study. The 
Investigator will explain the nature of the study and will inform the patient that participation 
is voluntary and that the patient can withdraw at any time. Written informed consent will be 
obtained for each patient prior to entry into the study. A copy of the signed consent form will 
be given to the patient and the original will be maintained with the patient¶s record. 
17.1
Responsibilities of the Investigator 
The Investigator shall be responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki as well as with the ICH guideline E6 GCP: Consolidated Guideline and applicable 
regulatory requirements. These documents state that the informed consent of patients is an 
essential precondition for participation in the clinical study. 
17.2
Patient Information 
An unconditional prerequisite for a patient participating in the study is his/her written 
informed consent.  Adequate information must therefore be given to the patient by the 
Investigator before informed consent is obtained. A person designated by the Investigator may 
give the information, if permitted by local regulations. A patient information sheet (informed 
consent document) in the local language and prepared in accordance with the ICH E6 will be 
provided by the Sponsor for the purpose of obtaining informed consent. In addition to this 
written information, the Investigator or his designee will inform the patient verbally. In doing 
so, the wording used will be chosen so that the information can be fully and readily 
understood by laypersons. 
The patient information sheet will be revised whenever important new information becomes 
available that may be relevant to the consent of patients. 
17.3
Patient Informed Consent 
This study will be conducted in full accordance with the current revision of the Declaration of 
Helsinki and the GCP: Consolidated Guideline approved by the ICH.
The written informed consent of the patient to participate in the clinical study has to be given 
before any study-related activities are carried out on the patient. It must be signed and 
personally dated by the patient and by the Investigator/person designated by the Investigator 
to conduct the informed consent discussion. 
Provision of consent will be confirmed in the CRF by the Investigator. The signed and dated 
declaration of informed consent will remain at the Investigator's site and must be safely 
archived by the Investigator so that the forms can be retrieved at any time for monitoring, 
auditing, and inspection purposes. A copy of the signed and dated information and consent 
should be provided to the patient prior to participation. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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This study will be conducted in compliance with ICH Guidelines for informed consent. 
Information should be given in both oral and written form, and patients or their legal 
representative must be given ample opportunity to inquire about details of the study. Writing 
consent documents will embody the elements of informed consent as describe in the 
Declaration of Helsinki and will also comply with local regulations.  
Patients must be informed about the aims, expected benefits, and possible risks (including the 
statements that the particular treatment or procedure may involve risks to the patients that are 
currently unforeseeable). They must also be informed of alternative procedures. Patients must 
receive explanation as to whether any compensation or medical treatments are available if 
injury occurs, and if so, what they consist of, or where further information may be obtained. 
They must be informed whom to contact for answers to any question relating to the research 
project. Patients must be informed that participation is voluntary and that they are free to 
withdraw from the study for any reason at any time, without penalty or loss of benefits to 
which they are otherwise entitled. The extent of confidentiality of the patient¶s record must be 
defined, and patients must be informed that applicable data protection legislation will be 
complied with. Patients must be informed that monitors(s), auditors(s), EC members, and 
regulatory authorities will be granted direct access to the patient¶s original medical records for 
verification of clinical trial procedures and/or data, without violating the confidentiality of the 
patient, to the extent permitted by the applicable laws and regulations and that, by signing a 
writing informed consent form, the patient¶s legally acceptable representative is authorised 
such access. 
The patient's representative willingness to participate in the study will be documented in 
writing in a consent form, which will be signed by the patient¶s legal representative and the 
person performing the informed consent procedure with the date and time of that signature 
indicated. The Investigator(s) will keep the original consent forms and copies will be given to 
the patients. 
Written and/or oral information about the study in a language understandable by the patient¶s 
legal representative will be given to all legal representatives. The information provided must 
include an adequate explanation of the aims, methods, anticipated benefits, potential hazards, 
and insurance arrangements in force. 
17.4
Subject Insurance 
The Sponsor confirms that an insurance covering the costs of treatment of trial subjects in the 
event of trial-related injuries according to applicable regulatory requirements in the 
participating countries has been arranged by the Sponsor. 
No other compensation (such as lost wages or payment for emotional distress) will be 
provided by the Sponsor. 
17.5
Ethics
This trial will be conducted in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Subjects, adopted by the General 
Assembly of the World Medical Association. 
The planning and conduct of this trial follows the respective national laws of the participating 
countries, the principles and guidelines for good clinical practice laid down in Directives 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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2001/20/EC and 2005/28/EC of the European Parliament and the Consensus paper of the 
International Conference on Harmonisation on good clinical practice (ICH-GCP) and the 
PARI Pharma GmbH SOPs that are based on the ICH-GCP guidelines. 
 
17.6
Notification to Competent Authorities (CA) and Ethics Committees (EC) 
17.6.1 Commencement of the Trial 
Before commencing the trial in any trial centre, the Sponsor will submit a valid request for 
authorisation to the CA in the participating countries including this protocol and a summary 
of essential pharmacological-toxicological and clinical data. 
In parallel, the Sponsor will submit a valid application to the competent ECs to give its 
opinion on the study protocol and the written subject information/informed consent. 
The constitution of the competent EC must meet the requirements of the participating country. 
A list of the EC members, with names and qualifications, will be requested. If such a list is 
unavailable, the Investigator must provide the name and address of the EC along with a 
statement from the EC that it is organised according to GCP and the applicable laws and 
regulations. The EC must also perform all duties outlined by the requirements of the 
participating country. 
The study will not start until the competent EC has issued a favourable opinion (positive vote) 
and if the CA in the country concerned has not informed the Sponsor of any grounds for non-
acceptance. 
17.6.2 Ending of the Trial 
Within 90 days of the end of the trial, the Sponsor will notify the CAs concerned and the ECs 
that the clinical trial has ended. If the trial has to be terminated early, the notification period 
will be reduced to 15 days and the reasons will be explained. 
17.6.3 Notification to Local Authorities 
According to local law, the conduct of this trial will be notified to the respective local 
authorities as well as the name and address of each Investigator. 
17.6.4 Protocol Amendment 
Should any change be required to the signed, final protocol, a protocol amendment will be 
required. The amendment must be signed by the project managers of the Sponsor and, if 
necessary, by the statistician.  
Substantial amendment 
If this amendment is substantial and is likely to have an impact on the safety of the trial 
subjects or to change the interpretation of the scientific documents in support of the conduct 
of the trial, or if it is otherwise significant, the Sponsor will notify the CAs of the Member 
State or the Member States concerned of the reasons for and content of this amendment and 
will inform the EC or ECs concerned. 
Should the opinion of the EC be favourable and the Competent Authorities of the Member 
States have raised no grounds for non-acceptance of the above-mentioned substantial 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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amendment, the Sponsor will proceed to conduct the clinical trial following the amended 
protocol. 
If the opinion of the EC is unfavourable, the Sponsor will not implement this substantial 
amendment to the protocol. The Sponsor will either take account of the grounds for non-
acceptance and adapt the proposed amendment to the protocol accordingly or withdraw the 
proposed amendment. 
Non-substantial amendments 
Protocol amendments only for logistical or administrative changes may be implemented 
immediately; the EC will be informed by the Sponsor accordingly. 
Urgent safety measures 
If any new event relating to the conduct of the trial or the development of the investigational 
medicinal product occurs that is likely to affect the safety of the subject, the Sponsor and the 
Investigator will take appropriate urgent safety measures to protect the subjects against any 
immediate hazard. The Sponsor will inform the CAs of this new event and the measures taken 
immediately and will ensure that the EC is notified at the same time. 
17.7
Confidentiality Regarding Study Patients 
All local legal requirements regarding data protection will be adhered to. 
All drug-related information obtained by the Investigator and supplied by the Sponsor is to be 
treated as confidential by the Investigator and all other personnel involved in the trial. Third 
persons who are not participating in or working on this clinical trial are not authorised to 
receive any trial data or material. 
The anonymity of participating subjects must be maintained and study findings will be treated 
confidentially. Throughout documentation and evaluation, the subjects will be identified on 
CRFs and other documents by their birth date, and their identification number (pseudonymous 
data recording). The subjects will be informed that all study findings will be stored on a 
computer and handled in the strictest confidence. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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18.
DATA HANDLING AND RECORD KEEPING 
18.1
Source Documents and Data’s Recorded on the Case Report Form 
Patient participation (e.g. number of study, patient's ID, date of inclusion, date of completion 
and adverse events) must be recorded in the patient's medical record according to Good 
Clinical Practice. 
Any data recorded directly on the Case Report Form (CRF), for which no other written or 
electronic record will be maintained in the patient's medical record, will be considered source 
data (e.g., body measurements or the drug administration procedure). 
The Investigator shall permit Sponsor, authorised agents of the Sponsor, and regulatory 
agency employees to enter and inspect any site where drug or records pertaining to the drug 
are held, and inspect and copy all records relating to an investigation, including patient 
records.  
Completed CRFs must be made available by the Investigator for review by the Sponsor, agent 
of the Sponsor, clinical monitor and regulatory agency. To ensure the accuracy of data 
submitted, it is mandatory that representatives of the Sponsor and regulatory agencies have 
direct access to source documents (patient medical records, charts, laboratory reports etc.). 
Patient confidentiality will be protected at all time. 
18.2
Case Report Forms 
The CRF and the protocol are both confidential. The CRF will remain the property of the 
Sponsor at all time. 
The Sponsor will supply the CRFs. The original is to be returned to the Sponsor and a 
copy left with the Investigator. 
All CRFs are to be completed by the examining personnel and reviewed and signed by 
the Investigator(s). 
All CRFs are to be completed in a neat, legible manner to ensure accurate 
interpretation of data. The CRF must be completed in black pen to ensure clarity of 
any reproduced copy of all CRFs. 
Any changes or corrections made on the CRFs must be dated and initialled by the 
person making the changes. In such cases, the best procedure is to cross out the 
original entry using a single line. DO NOT ERASE, OVERWRITE, OR USE LIQUID 
PAPER ON ORIGINAL CRF ENTRIES. 
It is each Investigator¶s responsibility to ensure that all DISCONTINUED orders or 
changes in the study or other medications entered on the patient¶s CRF correspond to 
entries in the patient medical records. 
CRFs for any patient leaving the study should be completed at the time medication is 
terminated for whatever reason. 
CRFs must accurately reflect data contained in the patient¶s medical records (e.g. 
source documents). 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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18.3
Case Report Form (CRF) Handling 
The main objective is to obtain those data required by the study protocol in a complete, 
accurate, legible, and timely fashion. The data in the CRF should be consistent with the 
relevant source documents. 
The data recorded in the course of this study must be documented in the CRFs and must be 
forwarded to the Sponsor or designee. They shall then be processed, evaluated, and stored in 
anonymous form in accordance with the data-protection regulations. 
The Investigator must ensure that the CRFs forwarded to the Sponsor or designee and any 
other associated documents contain no mention of any patient names.  
The CRFs must be filled in completely and legibly (with either black or blue ballpoint pen, 
acceptable for use on official documents). Any amendments and corrections necessary must 
be undertaken and countersigned by the Investigator or designee, stating the date of the 
amendment/correction. Errors must remain legible and may not be deleted with correction 
aids (e.g., Tipp-Ex®). The patient¶s medical source documents must support any changes 
made. 
In the case of missing data/remarks, the entry spaces provided for in the CRF should be 
cancelled out so as to avoid unnecessary follow-up inquiries. The CRFs are regulatory 
documents and must be suitable for submission to authorities. 
18.4
Source Data and Patient Files 
The Investigator has to keep a written or electronic patient file for every patient participating 
in the clinical study. In this patient file, the available demographic and medical information of 
a patient has to be documented, in particular the following: name, date of birth, sex, height, 
weight, patient history, concomitant diseases and concomitant medication (including changes 
during the study), statement of entry into the study, study identification, randomisation 
number, the date of informed consent, all study visit dates, pre-defined performed 
examinations and clinical findings, observed AEs (if applicable) and reason for withdrawal 
from study treatment or from the study (if applicable). It should be possible to verify the 
inclusion and exclusion criteria for the study from the available data in this file. It must be 
possible to identify each patient by using this patient file. 
Additionally, any other documents with source data, especially original printouts of data that 
were generated by technical equipment have to be filed. This may include laboratory value 
listings, ECG recordings, X-rays, CT scans, etc. (if applicable). All these documents have to 
bear at least the patient identification and the printing date printed by the recording device to 
indicate to which patient and to which study procedure the document belongs. The medical 
evaluation of such records should be documented as necessary and signed/dated by the 
Investigator. 
Printouts of computerised patient files must be signed and dated by the Investigator, 
countersigned by the monitor, and kept with the Investigator¶s copy of the CRF as a source 
document. 
 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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18.5
Investigator File and Archiving 
The Investigator will be provided with an Investigator¶s file at the start of the study. This file 
contains all relevant documents necessary for the conduct of the study. This file must be 
safely archived after termination of the study. 
It is the responsibility of the Investigator to ensure that the patient identification sheets are 
stored according the ICH-GCP and European Union Directive 2002/58/EC (see Section 21). 
All original patient files must be stored for the longest possible time permitted by the 
regulations at the hospital, research institute, or practice in question. If archiving can no 
longer be maintained at the site, the Investigator will notify the Sponsor. 
18.6
Monitoring, Quality Assurance, and Inspection by Authorities 
This study is to be conducted in accordance with ICH E6. The appointed clinical monitor will 
arrange regular visits to the trial centre(s) to check progress with the study and to collect 
completed CRFs. 
During monitoring visits, the monitors will: 
Help resolve any problems 
Examine all CRFs for omission of data, compliance and possible AEs 
Discuss inconsistencies in the trial data 
Ensure that all trial materials are correctly stored and dispensed 
Check adherence to the obligations of the Investigator 
Review consent forms, in particular the date of consent and signature 
Perform source data verification as described below 
In line with ICH E6, monitoring will include verification of data entered in the CRF against 
original patient records. This verification will be performed by direct access to the original 
patient records, and the Sponsor guarantees that patient confidentiality will be respected at all 
times. Participation in this study will be taken as agreement to permit direct source data 
verification. 
In addition, the representatives of the Sponsor¶s Quality Management department, their 
appointed monitoring organisations, and regulatory authorities are permitted to inspect the 
study documents (study protocol, CRFs, IMP, original medical records/files). All patient data 
shall be treated confidentially. 
In the course of the clinical study, the CRFs shall be forwarded to the Sponsor after 
completion of the individual sections (e.g., visits) of the study. The study protocol, each step 
of the data-recording procedure, and the handling of the data as well as the study report shall 
be patient to the review of the Sponsor¶s independent clinical Quality Management 
department. Audits can be conducted to assure the validity of the study data. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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18.7
Completing, Signing, and Archiving CRFs 
All materials or supplies provided by the Sponsor will be returned to the Sponsor upon study 
completion. The Investigator will notify the EC when the study has been completed. 
The Investigator must keep a separate patient identification list showing code numbers, 
names, and dates of birth to allow unambiguous identification of each patient included in the 
study. A note will be made in the hospital medical records that the patient is participating in a 
clinical study. The CRF will be completed legibly in black ball-point pen, with reasons given 
for missing data. 
The statement on the last page of the CRF will be signed by the Principal Investigator. Any 
used supplemental page will be signed by the Investigator. Corrections to the data will be 
made in a manner that does not obscure the original entry and will be dated and initialled by 
the Investigator or assigned designee. 
Because it is extremely important to have proper data collection in a timely manner, the 
Investigator shall complete the CRFs and continually deliver them to the monitor. When the 
monitor requests additional data or clarification of data for the CRF, the request must be 
answered satisfactorily before the next monitoring visit. 
18.8
Data Management and Data Control 
The Sponsor will be responsible for the processing and quality control of the data. Data 
management and filing will be carried out as described in the Sponsor's SOPs for clinical 
studies. 
Source data, source documents, CRFs, copies of protocols and protocol amendments, drug 
accountability forms, correspondence, patient identification lists, informed consent forms, and 
other essential documents must be retained for a period of 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/institution when these documents need no longer to 
be retained. 
The original CRFs will be archived by the Sponsor for the lifetime of the product. No study 
document or image should be destroyed without prior written agreement between the Sponsor 
and the Investigator. Should the Investigator wish to assign the study records to another party 
or move them to another location, advance written notice should be given to the Sponsor. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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19.
FINANCING AND INSURANCE 
A separate financial agreement (Clinical Investigators' Agreement) will be made between 
each Principal Investigator and the Sponsor before the investigational product is delivered. 
PARI Pharma GmbH has insurance coverage for study related IMP-induced injury and other 
liabilities incurred during clinical studies which will provide compensation for any study 
related injury according to the guidelines set out by the Association of the British 
Pharmaceutical Industry (ABPI), namely ³Clinical Studies Compensation for Medicine 
Induced Injury´. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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20.
REPORTING AND PUBLICATION OF RESULTS 
After conclusion of the study, an integrated clinical and statistical study report shall be written 
by the Sponsor or designee in consultation with the coordinating Investigator. The first 
publication will be a full publication of all data from all sites. Any publications of the results, 
either in part or in total (abstracts in journals or newspapers, oral presentations, etc.) by 
Investigators or their representatives will require pre-submission review by the Sponsor. The 
Sponsor is entitled to delay publication in order to obtain patent protection. For more details 
regarding publications, refer to the clinical study agreement/Investigator study agreement. 
The final report will be signed by the Sponsor and the Principal Investigator with the highest 
recruitment of evaluable patients. 
The result of the study will be published and/or presented in scientific meetings in a timely 
manner. Any formal publication of study will be a collaborative effort between the Sponsor 
and the Investigator(s). All manuscripts and abstracts will be reviewed and approved in 
writing by the Sponsor prior to submission.  
Policies regarding the publication of the study results are defined in the clinical Investigator's 
agreement. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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21.
ARCHIVING AND DATA RETENTION 
All study documents should be retained until at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product, in accordance with the 
European Union Directive 2002/58/EC. These documents should be retained for a longer 
period however, if required by regulatory requirements or by agreement with the Sponsor. It 
is the responsibility of the Sponsor to inform the Investigator/Institution as to when these 
documents no longer need to be retained. 
The final database will be archived by the Sponsor according to regulatory requirements. 
 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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22.
REFERENCES 
 
1. Armengot M, Juan G, Barona R, et al. Immotile cilia syndrome. Nasal mucociliary 
function and nasal ciliary abnormalities. Rhinology 1994; 32:109-111. 
2. Baraniu J, Maibach H. Pathophysiological classification of chronic rhinosinusitis. 
Respir Res 2005; 6:149. 
3. Bhattacharyya T, Piccirillo J, Wippold FJ. Relationship between patients-based 
descriptions of sinusitis and paranasal sinus computed tomographic findings. Arch
Otolaryngol Head Neck Surg 1997; 123:1189-92. 
4. Clement PA. Definitions of sinusitis. Acta Otorhinolaryngol Belg 1997; 51:201-3. 
5. Fokkens W, Lund V, Mollol J, et al. The European Position Paper of Rhinosinusitis 
and Nasal Polyps (EP3OS) group. Rhinology 2007; 45, Suppl. 20:1-137. 
6. Hopkins C, Browne DW, Slack R, et al. The Lund-Mackay staging system for chronic 
rhinosinusitis: How is it used and what does it predict? Otolaryngol Head Neck Surg 
2007; 137: 555-561. 
7. Mainz J, Mentzel HJ, Schneider G, et al. Sinu-nasal inhalation of Dornase alfa in CF. 
Results of a double-blind placebo-controlled pilot trial. J Cystic Fibrosis 2008; 7:S27. 
8. Min YG, Shin JS, Choi SH, et al. Primary ciliary dyskinesia. Ultrastructural defects 
and clinical features. Rhinology 1995; 33:189-193. 
9. Möller W, Schuschnig U, Meyer G, et al. Ventilation and drug delivery to the 
paranasal sinuses: studies in a nasal cast using pulsating airflow. Rhinology 2008; 46. 
10. Möller W, Schuschnig U, Meyer G, et al. Ventilation and aerosolized drug delivery to 
the paranasal sinuses using pulsating airflow ± a preliminary study. Rhinology 2009; 
47:405-412. 
11. Möller W, Schuschnig U, Saba GK, et al. Pulsating aerosols for drug delivery to the 
sinuses in healthy volunteers. Otolaryngology-Head and Neck Surgery 2010; 142: 
382-388. 
12. Penttila M, Poulsen P, Hollingworth K, et al. Dose-related efficacy and tolerability of 
fluticasone propionate nasal drops 400µg once daily and twice daily in the treatment 
of bilateral nasal polyposis: a placebo-controlled randomized study in adult patients. 
Clin Exp Allergy 2002; 30:94-102. 
13. Piccirillo J, Edwards D, Haiduk A, et al. Psychometric and clinimetric validity of the 
31-item Rhinosinusitis Outcome Measure (RSOM-31). Am J Rhinol 1995; 9:297-306. 
14. Rasp G, Kramer MF, Ostertag P, et al. Ein neues System zur Einteilung der 
Siebbeinpolyposis. Laryngo-Rhino-Otol 2000; 79:266-272. 
15. Sato Y, Hyo N, Sato M, et al. Intra-nasal distrubition of aerosols with or without 
vibration. Z Erkr Atmungsorgane 1981; 157:276-280. 
16. Stewart MH, Sicard MW, Piccirillo FJ, et al. Severity staging in chronic sinusitis: are 
CT scan findings related to patient symptoms? Am J Rhinol 1999; 13:161-7 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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17. Van Cauwenberge P, Watelet JB. Epidemiology of chronic rhinosinusitis. Thorax 
2000; 55:20S-1. 
18. Wabnitz DA, Nair S, Wormald PJ. Correlation between preoperative symptom scores, 
quality-of-life questionnaires, and staging with computed tomography in patients with 
chronic rhinosinusitis. Am J Rhinol 2005; 19:91-6. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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23.
APPENDIX I – CORE INFORMED CONSENT FORM 
The informed consent form must be adapted to local requirements but must contain at least 
the following points: 
That the trial involves research. 
The purpose of the trial. 
The trial treatment(s) and the probability for random assignment to each treatment. 
The trial procedures to be followed, including all invasive procedures. 
The patient¶s responsibilities. 
Those aspects of the trial that are experimental. 
The reasonably foreseeable risks or inconveniences to the patient and, when 
applicable, to an embryo, foetus, or nursing infant. 
The reasonably expected benefits. When there is no intended clinical benefit to the 
patient, the patient should be made aware of this. 
The alternative procedure(s) or course(s) of treatment that may be available to the 
patient, and their important potential benefits and risks. 
The compensation and/or treatment available to the patient in the event of trial related 
patient injury. 
The anticipated prorated payment, if any, to the patient for participating in the trial. 
The anticipated expenses, if any, to the patient for participating in the trial. 
That the patient¶s participation in the trial is voluntary and that the patient may refuse 
to participate or withdraw from the trial, at any time, without penalty or loss of 
benefits to which the patient is otherwise entitled. 
That the monitor(s), the auditor(s), the EC, and the regulatory authority(ies) will be 
granted direct access to the patientµs original medical records for verification of 
clinical trial procedures and/or data, without violating the confidentiality of the 
patient, to the extent permitted by the applicable laws and regulations and that, by 
signing a written informed consent form, the patient or the patientµs legally acceptable 
representative is authorizing such access. 
That records identifying the patient will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. If the results of the trial are published, the patient¶s identity will remain 
confidential. 
That the patient or the patient¶s legally acceptable representative will be informed in a 
timely manner if information becomes available that may be relevant to the patientµs 
willingness to continue participation in the trial. 
The person(s) to contact for further information regarding the trial and the rights of 
trial patients, and whom to contact in the event of trial-related injury. 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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The foreseeable circumstances and/or reasons under which the patient¶s participation 
in the trial may be terminated. 
The expected duration of the patient¶s participation in the trial. 
The approximate number of patients involved in the trial. 
 


 
Buparid in CRS with Polyposis nasi                                                                        EudraCT No.: 2013-002414-12 
 
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24.
APPENDIX II – ACCEPTABLE METHODS OF CONTRACEPTION 
According to the EMEA guideline 286/95, the following methods are allowed for 
contraception during the clinical trial with a failure rate of less than 1%: 
contraceptive implant 
injectable or patch hormone therapy 
combine oral contraceptives and barrier methods 
intrauterine device (IUD) 
sexual abstinence 
surgical sterilisation of the female or male partner 
 
In principle, pregnancy and the lactation period are exclusion criteria. In the event of a 
pregnancy occurring during the course of the study, the patient must be withdrawn from all 
IMP treatment immediately. The Investigator should report pregnancy cases occurring during 
the clinical trial to SGS Life Science Services Medical Affairs immediately using the SAE 
form. PARI Pharma GmbH must be notified without delay. Pregnancy cases will be followed-
up during the entire course of the pregnancy and postpartum period using SGS Life Science 
Services Drug Exposure during Pregnancy ± Pregnancy Form A and End of Pregnancy ± 
Pregnancy Form B. Parental and neonatal outcomes must be recorded even in they are 
completely normal and without AEs. The SAE reporting procedure should be followed, even 
though pregnancy is not considered a SAE. No ³serious criterion´ should be checked. The 
SAE report form is solely used to ensure expedited reporting. 

SAP_001.pdf: