Clinical trial NCT04123405
Conditions: Rhinosinusitis
Keywords: acute uncomplicated rhinosinusitis, acetylcysteine
Sponsor: Sandoz
Start date: 2020-10-22; Completion date: 2021-04-20
Enrollment: 944 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The trial was conducted as a prospective, randomized, multinational, multicenter, double-blind study in 4 parallel groups of patients.

Detailed description:
The study was the prospective, randomized, multinational, multicenter, double-blind study in 4 parallel groups of patients.

Patients underwent screening examinations at Visit 1. Patients who met all inclusion/ no exclusion criteria were randomized at the baseline visit (Day 1) to the double-blind treatment for a duration of 14 days but in case of delayed final visit (Day 15) the patient could voluntarily take reserve study medication for a maximum of 3 additional days.

After the end of the double-blind treatment phase, the patients underwent an end-of-treatment (EOT) examinations on Day 15 (+3).

A follow-up phone call within 7 days after Day 15 (or earlier in case of premature termination) was performed.

Arms: arm 1: one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily) arm 2: two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily) arm 3: four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily) arm 4: four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
Interventions: intervention 1: acetylcysteine intervention 2: Placebo
Intervention descriptions: intervention 1: 600 mg tablet intervention 2: Placebo to acetylcysteine

Protocol documents:
Prot_000.pdf: 
Official Title: 
Efficacy and Safety of Acetylcysteine for the Treatment of Acute 
Uncomplicated Rhinosinusitis: a Prospective, Randomized, Double-blind, 
Placebo-controlled Trial 
NCT Number: 
NCT04123405 
Document Date: 
Clinical Study Protocol Version 5: 14 August 2020 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 1 of 82 
 
CONSOLIDATED VERSION OF 
TRIAL PROTOCOL AFTER AMENDMENT 5.0 
TITLE 
Efficacy and safety of acetylcysteine for the treatment 
of acute uncomplicated rhinosinusitis: a prospective, 
randomized, double-blind, placebo-controlled trial 
 
 
Release date of protocol: 
24-Apr-2019 
Document status: 
Version Final 2.0 
Release date of consolidated version of 
protocol after Amendment 1.0: 
(GERMANY ONLY) 
 
23-Aug-2019 
 
Version Final 3.0 
Release date of consolidated version of 
protocol after Amendment 2.0: 
(BULGARIA AND MOLDOVA ONLY) 
 
10-Sep-2019 
 
Version Final 4.0 
Release date of consolidated version of 
protocol after Amendment 3.0: 
(RUSSIA ONLY) 
 
10-Oct-2019 
 
Version Final 5.0 
Release date of consolidated version of 
protocol after Amendment 4.0: 
(MOLDOVA ONLY) 
 
01-Nov-2019 
 
Version Final 6.0 
Release date of consolidated version of 
protocol after Amendment 5.0: 
(BULGARIA ONLY) 
 
14-Aug-2020 
 
Version Final 5.0 
 
 
Development phase: 
III 
 
 
CONTRACT RESEARCH ORGANIZATION: 
SPONSOR: 
 
  
 
 
 
Phone: 
Fax:
HEXAL AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
Phone:
Fax:
 
 
 
Trial No.: 
EudraCT No.: 
HEXAL AG 
 
2018-08-EFT-1 
2019-000060-20 
 
 
C1018001 
 
 
 
Project Management and Sponsor 
Representative: 
Project Management and Sponsor 
Representative: 
Lek Pharmaceuticals d.d. 
Lek Pharmaceuticals d.d. 
 
 
, PhD 
Lek Pharmaceuticals d.d. 
Verovškova 57 
1526 Ljubljana 
Slovenia 
Phone: 
 
Email: 
 
Lek Pharmaceuticals d.d. 
Verovškova 57 
1526 Ljubljana 
Slovenia 
Phone 
 
Mobile:
 
 
 
 
In Case of any Serious Adverse Event or Emergency, please refer to the contact data in section 9.3.5. 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to investigators, potential 
investigators, ethics committees and regulatory authorities. No disclosure should take place without the written authorization 
from HEXAL AG, except to the extent necessary to obtain informed consent from potential patients. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 2 of 82 
1 
Signatures of Coordinating Investigator and Other 
Parties Involved 
1.1 
Coordinating Investigator 
I, herewith, confirm that the trial protocol contains all the information and rules 
necessary to conduct the study according to Good Clinical Practice (GCP) and 
that the trial “Efficacy and safety of acetylcysteine for the treatment of acute 
uncomplicated rhinosinusitis: a prospective, randomized, double-blind, placebo-
controlled trial” will be carried out and documented in complete compliance with, 
the national laws and regulations and the Declaration of Helsinki and the GCP 
guideline.  
I recognize that all information concerning this trial is not previously published 
and is a confidential information. This includes the SmPC, trial protocol, case 
report forms, assay methods, technical methodology, and scientific data. 
The investigators will be informed about the pharmacological/toxicological tests 
and all new knowledge about the IMP as well as about any newly occurring, 
hitherto unknown adverse reactions of the test IMPs as soon as the information is 
available. 
I recognize that any changes in the protocol must be approved in writing by the 
coordinating investigator, principal investigator(s), HEXAL AG or its 
representative Lek Pharmaceuticals d.d., the Ethics Committee (IEC/IRB) and 
national regulatory authority before implementation except when necessary to 
eliminate immediate hazards to the subjects.  
By my signature below, I hereby certify that I have more than 2 years of 
experience in the conduct of clinical studies and that I have read, understood and 
agree to abide by all conditions, instructions, and restrictions contained in the 
protocol number 2018-08-EFT-1/C1018001 dated 14-Aug-2020 and also that I 
was trained in the sponsor’s serious adverse event (SAE) and pregnancy 
reporting obligations. 
 
 
Name:  
 
 
 
Address:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone: 
 
 
Fax: 
 
 
Email: 
 
 
 
 
_____________________________________________ 
Signature of Coordinating Investigator, Date 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 3 of 82 
1.2 
Principal Investigator 
I, herewith, confirm that the trial “Efficacy and safety of acetylcysteine for the 
treatment of acute uncomplicated rhinosinusitis: a prospective, randomized, 
double-blind, placebo-controlled trial” will be carried out and documented in the 
CRFs in complete compliance with the national laws and regulations and the 
Declaration of Helsinki and the Good Clinical Practice (GCP) guideline.  
I recognize that all information concerning this trial is not previously published 
and is a confidential information. This includes the SmPC, trial protocol, case 
report forms, assay methods, technical methodology, and scientific data. 
I recognize that any changes in the protocol must be approved in writing by the 
coordinating investigator, principal investigator(s), HEXAL AG or its 
representative Lek Pharmaceuticals d.d., Ethics Committee (IEC/IRB) and 
national regulatory authority before implementation except when necessary to 
eliminate immediate hazards to the subjects.  
By my signature below, I hereby certify that I have more than 2 years of 
experience in the conduct of clinical studies and that I have read, understood and 
agree to abide by all conditions, instructions, and restrictions contained in the 
protocol number 2018-08-EFT-1/C1018001 dated 14-Aug-2020 and also that I 
was trained in the sponsor’s serious adverse event (SAE) and pregnancy 
reporting obligations. 
 
Name:  
 
 
 
…………………………………………………. 
Name of Clinical Center:  
…………………………………………………. 
 
 
 
 
 
………………………………………………….. 
Address of Clinical Center: 
…………………………………………………. 
 
 
 
 
 
………………………………………………….. 
 
 
 
 
 
………………………………………………….. 
 
 
 
 
 
………………………………………………….. 
Phone: 
 
 
 
…………………………………………………. 
Fax: 
 
 
 
…………………………………………………. 
Email: 
 
 
 
…………………………………………………. 
 
 
_____________________________________________ 
Signature of Principal Investigator, Date 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 4 of 82 
1.3 
Sub-Investigator 
I, herewith, confirm that the trial “Efficacy and safety of acetylcysteine for the 
treatment of acute uncomplicated rhinosinusitis: a prospective, randomized, 
double-blind, placebo-controlled trial” will be carried out and documented in 
complete compliance with, the national laws and regulations and the Declaration 
of Helsinki and the Good Clinical Practice (GCP) guideline.  
I recognize that all information concerning this trial is not previously published 
and is a confidential information. This includes the SmPC, trial protocol, case 
report forms, assay methods, technical methodology, and scientific data. 
I recognize that any changes in the protocol must be approved in writing by the 
coordinating investigator, principal investigator(s), HEXAL AG or its 
representative Lek Pharmaceuticals d.d., Ethics Committee (IEC/IRB) and 
national regulatory authority before implementation except when necessary to 
eliminate immediate hazards to the subjects. 
By my signature below, I hereby certify that I have more than 2 years of 
experience in the conduct of clinical studies and that I have read, understood and 
agree to abide by all conditions, instructions, and restrictions contained in the 
protocol number 2018-08-EFT-1/C1018001 dated 14-Aug-2020 and also that I 
was trained in the sponsor’s serious adverse event (SAE) and pregnancy 
reporting obligations. 
 
Name:  
 
 
 
…………………………………………………. 
Name of Clinical Center:  
…………………………………………………. 
 
 
 
 
 
………………………………………………….. 
Address of Clinical Center: 
…………………………………………………. 
 
 
 
 
 
………………………………………………….. 
 
 
 
 
 
………………………………………………….. 
 
 
 
 
 
………………………………………………….. 
 
 
 
 
 
………………………………………………….. 
 
 
_____________________________________________ 
Signature of Investigator, Date 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 5 of 82 
1.4 
Contract Research Organization (CRO) 
 
 MD, PhD 
 
 
_____________________________________________ 
Signature, Date 
 
 
AUTHOR OF TRIAL PROTOCOL: 
 Dipl. Biol. 
 
 
_____________________________________________ 
Signature, Date 
 
 
 (Medical Expert): 
 MD, PhD 
 
 
_____________________________________________ 
Signature, Date 
 
 M.Sc. Biotech. 
 
 
_____________________________________________ 
Signature, Date 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 6 of 82 
, Dipl. Math. (FH) 
 
 
 
_____________________________________________ 
Signature, Date 
 
 
 Dipl. Biol., PhD 
 
 
 
_____________________________________________ 
Signature, Date 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 7 of 82 
1.5 
Project Management and Sponsor Representative 
 
Lek Pharmaceuticals d.d. 
 
 
 
_____________________________________________ 
Signature, Date 
 
 
 
 
Lek Pharmaceuticals d.d. 
, PhD 
 
 
_____________________________________________ 
Signature, Date 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 8 of 82 
1.6 
Trial Administrative Structure 
Sponsor: 
HEXAL AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
Phone: 
 
Fax: 
Project Management and 
Sponsor Representative, 
Lek Pharmaceuticals d.d. 
Verovškova 57 
1526 Ljubljana 
Slovenia 
Phone 
 
Mobile:
 
 
Project Management and 
Sponsor Representative, 
 
 
 PhD 
Lek Pharmaceuticals d.d. 
Verovškova 57 
1526 Ljubljana 
Slovenia 
Phone: 
 
Email:
 
 
Central CRO in Germany 
and Contract Partner to 
the Sponsor: 
  
 
 
 
Phone:
Fax:
 
of CRO: 
, MD, PhD 
  
 
, 
 
Phone: 
Fax: 
Email: 
 
 CRO/ 
Author of Trial Protocol: 
, Dipl. Biol. 
  
 
, 
 
Phone: 
 
Fax: 
 
Email: 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 9 of 82 
 
CRO (Medical Expert): 
, MD, PhD 
  
 
 
 
Phone: 
 
Fax:
 
Email:
 
CRO: 
, M.Sc. Biotech. 
  
 
, 
 
Phone:
 
Fax: 
 
Email:
 
 CRO: 
, Dipl. Math. (FH) 
  
 
 
 
Phone:
 
Fax: 
Email:
 
 
CRO: 
, 
 
  
 
 
 
Phone: 
 
Fax: 
 
Email: 
 
 
, Dipl. Biol., PhD 
  
 
 
 
Phone: 
 
Fax: 
 
Email: 
 
 
 
 
 
 
 
 
 
 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 10 of 82 
Local CRO in BULGARIA  
(on behalf of 
 
responsible for monitoring 
and submission to / 
correspondence with Ethics 
Committee and Regulatory 
Authority) 
 
 
 
Phone: 
Fax: 
Email:
 
 
Local CRO in MOLDOVA  
(on behalf of
responsible for monitoring 
and submission to / 
correspondence with Ethics 
Committee and Regulatory 
Authority) 
 
 
 
Mobile:
Mobile: 
Email:
 
Local CRO in RUSSIA  
(on behalf of 
 
responsible for monitoring 
and submission to / 
correspondence with Ethics 
Committee and Regulatory 
Authority) 
 
 
 
 
 
Phone: 
Email: 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 11 of 82 
2 
Trial Synopsis and Schedule of Assessments 
2.1 
Trial Synopsis 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
TITLE OF TRIAL 
Efficacy and safety of acetylcysteine for the treatment of acute 
uncomplicated rhinosinusitis: a prospective, randomized, double-blind, 
placebo-controlled trial 
TRIAL NUMBER 
2018-08-EFT-1 (sponsor) / C1018001 (CRO)  
PHASE 
Phase III 
INDICATION 
Acute uncomplicated rhinosinusitis 
TRIAL DESIGN 
Prospective, randomized, multinational, multicenter, double-blind study in 
4 parallel groups of patients 
PRIMARY OBJECTIVE 
To assess the efficacy of three different total daily doses of the 
investigational medicinal product containing 600 mg acetylcysteine per 
effervescent tablet compared to placebo for the treatment of acute 
uncomplicated rhinosinusitis. 
SECONDARY 
OBJECTIVES 
To assess the safety and tolerability of three different total daily doses of 
the investigational medicinal product containing 600 mg acetylcysteine 
per effervescent tablet compared to placebo for the treatment of acute 
uncomplicated rhinosinusitis. 
CONTRACT 
RESEARCH 
ORGANIZATION  
  
 
 
Phone: 
Fax: 
PLANNED SAMPLE 
SIZE 
Approximately 900 patients will be randomized in 4 different groups of 
approximately 225 subjects each: three different total daily doses of the 
test product, or placebo. 
SUBJECTS SELECTION 
CRITERIA 
Inclusion criteria: 
[1] 
Male or female subjects aged between 14 and 75 years inclusive 
on the date of consent 
[2] 
Diagnosis of acute, uncomplicated rhinosinusitis defined at 
screening Visit 1 and at Visit 2 as: 
a) 
major symptom score (MSS) assessed by the patient ≥8 and 
≤12 points for the following: rhinorrhea/ anterior discharge, 
postnasal drip, nasal congestion, headache, and facial 
pain/pressure, whereupon the nasal congestion is 
mandatory and no more than 3 of the 5 symptoms are rated 
as severe 
b) 
individual score for facial pain/pressure ≥1 (mild) and ≤2 
(moderate) 
c) 
presence of symptoms ≤3 days prior to screening visit 
[3] 
For adults (≥18 years): Informed consent to participate in the trial 
provided in written form;  


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 12 of 82 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
For adolescents (≥14 - <18 years): own subject informed consent/ 
assent to participate in the trial and the informed consent from all 
parent(s)/ legal guardian(s) provided in written form 
Exclusion/ Withdrawal Criteria 
[1] 
History of hypersensitivity or intolerance to the active substance or 
any of the excipients of the trial medication 
[2] 
Patient with history of hereditary fructose intolerance, galactose 
intolerance, lactase deficiency or glucose-galactose malabsorption 
[3] 
Chronic rhinosinusitis (symptoms lasting longer than 3 months) 
[4] 
Subjects who have undergone sinus or nasal surgery for chronic 
rhinosinusitis in the 6 months prior to screening visit 
[5] 
Sinus lavage within 7 days prior to screening visit 
[6] 
Odontogenic rhinosinusitis 
[7] 
Allergic (perennial or seasonal) rhinitis 
[8] 
Bronchial asthma or chronic obstructive pulmonary disease 
[9] 
Nasal polyposis or clinically relevant nasal septum deviation 
[10] 
Concomitant otitis 
[11] 
Intranasal or systemic use of corticosteroids within 30 days prior to 
screening visit 
[12] 
Intranasal or systemic use of antibiotics within 30 days prior to 
screening visit 
[13] 
Use of nasal decongestants within 2 days prior to screening visit 
[14] 
Concomitant treatment of common cold-like symptoms within 7 
days prior to screening visit with any of the following: 
a) 
Analgesics 
b) 
Non-steroidal anti-inflammatory drugs 
c) 
Antihistamines 
[15] 
Concomitant use of intranasal saline irrigation  
[16] 
Use of immunosuppressive agents within 30 days prior to 
screening visit 
[17] 
Immunocompromised state 
[18] 
Suspicion for acute bacterial rhinosinusitis (defined as presence of 
purulence for 3 to 4 days with fever ≥ 38.3°C) 
[19] 
Pregnant or breast-feeding female patient 
[20] 
Female patient of childbearing potential (not surgically sterilized/ 
hysterectomized or postmenopausal for at least 1 year) who is not 
currently using (documented at screening visit) and not willing to 
use medically reliable methods of contraception for the entire trial 
duration such as oral, injectable or implantable contraceptives, 
intrauterine contraceptive devices (IUD), sexual abstinence or 
vasectomized partner 
[21] 
Any other condition of the patient (e.g. serious or unstable medical 
or psychological condition, acute psychosis) that in the opinion of 
the investigator may compromise evaluation of the trial treatment 
or may jeopardize patient’s safety, compliance or adherence to 
protocol requirements 
[22] 
Participation in ANY research study involving another 
investigational medicinal product (IMP) within 30 days prior to 
screening visit, or simultaneous participation in another clinical 
study or previous participation in present study 
[23] 
Suspected alcohol/ drug dependence or abuse (including heavy 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 13 of 82 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
smoking: ≥ 20 cigarettes daily) 
[24] 
Use of snuff tobacco 
 
[25] 
Legal incapacity and/or other circumstances rendering the patient 
unable to understand the nature, scope and possible 
consequences of the trial 
[26] 
Subjects who are known or suspected: 
− 
not to comply with the trial directives 
− 
not to be reliable or trustworthy 
− 
to be a dependent person, e.g. a relative, family member, or 
member/ employee of the investigator’s or sponsor’s staff 
− 
subject is in custody or submitted to an institution due to a 
judicial order. 
CLINICAL TRIAL 
CENTERS 
Approximately 40 centers located in Germany, Bulgaria, Russia and 
Moldova. 
TEST PRODUCT 
Name: 
Acetylcysteine 600 mg effervescent tablet 
Marketing authorization  
holder in Germany: 
HEXAL AG 
Marketing authorization No: 
 
Formulation: 
effervescent tablet 
Active substance: 
acetylcysteine 
Strength: 
600 mg acetylcysteine per effervescent 
tablet 
Dosing schedule: 
over 14 days according to the 
randomized double-blind treatment (see 
randomization section) 
Route of administration: 
oral; tablets should be taken during the 
meal (breakfast or lunch) dissolved in a 
glass of water (about 200 mL). 
Manufacturer: 
 
PLACEBO TO TEST 
PRODUCT 
Name: 
Placebo 
Formulation: 
effervescent tablet 
Active substance/ Strength: none 
Dosing schedule: 
over 14 days according to the 
randomized double-blind treatment (see 
randomization section) 
Route of administration: 
oral, tablets should be taken during the 
meal (breakfast or lunch) dissolved in a 
glass of water (about 200 mL).  
Manufacturer: 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 14 of 82 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
BLINDING 
The present trial will be double-blind.  
 
The tablets containing the Test product and Placebo will be identical in 
their appearance and the labels will not contain any information about the 
identity of the respective product. 
 
To maintain blinding, all patients will receive 4 tablets per day (2 tablets 
in the morning and 2 tablets at noon) provided in a daily kit. 
RANDOMIZATION 
Patients will be allocated to identification numbers in sequential order 
according to their admission to the trial.  
 
Patients who meet the inclusion/ no exclusion criteria will be randomized 
to double-blind treatment with one of the following: 
 Group A: 600 mg acetylcysteine: one tablet test product plus 
three tablets placebo per day (to be taken as two tablets 
dissolved in a glass of water, twice daily) OR 
 Group B: 1200 mg acetylcysteine: two tablets test product plus 
two tablets placebo per day (to be taken as two tablets dissolved 
in a glass of water, twice daily) OR 
 Group C: 2400 mg acetylcysteine: four tablets test product per 
day (to be taken as two tablets dissolved in a glass of water, 
twice daily) OR 
 Group D: Placebo: four tablets placebo per day (to be taken as 
two tablets dissolved in a glass of water, twice daily).  
DURATION OF 
TREATMENT  
Patients will undergo screening examinations at Visit 1. 
 
Patients who meet all inclusion/ no exclusion criteria will be randomized 
at the baseline visit (Visit 2) to the double-blind treatment for a duration of  
14 days but in case of delayed final visit (Visit 6) the patient can 
voluntarily take reserve study medication for a maximum of 3 additional 
days. 
 
After the end of the double-blind treatment phase, the patients will 
undergo an end-of-treatment (EOT) examination at Visit 6 on Day 15 
(+3). 
 
A follow-up phone call within 7 days after Visit 6 (or earlier in case of 
premature termination) will be performed for all patients. 
CONCOMITANT 
MEDICATION/ OTHER 
THERAPEUTIC 
MEASURES 
Not allowed: 
• 
Intranasal or systemic use of corticosteroids within 30 days prior to 
screening visit and during the trial; 
• 
Intranasal or systemic use of antibiotics within 30 days prior to 
screening visit and during the trial;  
• 
Use of nasal decongestants within 2 days prior to screening visit and 
during the trial; 
• 
Concomitant treatment within 7 days prior to screening visit of 
common cold-like symptoms with any of the following: 
– 
Analgesics 
– 
Non-steroidal anti-inflammatory drugs 
– 
Antihistamines 
• 
Concomitant use of intranasal saline irrigation; 
• 
Use of immunosuppressive agents within 30 days prior to screening 
visit and during the trial. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 15 of 82 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
• 
Therapeutic measures available at home, e.g. infrared light, hot 
and/or warm pads/compresses, and home remedies, e.g. fragrance 
lamps with essential oils like rosemary, thyme eucalyptus and mint 
oil etc. 
 
Allowed: 
• 
Other long-term therapy for any chronic disease (if expected to 
remain stable for the duration of the entire trial). 
EFFICACY 
PARAMETERS 
Patient’s assessments: 
• 
Major Symptom Score (MSS):  
MSS will be assessed by the patient at screening (Visit 1) and 
immediately before randomization (Visit 2; this will constitute 
the baseline value). Both MSS assessments will be transcribed 
from the Trial Specific Source Form (TSSF) into the CRF.  
Thereafter, the patient will document the MSS in the patient diary 
once a day before the intake of the morning dose, starting with 
Day 2 until Day 14 (end of treatment or earlier in case of drop-
out).  
The last MSS will be will be assessed by the patient during Visit 
6 and transcribed into the CRF. 
• 
Sino-Nasal Outcome Test (SNOT-22) questionnaire: 
SNOT-22 will be assessed by the patient in the patient diary on 
Day 1, Day 7 and Day 14. 
Investigator’s assessments: 
• 
Investigator’s assessment of the overall response to 
treatment:  
The investigator will assess the overall response to treatment at 
each visit after baseline: on Day 4 (Visit 3), Day 7 (Visit 4), Day 
10 (Visit 5), and Day 15 (Visit 6). 
SAFETY PARAMETERS • 
Adverse events (AEs): AEs will be recorded by the investigator at 
each visit until the follow-up phone call (within 7 days after Visit 6 or 
earlier in case of premature termination). AEs will be assessed for 
seriousness, severity and drug-event relationship.  
• 
Vital signs: Blood pressure, pulse rate, and body temperature will 
be recorded at each visit: at screening (Visit 1), immediately before 
randomization (Visit 2; this will constitute the baseline value), and 
on Day 4 (Visit 3), Day 7 (Visit 4), Day 10 (Visit 5), and Day 15 (Visit 
6). 
• 
Safety laboratory: Hematology and blood chemistry at screening 
(Visit 1) and at Visit 6. 
In all female patients a serum pregnancy test for measurement of 
human chorionic gonadotropin (hCG) will be performed at screening 
(Visit 1) and at Visit 6. 
• 
Overall assessment of tolerability by the patient and by the 
investigator on Day 7 (Visit 4) and Day 15 (Visit 6). 
PRIMARY ENDPOINT 
Mean change from baseline in the daily MSS over the entire treatment 
period: 
 
1
14
෍൫𝑥𝑥𝑖𝑖−𝑥𝑥 𝐷𝐷𝐷𝐷𝐷𝐷 1 (𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏)൯ 
𝐷𝐷𝐷𝐷𝐷𝐷 15
𝑖𝑖=𝐷𝐷𝐷𝐷𝐷𝐷 2
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 16 of 82 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
SECONDARY 
ENDPOINTS 
• 
Time to onset of action defined as first day of active treatment on 
which MSS shows statistically significant difference from placebo 
• 
MSS development over the course of the study 
• 
SNOT-22 by visit and changes versus baseline 
• 
Percentage of responders and non-responders to treatment based 
on the assessment of overall response to treatment by the 
investigator. 
SAFETY ENDPOINTS 
• 
Incidence and severity of adverse events 
• 
Incidence and severity of drug-related adverse events 
• 
Clinically relevant changes in laboratory parameters, vital signs, 
physical and ENT examination parameters from Visit 1 to Visit 6 (or 
early termination)  
• 
Overall assessment of tolerability by patient and by investigator. 
DATASETS FOR 
STATISTICAL 
ANALYSIS 
• 
Safety Set: all randomized patients who received at least one dose 
of the trial medication. 
• 
Full-Analysis Set (FAS): all randomized patients who received at 
least one dose of the trial medication and who have at least one 
post-baseline assessment of MSS during the double-blind treatment 
period. 
• 
Per-Protocol Set (PPS): all FAS-evaluable patients who completed 
the double-blind treatment period without major protocol violations 
that could affect the efficacy evaluation. 
STATISTICAL 
ANALYSIS 
Efficacy: 
Efficacy of the test product will be shown by testing superiority of the 
three different doses in a hierarchical test procedure starting from the 
highest to the lowest dose compared to placebo. 
 
Hierarchical ordered hypotheses will be tested at the type I error rate of 
α=0.05 (two-sided) until the first non-rejection. No error rate adjustment is 
required. 
 
For the primary efficacy an endpoint analysis of covariance (ANCOVA) 
will be carried out using treatment and center as factors and baseline 
MSS as a covariate.  
 
The trial will be powered to demonstrate superiority of the test product 
over placebo in the primary efficacy endpoint. 
 
The confirmatory analysis of the primary endpoint will be performed in 
the FAS.  
 
In addition, the analyses used for the primary efficacy endpoint will be 
performed in the PPS. 
 
This analysis is intended to provide supportive evidence and will be 
considered descriptive. 
 
 
 
 
 
 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 17 of 82 
NAME OF COMPANY: 
 
HEXAL AG 
NAME OF INVESTIGATIONAL MEDICINAL 
PRODUCT (IMP): 
Acetylcysteine 600 mg effervescent tablet  
NAME OF ACTIVE 
INGREDIENT: 
acetylcysteine 
Safety: 
The Safety Set will be used for the analysis of the safety data. All safety 
data obtained in this trial will be tabulated descriptively with descriptive 
group statistics (mean, standard deviation, minimum, maximum, number 
of valid cases) where appropriate. This will include also the overall 
assessment of tolerability by the patient and by the investigator on Day 7 
(Visit 4) and Day 15 (Visit 6). 
 
AEs will be summarized by primary system organ class (SOC) and 
preferred term (PT). Severity and drug-event relationship of treatment 
emergent AEs are summarized separately. All adverse events will be 
listed. 
 
Vital signs, including changes from baseline will be summarized. A 
frequency table will be presented for abnormal values of laboratory 
parameters. 
CALCULATION OF 
SAMPLE SIZE 
The sample size is calculated in respect of the primary endpoint. For the 
calculation of sample size, the following parameters were taken into 
consideration based on data published by Jund et al. (2015)1: 
 
α 
 
 
 
= 0.05 (two-sided) 
ß 
 
 
 
= 0.20 (power = 80%) 
mean MSS change (test) 
= 5.4 
mean MSS change (placebo) 
= 4.5 
Standard deviation 
 
= 3.4 
Randomization ratio 
 
= 1 (1:1:1:1, 3 doses of test 
 
 
 
 
vs. placebo) 
Sample size per group:  
= 225 subjects 
The numbers above refer to the FAS. 
 
The number of patients to be randomized in each of the groups is 
approximately 225. The total number of patients to be randomized is thus 
equal to 900.  
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020 
CONFIDENTIAL 
page 18 of 82 
2.1 Flow Chart 
 
Double-blind Treatment Period 
 
 
 
 
 
 
 
 
 
 
Acetylcysteine 600 mg per day 
 
 
 
 
 
 
 
 
 
 
 
 
Acetylcysteine 1200 mg per day 
 
 
 
 
Screening 
Randomization  
 
 
 
 
 
Acetylcysteine 2400 mg per day 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
Day -1* 
Day 1 
Day 4 
Day 7 
Day 10 
Day 14 
Day 15 (+3) 
Follow-up 
Phone Call 
VISIT 1 
VISIT 2 
 
VISIT 3 
 
VISIT 4 
 
VISIT 5 
no visit 
 
VISIT 6 
 
SCREENING 
START OF 
TREATMENT 
In the morning 
between 7 and 9 
a.m. 
LAST DAY OF 
TREATMENT 
[but in case of delayed 
Visit 6 the patient can 
voluntarily take reserve 
study medication for a 
maximum of 3 additional 
days]  
within 7 days after 
Visit 6  
(or earlier in case 
of premature 
termination) 
 
 
* presence of symptoms ≤3 days prior to Visit 1 (screening) 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 10-Sep-2019 
CONFIDENTIAL 
page 19 of 82 
2.2 Planned Assessments 
Type of Assessment planned 
VISIT 1 
 
Day -1* 
 
SCREENING 
VISIT 2 
 
Day 1 
 
RANDOMIZATION 
VISIT 3 
 
Day 4 
VISIT 4 
 
Day 7 
VISIT 5 
 
Day 10 
VISIT 6 
 
Day 15 (+3)† 
FOLLOW-UP  
Phone Call 
 
within 7 days after Visit 6  
(or earlier in case of 
premature termination) 
Informed consent 
 
 
 
 
 
 
 
Demography 
 
 
 
 
 
 
 
Life style, habits 
 
 
 
 
 
 
 
Additional anamnestic information (last participation in 
any clinical trial, last administration of any investigational 
drug, allergy/ perennial or seasonal rhinitis, drug 
hypersensitivity or intolerance)  
 
 
 
 
 
 
 
Specific history (anamnesis) of acute rhinosinusitis 
 
 
 
 
 
 
 
MSS by Patient transcribed from TSSF into the CRF 
 
 
 
 
 
 
 
Check of MSS documentation in the patient diary‡ 
 
 
 
 
 
 
 
SNOT-22 questionnaire by Patient (documented in the 
diary) 
 
 (Day 1) 
 
 (Day 7) 
 
 (Day 14) 
 
Medical and surgical history (concomitant/ previous 
diseases and medications inclusive any treatment of 
rhinosinusitis, medical and other therapeutic measures) 
 
 
 
 
 
 
 
Changes of concomitant diseases/ medications and 
medical and other therapeutic measures 
 
 
 
 
 
 
 
Contraceptive method used by female patient 
 
 
 
 
 
 
 
 
* presence of symptoms ≤3 days prior to Visit 1 (screening) 
† End of Treatment on Day 14, but in case of delayed final visit (Visit 6) the patient can voluntarily take reserve study medication for a maximum of 3 additional days 
‡ MSS in the patient diary once a day before the intake of the morning dose, starting with Day 2 until Day 14 (end of treatment or earlier in case of drop-out) and for a 
maximum of 3 additional days 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 10-Sep-2019 
CONFIDENTIAL 
page 20 of 82 
Type of Assessment planned 
VISIT 1 
 
Day -1* 
 
SCREENING 
VISIT 2 
 
Day 1 
 
RANDOMIZATION 
VISIT 3 
 
Day 4 
VISIT 4 
 
Day 7 
VISIT 5 
 
Day 10 
VISIT 6 
 
Day 15 (+3)† 
FOLLOW-UP  
Phone Call 
 
within 7 days after Visit 6  
(or earlier in case of 
premature termination) 
Vital signs (blood pressure, pulse rate, body temperature) 
 
 
 
 
 
 
 
Physical examination per body system; general/ 
nutritional state 
 
 
 
 
 
 
 
Examination of nose, ears, mouth/throat (ENT) 
 
 
 
 
 
 
 
Safety laboratory examination of blood (hematology, 
blood chemistry) 
 
 
 
 
 
 
 
Serum pregnancy test (hCG) in all female patients 
 
 
 
 
 
 
 
Inclusion criteria 
 
 
 
 
 
 
 
Exclusion criteria 
 
 
 
 
 
 
 
RANDOMIZATION to double-blind treatment 
 
 
 
 
 
 
 
Dispensation of blinded medication  
 
 
 
 
 
 
 
Return and check of used blinded medication 
 
 
 
 
 
 
 
Dispensation of patient diary 
 
 
 
 
 
 
 
Return and check of patient diary 
 
 
 
 
 
 
 
Check of further patient eligibility 
 
 
 
 
 
 
 
Assessment of overall response to treatment by 
investigator 
 
 
 
 
 
 
 
Overall assessment of tolerability by patient 
 
 
 
 
 
 
 
Overall assessment of tolerability by investigator 
 
 
 
 
 
 
 
Adverse event questioning 
 
 
 
 
 
 
 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 21 of 82 
3 
Table of Contents 
TITLE PAGE ......................................................................................................................... 1 
1 
SIGNATURES OF COORDINATING INVESTIGATOR AND OTHER PARTIES 
INVOLVED ............................................................................................................... 2 
1.1 
COORDINATING INVESTIGATOR .......................................................................... 2 
1.2 
PRINCIPAL INVESTIGATOR ................................................................................. 3 
1.3 
SUB-INVESTIGATOR .......................................................................................... 4 
1.4 
CONTRACT RESEARCH ORGANIZATION (CRO) ................................................... 5 
1.5 
PROJECT MANAGEMENT AND SPONSOR REPRESENTATIVE .................................. 7 
1.6 
TRIAL ADMINISTRATIVE STRUCTURE .................................................................. 8 
2 
TRIAL SYNOPSIS AND SCHEDULE OF ASSESSMENTS ................................... 11 
2.1 
TRIAL SYNOPSIS ............................................................................................. 11 
2.1 
FLOW CHART .................................................................................................. 18 
2.2 
PLANNED ASSESSMENTS ................................................................................. 19 
3 
TABLE OF CONTENTS ......................................................................................... 21 
3.1 
FIGURES REFERRED TO IN THE TEXT................................................................ 23 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................ 24 
5 
ETHICAL AND LEGAL ASPECTS OF THE CONDUCT OF THE TRIAL .............. 25 
5.1 
INDEPENDENT ETHICS COMMITTEE (IEC) OR INSTITUTIONAL REVIEW BOARD (IRB)
...................................................................................................................... 25 
5.2 
REGULATORY AUTHORITIES ............................................................................. 26 
5.3 
PROTOCOL MODIFICATION ............................................................................... 26 
5.4 
PATIENT INFORMATION AND INFORMED CONSENT ............................................. 27 
5.5 
PATIENT INSURANCE ....................................................................................... 28 
5.6 
PATIENT’S CONFIDENTIALITY ........................................................................... 28 
6 
INTRODUCTION .................................................................................................... 29 
6.1 
ACUTE RHINOSINUSITIS ................................................................................... 29 
6.2 
MODE OF ACTION OF ACETYLCYSTEINE ............................................................ 30 
6.3 
CLINICAL USE OF ACETYLCYSTEINE FOR INDICATION SINUSITIS ......................... 31 
6.4 
PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES ............................... 32 
6.4.1 
Pharmacodynamics ....................................................................................... 32 
6.4.2 
Pharmacokinetics .......................................................................................... 32 
7 
TRIAL OBJECTIVES ............................................................................................. 34 
7.1 
PRIMARY OBJECTIVE ....................................................................................... 34 
7.2 
SECONDARY OBJECTIVES ................................................................................ 34 
8 
INVESTIGATIONAL PLAN .................................................................................... 35 
8.1 
OVERALL TRIAL DESIGN .................................................................................. 35 
8.2 
DISCUSSION OF THE TRIAL DESIGN AND RATIONALE.......................................... 35 
8.3 
BENEFIT-RISK EVALUATION ............................................................................. 38 
8.3.1 
Adverse Drug Reactions Described in the SmPC of Acetylcysteine 600 mg 
effervescent tablet ......................................................................................... 38 
8.4 
SELECTION OF TRIAL POPULATION ................................................................... 39 
8.4.1 
Inclusion Criteria ........................................................................................... 39 
8.4.2 
Exclusion/ Withdrawal  Criteria ..................................................................... 39 
8.4.2.1 
Other Conditions ........................................................................................... 41 
8.5 
TRIAL MEDICATION.......................................................................................... 41 
8.5.1 
Identity of Investigational Products ................................................................ 41 
8.5.1.1 
Test Product .................................................................................................. 41 
8.5.1.2 
Placebo to Test Product ................................................................................ 42 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 22 of 82 
8.5.2 
IMP Administration and Duration of Treatment .............................................. 42 
8.5.3 
Packaging and Labelling ............................................................................... 42 
8.5.4 
Methods of Assigning Patients to Treatment Group ...................................... 45 
8.5.5 
Blinding ......................................................................................................... 46 
8.5.6 
Storage and IMP Accountability .................................................................... 47 
8.5.7 
IMP Non-Conformances ................................................................................ 48 
8.5.8 
Prior and Concomitant Medication, Therapeutic Measures ........................... 48 
9 
TRIAL PROCEDURES .......................................................................................... 50 
9.1 
TRIAL SPECIFIC EFFICACY ASSESSMENTS ........................................................ 56 
9.2 
TRIAL SPECIFIC SAFETY ASSESSMENTS ........................................................... 57 
9.3 
ADVERSE EVENTS........................................................................................... 58 
9.3.1 
Definitions ..................................................................................................... 58 
9.3.2 
Severity of Adverse Events ........................................................................... 59 
9.3.3 
Relationship to the IMP ................................................................................. 59 
9.3.4 
Adverse Events Documentation .................................................................... 60 
9.3.5 
SAE Reporting .............................................................................................. 61 
9.3.6 
Emergency Unblinding for the Treatment of SAEs ........................................ 63 
9.3.7 
Pregnancies .................................................................................................. 63 
9.3.8 
IMP Related Complaints ................................................................................ 63 
9.3.9 
Special Case Scenarios ................................................................................ 64 
9.3.10 
Reconciliation ................................................................................................ 64 
9.3.11 
Investigator Training ...................................................................................... 64 
9.3.12 
Abnormal Clinical Laboratory Values ............................................................. 65 
9.3.13 
Safety Assessment ....................................................................................... 65 
9.4 
PREMATURE TRIAL DISCONTINUATION .............................................................. 65 
9.4.1 
Withdrawal of Patients................................................................................... 65 
9.4.2 
Replacement of Drop-Outs ............................................................................ 66 
9.4.3 
Premature Termination of the Trial ................................................................ 66 
9.5 
DATA QUALITY ASSURANCE............................................................................. 66 
9.5.1 
Monitoring ..................................................................................................... 66 
9.5.2 
Protocol Deviation Definition and Reporting .................................................. 67 
9.5.3 
Data Management ......................................................................................... 68 
9.5.4 
Auditing ......................................................................................................... 69 
9.5.5 
Quality Assurance System ............................................................................ 69 
10 
BIOMETRICS AND STATISTICAL ASPECTS ...................................................... 70 
10.1 
STATISTICAL ANALYSIS PLAN ........................................................................... 70 
10.2 
ENDPOINTS .................................................................................................... 70 
10.2.1 
Primary Endpoint ........................................................................................... 70 
10.2.2 
Secondary Endpoints .................................................................................... 70 
10.2.3 
Safety Endpoints ........................................................................................... 71 
10.3 
POPULATIONS FOR ANALYSIS .......................................................................... 71 
10.3.1 
Safety Set ..................................................................................................... 71 
10.3.2 
Full Analysis Set............................................................................................ 71 
10.3.3 
Per Protocol Set ............................................................................................ 72 
10.4 
STATISTICAL TESTS ........................................................................................ 72 
10.5 
CALCULATION OF SAMPLE SIZE ....................................................................... 73 
10.6 
CODING AND RANDOMIZATION ......................................................................... 73 
10.7 
DATA PRESENTATION ...................................................................................... 74 
10.8 
INTERIM EVALUATION ...................................................................................... 74 
11 
TRIAL DOCUMENTATION .................................................................................... 75 
11.1 
SOURCE DOCUMENTS ..................................................................................... 75 
11.2 
CASE REPORT FORM (CRF) ............................................................................ 76 
11.3 
PATIENT DIARY ............................................................................................... 76 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 23 of 82 
11.4 
INVESTIGATOR'S FILE ...................................................................................... 76 
11.5 
TRIAL MASTER FILE ........................................................................................ 76 
11.6 
FINAL REPORT ................................................................................................ 77 
11.7 
ARCHIVING ..................................................................................................... 77 
12 
QUALIFICATION OF THE INVESTIGATOR AND AGREEMENTS ....................... 78 
12.1 
QUALIFICATION OF THE COORDINATING INVESTIGATOR, PRINCIPAL INVESTIGATOR 
AND SUB-INVESTIGATOR(S) ............................................................................. 78 
12.2 
AGREEMENTS ................................................................................................. 78 
12.2.1 
Trial Initiation ................................................................................................. 78 
12.2.2 
Confidentiality ............................................................................................... 78 
12.2.3 
Investigator’s Signature ................................................................................. 79 
12.2.4 
Publication .................................................................................................... 79 
12.2.5 
Investigator Fee ............................................................................................ 79 
13 
REFERENCES ...................................................................................................... 80 
 
3.1 
Figures Referred to in the Text 
TF 1 
Composition of one patient kit ...................................................................... 44 
TF 2 
Composition of one daily kit ......................................................................... 45 
 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 24 of 82 
4 
List of Abbreviations and Definitions of Terms 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARS 
Acute rhinosinusitis 
ATC 
Anatomical therapeutic chemical classification system 
b.i.d 
Twice a day 
BDRM 
Blind Data Review Meeting 
CDMS 
Clinical data management system 
CHMP 
Committee for Medicinal Products for Human Use 
CIOMS 
Council for International Organizations of Medical Sciences 
COPD 
Chronic obstructive pulmonary disease 
CPMP 
Committee for Proprietary Medicinal Products 
CR 
Clinically relevant 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract research organization 
DMP 
Data management plan 
ENT 
Ears, Nose, Throat 
EOT 
End of treatment 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
ICH 
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC/ IRB 
Independent Ethics Committee/ Institutional Review Board 
IMP 
Investigational medicinal product 
ITF 
Investigator’s trial file 
MCH 
Mean corpuscular Haemoglobin 
MCHC 
Mean cell Haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mm 
Millimeter 
mmHg 
Millimeters of mercury 
MSS 
Major Symptom Score 
NA 
Not applicable 
NAC 
N-acetylcysteine 
NCR 
Not clinically relevant 
p. 
Page 
p.o. 
Oral 
PPS 
Per protocol set 
PT 
Preferred term 
QMD 
Quality management department 
RA 
Regulatory authority 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SmPC/SPC 
Summary of product characteristics 
SNOT 
Sino-Nasal Outcome Test (questionnaire) 
SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TSSF 
Trial Specific Source Form 
V 
Visit 
WHO 
World Health Organization 
WMA 
World Medical Association 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 25 of 82 
5 
Ethical and Legal Aspects of the Conduct of the 
Trial 
This trial will be conducted in accordance with the following: 
 
Declaration of Helsinki (1964) in the current amended version2 
 
ICH Topic E 6. GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2) Step 5 
(EMA/CHMP/ICH/135/1995)3 
 
ICH Topic E 8. Note for Guidance on General Considerations for Clinical Trials 
(CPMP/ICH/291/95)4 
 
ICH Topic E 9. Note for Guidance on Statistical Principles for Clinical Trials 
(CPMP/ICH/363/96)5 
 
ICH Topic E 3. Note for Guidance on Structure and Content of Clinical Study 
Reports (CPMP/ICH/137/95)6 
 Directive 2001/20/EC of the European Parliament and the Council of 4 April 
20017 
 Directive 2005/28/EC of the European Parliament and the Council of 8 April 
20058 
 
Detailed guidance on the request to the competent authorities for authorisation 
of a clinical trial on a medicinal product for human use, the notification of 
substantial amendments and the declaration of the end of the trial (CT-1) 
(2010/C 82/01)9 
 
Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinical trials on medicinal products for 
human use (‘CT-3’) (2011/C 172/01)10 
 
Regulation (EU) 2016/679 of the European Parliament and of the Council of 
27 April 2016 on the protection of natural persons with regard to the 
processing of personal data and on the free movement of such data, and 
repealing Directive 95/46/EC (General Data Protection Regulation)11 
 
Drug laws and regulations in the countries of the clinical centers involved 
 
 standard operating procedures (SOPs). 
5.1 
Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) 
Prior to the initiation of the trial, the protocol, the appropriate information about 
the active compound (e.g. investigator’s brochure or summary of product 
characteristics [SmPC]), the subject insurance cover, the curriculum vitae of the 
principal investigator(s), the subject information leaflet, the informed consent/ 
assent, and the CRF will be submitted to the IEC/IRB responsible for the principal 
investigator in the country of clinical center(s) for review and approval.  
The trial will only be performed when a full approval of this protocol has been 
obtained from the IEC/IRB in the country of the clinical center(s). 
Following approval by the IEC/IRB and regulatory authority (section 5.2) the trial 
can be initiated immediately after a copy of the ethics vote and the authority 
approval has been sent to the sponsor/its representative. A list of the members of 
the IEC/IRB will be attached to the copy of the approval. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 26 of 82 
In accordance with the national drug law all approvals needed for conducting the 
trial in the respective country will be obtained. 
5.2 
Regulatory Authorities 
Prior to the initiation of the trial all relevant documents as required by the national 
legislation will be submitted to the regulatory authority(ies) (RA) responsible for 
the trial approval in the respective country.  
In accordance with the national drug law all approvals needed for conducting the 
trial in the respective country will be obtained. 
5.3 
Protocol Modification 
Substantial amendments to the conduct of the clinical trial may arise from 
changes to the protocol or from new information related to the scientific 
background of the trial. 
All amendments must be discussed and signed by the sponsor/its representative, 
 and the coordinating investigator prior to implementation. 
Amendments to the trial are regarded as “substantial”5 where they are likely to 
have a significant impact on: 
 the safety or physical or mental integrity of the patients, or 
 the scientific value of the trial. 
In all cases, an amendment is only to be regarded as ‘substantial’ when one or 
both above criteria are met. 
When the sponsor/its representative intends to make a substantial amendment to 
the protocol that would meet the above-mentioned criteria, he should notify 
. The sponsor/its representative authorizes 
 to supervise 
all necessary notifications to the ECs and RAs and to receive all approvals 
needed before an amendment is implemented. 
Amendments which might have an impact on the safety, physical or mental 
integrity of the patients (and/or could influence on the patients’ decision to 
participate in the trial) require new patient information and a new informed 
consent/ assent form that is to be signed by all patients enrolled in the trial who 
are affected by the amendment.  
In case of minor changes to the protocol (administrative, logistical), the non-
substantial amendment will be prepared and signed by both 
 and 
sponsor or its representative. A written approval of sponsor/its representative 
before implementation is required, however not from ECs and RAs. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 27 of 82 
5.4 
Patient Information and Informed Consent 
Before being enrolled into the trial, patients must have consented to participate in 
response to a complete written and verbal explanation of the nature, scope and 
possible consequences of the trial by a physician in a form and language 
understandable to them. 
The patients must be able to understand the full implications of their decision. 
The patient information and informed consent will be prepared by 
 
and will be translated into the respective local language of the clinical center(s) 
whereby the translated documents will be used for confirmation of the patient's 
consent by the signature of the investigator, the patient and in case of 
adolescents by the signatures of the parent(s)/ guardian(s). 
For adult patients (≥18 years) the informed consent to participate in the trial 
must be provided in written form. 
For adolescent patients (≥14 - <18 years) the own subject informed 
consent/ assent to participate in the trial must be provided in written form 
with the mandatory written informed consent from all parent(s)/ legal 
guardian(s). 
The patient information and informed consent will explain the nature of the trial, 
its objectives and potential risks. Both the informed consent discussion and the 
written informed consent form and any other written information to be provided to 
patients will include explanations of the points mentioned in section 4.8.10 of the 
ICH Guidance on Good Clinical Practice E6(R2) (CPMP/ICH/135/95)3. 
Personal information will be treated as strictly confidential and will not be publicly 
available. 
As required by the ICH-GCP guideline, the patient authorizes in written form that 
the patient’s original medical records may be verified by the CRA(s), the 
auditor(s), and the regulatory authorities by direct access in accordance with the 
applicable laws and regulations. 
As required by the ICH-GCP guideline, the trial specific information for patients 
and informed consent will be received as one original and enough ample time will 
be given to the patients to read the document. The personally signed and dated 
original will remain with the investigator as part of the confidential data and will be 
kept there (in the ITF) for at least 25 years after the trial has been completed. A 
certified copy of the personally signed and dated original will be handed over to 
the patient. 
To ensure medical confidentiality and data protection, the patient identification 
and all other essential documents as addressed in chapter 8 of the ICH-GCP 
guideline will be located in the ITF and must be archived for at least 25 years 
after the trial has been completed (please refer to protocol sections 9.5.3, 11.1 
and 11.7).  
The individual medical health records/ files of the clinical center(s) shall be kept 
for the maximum period of time permitted by the national law of the country of the 
clinical center. Image carriers or other data carriers can be used for storage.  
The investigator will allow these documents to be inspected on request and will 
affirm - by signing and dating - in the case report forms that informed consent has 
been obtained before start of any trial-related procedure(s). 


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The investigator will not undertake any investigations specifically required only for 
the trial until valid consent has been obtained. 
5.5 
Patient Insurance 
Every subject is insured in accordance with the provisions of the national law of 
the countries involved against damage to health which might occur during the 
conduct of the clinical trial and the material damages which might occur in 
connection thereto.  
Excluded from the insurance cover are damages to health and worsening of 
previous existing diseases which would have occurred or continued if the patient 
had not taken part in the clinical trial. Following the clauses of the insurance, the 
insured patients are to be informed about the existence of the insurance contract.  
A copy of the insurance certificate will be filed in the investigator’s trial file (ITF). 
5.6 
Patient’s Confidentiality 
To maintain patient’s confidentiality, all data recorded during the trial will be 
identified by patient’s screening/ randomization number and patient’s date of 
birth. However, the investigator agrees to record the complete patient 
identification. This information will be treated with strict adherence to 
confidentiality and will be filed in the investigator’s trial file (ITF). 


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6 
Introduction 
6.1 
Acute Rhinosinusitis 
Acute rhinosinusitis (ARS) is a very common condition that is primarily 
managed in primary care. Prevalence rates vary from 6-15% depending on the 
study parameters, although studies specifying ARS report 6-12%, with a 
prevalence of recurrent ARS estimated at 0.035%. 
The primary causes of ARS are viruses with 0.5-2.0% of patients developing 
acute bacterial rhinosinusitis secondary to a viral infection. Prevalence of ARS 
varies with season (higher in the winter months) and climatic variations, and 
increasing with a damp environment and air pollution (European Position Paper 
on Rhinosinusitis and Nasal Polyps; Fokkens et al., 201212). 
ARS in adults is defined as: 
Sudden onset of two or more symptoms: 
 nasal blockage/ obstruction/ congestion 
 or nasal discharge (anterior/posterior nasal drip) 
 ± facial pain/pressure 
 ± reduction or loss of smell  
for <12 weeks. 
ARS can be sub-divided into “acute viral rhinosinusitis (synonymous with 
“common cold”), in which the duration of symptoms is less than 10 days, usually 
a self-limiting condition that frequently does not present to clinicians, and “acute 
post-viral rhinosinusitis”, defined by an increase in symptoms after 5 days or 
persistence beyond 10 days. 
Typical symptoms of spontaneous rhinovirus infections peak at days 2 to 3 and 
wane thereafter but may persist 14 days or longer. Symptoms of viral 
rhinosinusitis may persist for longer than 10 days, but they gradually decrease in 
severity (see figure below taken from Rosenfeld et al., 201513; US Clinical 
Practice Guideline on Adult Sinusitis). 
 


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According to the German Society of General Practice/Family Medicine (DEGAM, 
201714), viral rhinosinusitis episodes are clinically cured after a maximum of three 
weeks. 
A clinician should diagnose acute “bacterial” rhinosinusitis (ABRS) when 
symptoms or signs of acute rhinosinusitis persist without evidence of 
improvement for at least 10 days beyond the onset of upper respiratory 
symptoms. 
Fever is present in some patients with viral rhinosinusitis in the first few days of 
illness but does not predict bacterial infection as an isolated diagnostic criterion. 
Fever has a sensitivity and specificity of only about 50% for ABRS. 
Adjunctive treatments for rhinosinusitis that may aid in symptomatic relief include 
analgesics, decongestants (α-adrenergic), corticosteroids, saline irrigation, and 
mucolytics. None of these products has been specifically approved by the FDA 
for use in ARS (as of March 2014), and only some have data from controlled 
clinical studies supporting this use. Moreover, existing trials often include co-
interventions and a heterogeneous population of patients with viral, recurrent 
bacterial, chronic, and allergic rhinosinusitis. 
With regard to mucolytics the “European Position Paper on Rhinosinusitis and 
Nasal Polyps12” states: 
“Mucolytics are used as adjuncts to antibiotic and/or decongestant treatment in 
ARS in order to reduce the viscosity of sinus secretion. Although some drugs 
have been shown to have mucolytic effect and were recommended as adjunct 
treatment for ARS, the benefit of such treatment is not clear due to the lack of 
standardization in pharmacodynamic and pharmacokinetic properties of these 
drugs, and also double-blinded, placebo-controlled (DBPC) randomized studies 
to prove their efficacy. In future, more standardization of mucolytics and larger 
scale DBPC randomized studies still need to be done in order to fully assess the 
efficacy of mucolytics in the treatment of ARS.”  
This position is also transparent in the current guideline on rhinosinusitis of the 
“German Society of General Practice/Family Medicine” (DEGAM, 2017), stating 
that mucolytics like acetylcysteine or ambroxol are commonly used as adjunctive 
therapies, although the benefit of these medications lacks clinical evidence. 
6.2 
Mode of Action of Acetylcysteine 
Acetylcysteine (NAC) is the N-acetyl derivative of the amino acid L-cysteine and 
a precursor in the formation of the antioxidant glutathione in the body. The thiol 
(sulfhydryl) group confers antioxidant effects and is able to reduce free radicals. 
The mucolytic activity of NAC is considered to be dual in origin:  
(1) its sulfhydryl group breaks the disulfide bonds between the 
mucopolysaccharide fibers, and  
(2) disrupts polymerization bonds of DNA fibers (in purulent mucus).  
These mechanisms are thought to decrease the viscosity of the mucus. 
Oral preparations containing up to 600 mg of NAC as a single dose have been 
marketed by pharmaceutical companies within the EU to a large extent for many 
decades, with recognized efficacy and proven safety in the mucolytic treatment of 
lower respiratory pathologies such as acute and chronic bronchitis and related 
diseases. 


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6.3 
Clinical Use of Acetylcysteine for Indication Sinusitis  
Pharmacotherapeutic group: Cough and cold preparations; Mucolytics (SmPC 
ACETYLCYSTEINE 600 MG EFFERVESCENT TABLET15) 
ATC code: R05CB01 
Therapeutic indications: Secretolytic therapy in acute and chronic 
bronchopulmonary diseases accompanied by impaired formation and transport of 
mucus in adults and adolescents from 14 years of age.15  
The upper and the lower respiratory tracts constitute a continuum, in particular 
with respect to the histological structure of the epithelium and of the secretory 
cells. There is parallelism in the pathologies of upper and lower airways:  
Thus we find comparable symptoms of cellular inflammation with a predominance 
of eosinophilia in bronchial asthma and allergic rhinitis.  
Likewise, there are analogies between acute and chronic bronchitis and 
rhinosinusitis, in which the neutrophilic inflammation is predominant.  
Given the well-established use of acetylcysteine in bronchitis, it makes sense to 
pursue this therapeutic approach in rhinosinusitis as well. Indeed the first clinical 
investigations were reported more than 50 years ago. In a study of 32 sinusitis 
patients treated with a NAC solution administered by sinus irrigations, the authors 
concluded that NAC is an effective mucolytic agent (Komet et al.16, 1965). About 
20 years later Boner et al. (1984)17 conducted a study in children for the 
treatment of sinusitis with NAC administered intramuscularly in combination with 
an antibiotic. In a publication by Zeiger (1992)18 on “Prospects for ancillary 
treatment of sinusitis in the 1990s” the author stated that based on the apparent 
efficacy and relative safety of oral NAC in chronic bronchitis, “controlled” trials 
investigating its use in the treatment of chronic sinusitis should be encouraged. 
However also a more recently published phase 3 study in the indication of 
recurrent acute sinusitis did not meet the expectations for a recommendation of 
mucolytics in the current treatment guidelines for rhinosinusitis. This study, 
reported by Macchi et al. (2012)19, employed only a single-blind design and NAC 
or the comparator substance were given in addition to the basic therapy of a 
nasal corticosteroid. Besides a very small sample size, a study reported by 
Bahtouee et al. (2017)20 revealed even more weaknesses by adding NAC to 
amoxicillin-clavulanic acid, pseudoephedrine, and intranasal normal saline. 
Hence to the best of our knowledge the proposed randomized controlled trial 
represents the first investigation to assess the efficacy and safety of NAC in 
rhinosinusitis according to current regulatory requirements.


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6.4 
Pharmacodynamic and Pharmacokinetic Properties 
6.4.1 Pharmacodynamics 
Data from the Summary of Product Characteristic (SmPC).15 
Acetylcysteine is a derivative of the amino acid cysteine. The efficacy of 
acetylcysteine is secretolytic and secretomotoric in the area of the respiratory 
tract. It is discussed that it splits off the interconnecting disulphide bonds between 
the mycopolysaccharide chains and that it has a depolymerizing effect on DNA-
chains (in purulent mucus). Due to these mechanisms, the viscosity of mucus 
should be reduced.  
An alternative mechanism of acetylcysteine is meant to be based on the capacity 
of its reactive SH group to bind chemical radicals and to detoxify them in this 
way. 
Furthermore, acetylcysteine contributes to an increase in glutathione synthesis, 
which is important for the detoxification of noxae. This provides the explanation 
for its antidotal effect in paracetamol intoxication.  
A protective effect on the frequency and severity of bacterial exacerbations – 
when acetylcysteine is administered prophylactically - is described in patients 
with chronic bronchitis/mucoviscidosis.  
6.4.2 Pharmacokinetics 
Absorption15 
Following oral administration, acetylcysteine is rapidly and almost completely 
absorbed and metabolized in the liver to cysteine, the pharmacologically active 
metabolite, as well as to diacetylcystine, cystine and further mixed disulphides. 
Distribution15 
Due to the high first-pass effect, the bioavailability of orally administered 
acetylcysteine is very low (approx. 10%). In humans, maximum plasma 
concentrations are achieved after 1-3 hours with the maximum plasma 
concentration of the metabolite cysteine in the range of approx. 2 μmol/l. The 
protein binding of acetylcysteine was determined to be about 50%. 
Biotransformation15 
Acetylcysteine and its metabolites occur in three different forms in the organism: 
partially in free form, partially bound to proteins via labile disulphide bonds and 
partially as incorporated amino acid. Acetylcysteine is excreted almost 
exclusively in the form of inactive metabolites (inorganic sulphates, 
diacetylcystine) via the kidneys. The plasma half-life of acetylcysteine is 
approximately 1 hour and is mainly determined by the rapid hepatic 
biotransformation. Impaired hepatic function therefore leads to prolonged plasma 
half-lives of up to 8 hours.


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Elimination15 
Pharmacokinetic studies with intravenous administration of acetylcysteine 
revealed a distribution volume of 0.47 l/kg (in total) or 0.59 l/kg (reduced); the 
plasma clearance was determined to be 0.11 l/h/kg (in total) and 0.84 l/h/kg 
(reduced), respectively. The elimination half-life after intravenous administration 
is 30-40 minutes while excretion follows three-phase kinetics (alpha, beta, and 
terminal gamma phase). 
Acetylcysteine crosses the placenta and is detected in cord blood. No information 
is available regarding excretion into breast milk. 
No knowledge is available concerning the behaviour of acetylcysteine at the 
blood-brain barrier in humans. 


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7 
Trial Objectives 
7.1 
Primary Objective 
The primary objective of the present trial is the assessment of the efficacy of 
three different total daily doses of the investigational product containing 600 mg 
acetylcysteine per effervescent tablet compared to placebo for the treatment of 
acute uncomplicated rhinosinusitis. 
7.2 
Secondary Objectives 
The secondary objective of the present trial is the assessment of safety and 
tolerability of three different total daily doses of the investigational product 
containing 600 mg acetylcysteine per effervescent tablet compared to placebo for 
the treatment of acute uncomplicated rhinosinusitis. 


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8 
Investigational Plan 
8.1 
Overall Trial Design 
The trial will be conducted as a prospective, randomized, multinational, 
multicenter, double-blind study in 4 parallel groups of patients.  
Approximately 900 patients with acute, uncomplicated rhinosinusitis will be 
randomized.  
8.2 
Discussion of the Trial Design and Rationale 
The test product (Acetylcysteine 600 mg effervescent tablet) is registered in 
many EU as well as non-EU countries for the secretolytic therapy in acute and 
chronic bronchopulmonary diseases.  
The primary aim of this trial is to assess the efficacy of three different total daily 
doses of the investigational product containing 600 mg acetylcysteine per 
effervescent tablet compared to placebo for the treatment of acute uncomplicated 
rhinosinusitis. 
The trial design was chosen according to the recommendation of the current 
guidelines EMA/CHMP/ICH/135/19953 and CPMP/ICH/291/954. 
Choice of a double-blind design: Such design has been selected as the 
blinding of the study personnel and patients is important to reduce any risk of the 
bias in trial where the outcome efficacy and safety assessments of investigator/ 
patient can be affected by the type of the IMP administered. 
Male and female subjects (patients) with the diagnose of acute, 
uncomplicated rhinosinusitis defined by the investigator at screening (Visit 1) 
as a) major symptom score (MSS) assessed by the patient ≥8 and ≤12 points21, 22 
for the following: rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, 
headache, and facial pain/pressure, whereupon the nasal congestion is 
mandatory and no more than 3 of the 5 symptoms are rated as severe; b) 
individual score for facial pain/pressure ≥1 (mild) and ≤2 (moderate), and c) 
presence of symptoms ≤3 days prior to inclusion will be enrolled in the present 
trial. 
Choice of duration of treatment: Taking into consideration that a randomized, 
placebo-controlled trial investigating the clinical efficacy of a dry extract of five 
herbal drugs (BNO 1060) in acute viral rhinosinusitis (Jund et al., 2015)1 showed 
statistically significant and clinically relevant improvements in symptoms by end 
of treatment (14 days) compared to placebo, a 2 weeks treatment phase was 
chosen for the current trial. 
The assessment of efficacy and safety of the treatments will be performed before 
the first dose and after 3, 6, 9, and 14 days of treatment. 
Choice of endpoints: For evaluation of efficacy, the disease activity will be 
assessed by the defined Major Symptom Score (MSS) and Sino-Nasal Outcome 
Test (SNOT-22) questionnaire and based on the clinical evaluation of patient-
reported relief of symptoms before and during the treatment.


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The primary endpoint corresponds to improvements of the clinical condition as 
defined by the decrease in MSS. Safety will be based on all information available 
on patient’s reports of AEs, vital signs, clinical findings and ENT examination, and 
overall assessment of tolerability. Adverse events will be recorded by the 
investigator at each visit until the follow-up phone call (within 7 days after Visit 6, 
or earlier in case of premature termination). 
Safety of higher doses of N-acetylcysteine (NAC): 
Not only the NAC doses proposed in this study (up to 1200 mg per intake and up 
to 2400 mg as total daily dose), but also higher single and/or daily doses have 
been used in a number of controlled studies in patients with chronic bronchitis 
and for numerous other indications. 
These indications, for example, include other pathologies involving the pulmonary 
system, such as idiopathic pulmonary fibrosis (Meyer et al. 1994 23, Demedts et 
al. 200524) or fibrosing alveolitis (Behr et al. 199725), from which a similar safety 
profile can be derived as with lower oral daily doses. 
As an outcome of a meta-analysis reported by Cazzola et al. (2015)26 the authors 
concluded that in COPD with an objective confirmation of airway obstruction, 
NAC should be administered at a dose of ≥1200 mg per day to prevent 
exacerbations. 
Further evidence for the safety of doses of 1200 mg twice daily can be derived 
from the use of NAC in the treatment of other non-airway-related pathologies:  
 Paracetamol poisoning 
In paracetamol poisoning, NAC has been regularly administered in doses far 
beyond 2400 mg per day. The standard antidote for acetaminophen toxicity has 
been oral NAC with a loading dose of 140 mg/kg, followed by 17 doses of 70 
mg/kg every 4 hours (Smilkstein et al. 198827). This corresponds to a daily dose 
of 39200 mg for 70 kg of body weight. 
 Contrast-induced nephropathy (CIN)  
Richter et al.28 recently presented an overview of 17 clinical studies on the use of 
NAC for CIN in more than 2000 patients. The study medication ranged mostly 
from 600 mg b.i.d. to 1500 mg b.i.d orally administered. The authors concluded 
that the low incidence of adverse events associated with NAC forms the basis of 
its recommendation in the guidelines (Richter and Crannage 201528). This 
conclusion is likewise supported by a similar systematic review and meta-
analysis by Kang et al. (2015)29, who analyzed 20 randomized controlled studies 
involving 3466 subjects (1756 assigned to NAC). Subjects received either 2400 
mg/d p.o. or 2400 ± 2000 mg while in one of the studies the dose was even 
10000 mg. In CIN the cumulative NAC doses and routes of administration may 
also reach 6000 mg p.o. as reviewed by Trivedi et al. (2009)30. These authors 
suggested that in patients at risk of CIN, it is prudent to prescribe NAC 1200 mg 
orally twice per day for 48 hours without raising any safety concerns. 
 Neuropsychiatric disorders 
In a comprehensive review, Deepmala et al. (2015)31 analyzed the state of 
scientific knowledge for the use of NAC in treating psychiatric and neurological 
disorders. A total of 65 publications met the inclusion and exclusion criteria for 
the systematic review. 


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The number of patients under high-dose NAC was over 1400, the oral dose 
regimen ranged from 1200 mg/d up to 6000 mg/d, and the duration of studies 
from 16 days to 60 months. Most of the studies used the dose around 2000–2400 
mg per day, which appeared to be effective and well tolerated, with no significant 
between-group differences observed in most of the controlled trials. 
Gastrointestinal symptoms were the most common adverse events, including 
mild abdominal pain, mild abdominal discomfort, heartburn, flatulence, cramps, 
nausea, vomiting, and diarrhea. 
These results have been confirmed in a recent review by Ooi et al. (2018)32 
concluding that oral NAC is safe and well tolerated without any considerable 
adverse effects. Current evidence supports its use as an adjunctive therapy for 
psychiatric conditions, administered concomitantly with existing medications, with 
a recommended dosage between 2000 and 2400 mg per day. 
 Cardioprotection  
A meta-analysis investigating whether NAC can prevent postoperative atrial 
fibrillation (POAF) after cardiac surgery examined 10 randomized controlled trials 
enrolling a total of 1026 patients. The dose regimen included, among others, 
1200 mg b.i.d. p.o. In one of the trials the total dose of NAC administered 
intravenously over a period of 24 hours was 300 mg/kg, corresponding to 21000 
mg for a person with 70 kg body weight. In this meta-analysis, NAC had a 
generally good safety profile, with no statistical difference being found when 
compared with control groups (Liu et al., 2014)33.  
 Systemic lupus erythematosus  
In a randomized, double-blind, placebo-controlled study, a total of 36 patients 
with systemic lupus erythematosus received either daily placebo or 1200, 2400 or 
4800 mg of NAC p.o. for 3 months. NAC dosages up to 2400 mg daily were well 
tolerated by all patients (Lai et al. 2012)34. 
 
Summarizing this body of evidence, it can be stated that the intake of 1200 mg 
acetylcysteine given as 2 tablets of 600 mg twice daily (for a total of 2400 mg 
daily) over a short period of 14 days appears to pose no safety risk. 
This conclusion holds true for adults as well as for adolescents, based on 
recently published studies. A randomized controlled trial of pharmacotherapy for 
cannabis dependence in 116 adolescents revealed that the NAC dose of 1200 
mg twice daily over 8 weeks was well tolerated, with minimal adverse events 
(Gray et al. 2012)35. Similarly, Ghanizadeh et al. (2017)36 demonstrated NAC to 
be an effective add-on to citalopram in improving resistance/ control to 
compulsions in children and adolescents with obsessive-compulsive disorder in a 
double-blind, placebo-controlled trial with 34 pediatric patients. Significant 
reduction in the score of resistance/control to obsessions was detected in the 
intervention group after supplementing with NAC (titrated up to 2400 mg/day) for 
10 weeks. NAC was well tolerated and the rates of adverse effects were not 
different between NAC and placebo groups. 


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8.3 
Benefit-Risk Evaluation 
8.3.1 Adverse Drug Reactions Described in the SmPC of 
Acetylcysteine 600 mg effervescent tablet 
Data from the Summary of Product Characteristic (SmPC)15 
The evaluation of undesirable effects is based on the following information on 
frequencies:  
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). 
 
Immune system 
disorders 
Uncommon 
Very rare 
Hypersensitivity reactions 
Anaphylactic shock, 
anaphylactic / 
anaphylactoid reactions 
Nervous system Disorders 
Uncommon 
Headache 
Cardiac disorders 
Uncommon 
Tachycardia 
Vascular disorders 
Uncommon 
Very rare 
Hypotension 
Hemorrhage 
Respiratory, thoracic and 
mediastinal disorders tract 
Rare 
Dyspnea, bronchospasm – 
predominantly in patients 
with hyperreactive 
bronchial system in case of 
bronchial asthma 
Gastrointestinal 
disorders 
Uncommon 
 
 
Rare 
Stomatitis, abdominal pain, 
nausea, vomiting, and 
Diarrhoea 
Dyspepsia 
Skin and subcutaneous 
tissue disorders 
Uncommon 
Urticaria, rash, 
angioedema, itching, 
exanthema 
Ear and labyrinth disorders 
Uncommon 
Tinnitus 
General disorders and 
administration site 
conditions 
Uncommon 
Not known 
Fever 
Facial enema 
 
A very rare occurrence of serious skin reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported in temporal 
association with the use of acetylcysteine. In most of these cases reported at 
least one other drug was administered at the same time, which may have 
possibly enhanced the described mucocutaneous effects. 
In case of recurrence skin and mucosal lesions, medical advice should be sought 
at once and the use of acetylcysteine terminated immediately. 
In addition, the occurrence of hemorrhages in association with the administration 
of acetylcysteine has very rarely been reported, partially with hypersensitivity 
reactions. A decreased blood platelet aggregation in the presence of 
acetylcysteine has been confirmed by various studies. The clinical relevance has 
not yet been clarified to date. 


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8.4 
Selection of Trial Population 
8.4.1 Inclusion Criteria 
Only patients fulfilling all of the following criteria should be randomized in the 
present trial: 
[1] 
Male or female subjects aged between 14 and 75 years inclusive on the 
date of consent 
[2] 
Diagnosis of acute, uncomplicated rhinosinusitis defined at screening Visit 
1 and at Visit 2 as: 
a) major symptom score (MSS) assessed by the patient  
≥8 and ≤12 points for the following: rhinorrhea/ anterior discharge, 
postnasal drip, nasal congestion, headache, and facial pain/pressure, 
whereupon the nasal congestion is mandatory and no more than 3 of the 
5 symptoms are rated as severe 
b) individual score for facial pain/pressure ≥1 (mild) and ≤2 (moderate) 
c) presence of symptoms ≤3 days prior to screening visit 
[3] 
For adults (≥18 years): Informed consent to participate in the trial provided 
in written form; For adolescents (≥14 - <18 years): own subject informed 
consent/ assent to participate in the trial and the informed consent from all 
parent(s)/ legal guardian(s) provided in written form. 
8.4.2 Exclusion/ Withdrawal* Criteria 
Patients presenting with any of the following criteria will not be included in the 
trial: 
[1] 
History of hypersensitivity or intolerance to the active substance or any of 
the excipients of the trial medication 
[2] 
Patient with history of hereditary fructose intolerance, galactose 
intolerance, lactase deficiency or glucose-galactose malabsorption 
[3] 
Chronic rhinosinusitis (symptoms lasting longer than 3 months) 
[4] 
Subjects who have undergone sinus or nasal surgery for chronic 
rhinosinusitis in the 6 months prior to screening visit 
[5] 
Sinus lavage within 7 days prior to screening visit 
[6] 
Odontogenic rhinosinusitis 
[7] 
Allergic (perennial or seasonal) rhinitis 
[8] 
Bronchial asthma or chronic obstructive pulmonary disease 
[9] 
Nasal polyposis or clinically relevant nasal septum deviation 
[10] Concomitant otitis 
[11] Intranasal or systemic use of corticosteroids within 30 days prior to 
 
* Withdrawal criteria: exclusion criteria registered starting with Day 1 (Visit 2) and thereafter. Additional 
withdrawal conditions are specified in protocol section 9.4.1. 


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screening visit 
[12] Intranasal or systemic use of antibiotics within 30 days prior to screening 
visit 
[13] Use of nasal decongestants within 2 days prior to screening visit 
[14] Concomitant treatment of common cold-like symptoms within 7 days prior 
to screening visit with any of the following: 
a) 
Analgesics 
b) 
Non-steroidal anti-inflammatory drugs 
c) 
Antihistamines 
[15] Concomitant use of intranasal saline irrigation  
[16] Use of immunosuppressive agents within 30 days prior to screening visit 
[17] Immunocompromised state 
[18] Suspicion for acute bacterial rhinosinusitis (defined as presence of 
purulence for 3 to 4 days with fever ≥ 38.3°C) 
[19] Pregnant or breast-feeding female patient 
[20] Female patient of childbearing potential (not surgically sterilized/ 
hysterectomized or postmenopausal for at least 1 year) who is not currently 
using (documented at screening visit) and not willing to use medically 
reliable methods of contraception for the entire trial duration such as oral, 
injectable or implantable contraceptives, intrauterine contraceptive devices 
(IUD), sexual abstinence or vasectomized partner 
[21] Any other condition of the patient (e.g. serious or unstable medical or 
psychological condition, acute psychosis) that in the opinion of the 
investigator may compromise evaluation of the trial treatment or may 
jeopardize patient’s safety, compliance or adherence to protocol 
requirements 
[22] Participation in ANY research study involving another investigational 
medicinal product (IMP) within 30 days prior to screening visit, or 
simultaneous participation in another clinical study or previous participation 
in present study 
[23] Suspected alcohol/ drug dependence or abuse (including heavy smoking: 
≥ 20 cigarettes daily) 
[24] Use of snuff tobacco 
[25] Legal incapacity and/or other circumstances rendering the patient unable to 
understand the nature, scope and possible consequences of the trial 
[26] Subjects who are known or suspected: 
− 
not to comply with the trial directives 
− 
not to be reliable or trustworthy 
− 
to be a dependent person, e.g. a relative, family member, or member/ 
employee of the investigator’s or sponsor’s staff 
− 
subject is in custody or submitted to an institution due to a judicial order. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 41 of 82 
8.4.2.1 
Other Conditions 
Disease(s) present at screening (Visit 1) is regarded as concomitant disease 
and will be carefully documented in the CRF and assessed by the investigator in 
context of the exclusion/ withdrawal criteria listed in section 8.4.2. 
Disease(s) occurred within the last 6 months and stopped prior to screening Visit 
1 is regarded as previous disease and will be carefully documented in the CRF 
and assessed by the investigator in context of the exclusion/ withdrawal listed in 
section 8.4.2. 
Disease(s) newly occurring during the trial (intercurrent disease) or any 
aggravation of a pre-existing (concomitant) disease will be regarded as 
Adverse Event (AE) and will be documented on the CRF pages for 
documentation of the concomitant disease(s) and in the AE form.  
If medically required in respect of the patient’s safety, the patient is to be 
withdrawn from the trial and the "protocol for termination of the trial" will be filled 
in by the investigator. 
8.5 
Trial Medication 
8.5.1 Identity of Investigational Products 
8.5.1.1 
Test Product 
Name: 
Acetylcysteine 600 mg effervescent tablet15 
Marketing authorization  
holder in Germany: 
HEXAL AG 
Marketing authorization No: 
 
Formulation: 
effervescent tablet 
Active substance: 
acetylcysteine 
Excipients: 
 
 
 
 
 
 
 
 
 
Strength: 
600 mg acetylcysteine per effervescent tablet 
Dosing schedule: 
over 14 days according to the randomized 
double-blind treatment (see randomization 
section) (please refer to 8.5.4) 
Route of administration: 
oral; tablets should be taken during the meal 
(breakfast or lunch) dissolved in a glass of 
water (about 200 mL). 
Manufacturer: 
 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 42 of 82 
8.5.1.2 
Placebo to Test Product 
Name: 
Placebo 
Formulation: 
effervescent tablet 
Active substance: 
none 
Excipients: 
 
 
Strength: 
none 
Dosing schedule: 
over 14 days according to the randomized 
double-blind treatment (see randomization 
section) (for details please refer to 8.5.4) 
Route of administration: 
oral; tablets should be taken during the meal 
(breakfast or lunch) dissolved in a glass of 
water (about 200 mL) 
Manufacturer: 
 
8.5.2 IMP Administration and Duration of Treatment 
Patients will undergo a screening visit (Visit 1) within one day prior to 
randomization (Visit 2 or baseline visit).  
Patients who meet the inclusion/ no exclusion criteria will be randomized to one 
of the following double-blind treatment on Day 1 (Visit 2): 
 Group A: 600 mg acetylcysteine: one tablet test product plus three tablets 
placebo per day (to be taken as two tablets dissolved in a glass of water, 
twice daily) OR 
 Group B: 1200 mg acetylcysteine: two tablets test product plus two tablets 
placebo per day (to be taken as two tablets dissolved in a glass of water, 
twice daily) OR 
 Group C: 2400 mg acetylcysteine: four tablets test product per day (to be 
taken as two tablets dissolved in a glass of water, twice daily) OR 
 Group D: Placebo: four tablets placebo per day (to be taken as two tablets 
dissolved in a glass of water, twice daily). 
The IMP treatment period will last for 14 days but in case of delayed final 
visit (Visit 6) the patient can voluntarily take reserve study medication for a 
maximum of 3 additional days. The double-blinded medication will be 
dispensed to the patients on Day 1 (Visit 2). 
The route of administration of the trial medication is described in sections 8.5.1.1 
and 8.5.1.2. 
8.5.3 Packaging and Labelling 
 (subcontracted by HEXAL AG) will pack 
and supply the trial medication together with sealed envelopes for unblinding in 
case of emergency. 
Packaging, labelling and blinding will be according to GMP requirements, 
international and national laws and regulations.  


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 43 of 82 
The master labels will be prepared in English and translated into the respective 
local language(s). 
 will ship the trial medication (in boxes of 4 
patient kits inclusive emergency envelopes) to the respective central depot in the 
countries involved (see below). 
Germany 
 
  
 
 
Contact person: 
 
Phone.:
 
mobile:
 
Email:
 
Bulgaria 
 
 
  
 
 
 
Contact person: 
 
mobile: 
 
email: 
 
Russia 
 
 
 
 
Phone: 
 
Contact persons 
  
Phone: 
 (ext. 
  
Fax: 
  
mobile: 
 
E-mail:
 
, 
  
Phone:
(ext.
  
Fax: 
  
mobile: 
 
Email:
 
Moldova 
 
 
 
  
 
Contact person:  
 
mobile: 
 
Email: 
 
 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 44 of 82 
The randomized Patient Kit (box) carrying a tear-off label will include 14 
Daily Kits (numbered 1-14) and one separate color-coded box with 3 
Replacement/ Reserve Daily Kits (numbered 1-3). The composition of one 
Patient Kit (box) is presented in TF 1.  
Each Daily Kit and the Replacement/Reserve Daily Kits will contain 2 tablets 
for the morning intake and 2 tablets for the noon intake. The composition of one 
Daily Kit is presented in TF 2. 
The Replacement medication (in case of lost or damaged IMP) or the 
Reserve medication (in case of delayed final visit will be provided for 3 
days and the voluntary use of this reserve medication will be documented 
in the patient diary.  
The Patient Kit (box) will be handed out to the patient on Visit 2 by the 
investigator. 
 
 
TF 1 
Composition of one patient kit 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 45 of 82 
Upper panel: Wallet with 2 tablets (1 and 2) for one dose, labeled on the back side for morning or noon. 
 
 
 
Lower panel: 2 wallets (for morning and noon dose) packed in one daily kit. 
 
TF 2 
Composition of one daily kit 
8.5.4 Methods of Assigning Patients to Treatment Group 
The trial medication will be pre-labelled in accordance with the randomization list 
(see section 10.6).  
The patients will be assigned a unique per site 3-digit screening number 
reflecting the order in which screening took place at the clinical center. 
At Visit 2 all patients eligible for randomization will be assigned a unique  
4-digit randomization (patient) number, which is printed on the labels of IMP 
patient kits provided to centers. Patients will be randomized to the double-blind 
treatment in one of the following four treatment groups: 
 Group A: 600 mg acetylcysteine: one tablet test product plus three tablets 
placebo per day (to be taken as two tablets dissolved in a glass of water, 
twice daily) OR 
 Group B: 1200 mg acetylcysteine: two tablets test product plus two tablets 
placebo per day (to be taken as two tablets dissolved in a glass of water, 
twice daily) OR 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 46 of 82 
 Group C: 2400 mg acetylcysteine: four tablets test product per day (to be 
taken as two tablets dissolved in a glass of water, twice daily) OR 
 Group D: Placebo: four tablets placebo per day (to be taken as two tablets 
dissolved in a glass of water, twice daily). 
The act of randomization is equivalent to assigning a randomization number to a 
patient during the Visit 2 and the administration of the first dose of IMP. 
8.5.5 Blinding 
The present trial will have a double-blind design for the whole duration of 
the trial (see section 10.6). 
At Visit 1 the patients will receive a “Trial Identity Card” which needs to be carried 
along for any case of emergency. 
The Test IMP and the Placebo will be identical in their appearance and the labels 
will not contain any information about the identity of the product.  
The investigator will be held blind and will receive one set of sealed emergency 
envelopes for each patient. Another set will be stored at the sponsor’s 
responsible pharmacovigilance function. The emergency envelopes contain 
information about the IMP identity according to the randomization schedule for 
each subject. The emergency envelope may only be opened in the case of 
necessary identification of the study medication. 
The emergency envelopes of all treated patients will be kept in the ITF during the 
study. The state of all emergency envelopes will be checked by the CRAs at each 
regular monitoring visit. 
Emergency unblinding of treatment assignment 
In an emergency, the code for each separate subject can be opened to identify 
the treatment given to that subject. The code is not to be opened for any reason, 
other than an emergency where unblinding is required for the medical 
management of the patient. Where possible, the clinical research manager (Lek 
Pharmaceuticals d.d.) and the project manager(s) at 
 have to be 
contacted before breaking the blind for any patient.  
When the investigator opens any individual code, he/ she must record the date 
and reason for breaking the code in the CRF. The investigator must also 
immediately inform the responsible persons, clinical research manager (Lek 
Pharmaceuticals d.d.) and the project manager(s) at 
 (see section 
9.3.6). 
Decoding by opening the emergency envelope leads to an immediate cessation 
of the trial for this patient but the subject should be followed until resolution of the 
(serious) adverse event.  
After completion of the clinical part, sealed emergency envelopes will be returned 
to central depot(s) along with the unused trial medication.


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 47 of 82 
8.5.6 Storage and IMP Accountability 
HEXAL will supply the study centers via central depots with the study medication 
and demonstration samples. Shipments from the central depot to study centers 
and transfers back to the central depot will be documented on shipment forms 
including shipment date, patient number, visit number, batch number, quantity of 
study medication or demonstration samples, date received and method of 
shipment and will be confirmed by the investigator with his/her signature (or by 
signature of designated personnel). A copy of this receipt form must be kept by 
the investigator and another copy will be stored in the TMF at 
. 
The investigator will be responsible for proper storage of the investigational 
medicinal products (IMPs) according to the temperature conditions printed on the 
medication labels, until the IMP dispensation to the patient. 
The IMPs have to be stored in the clinical center(s) according to the sponsor’s 
instruction printed on the labels. 
All IMPs must be stored separately from all other hospital/ practice stocks, locked 
and only accessible for authorized study personnel. Temperature monitoring has 
to be performed by means of electronic device in the clinical center and the 
temperature records must be monitored by the local CRAs.  
The trial medication will be provided by the sponsor in a sufficient quantity for the 
needs of the whole trial. The sponsor is responsible for keeping an appropriate 
amount of each trial medication to allow repeated pharmaceutical analysis.  
The patients will receive the trial medication for the IMP intake at home and will 
be informed to store the medication according to the sponsor’s instruction printed 
on the labels. The patients have to bring back on each visit the empty IMP 
packaging of used medication and the unused trial medication on Visit 6. 
All IMPs must be accounted for at the end of the trial. It is not allowed to use the 
trial medication for any other purpose. The receipt, dispensation to the patient 
and return of trial medication is to be documented by the investigator in an IMP 
accountability form and is to be monitored by the local CRAs in the respective 
countries. 
IMP destruction at the central depots or by a subcontracted company will be 
authorized by HEXAL/its representative. After completion of the destruction 
procedure the respective document(s) will be sent to the responsible Clinical 
Research Manager at Lek Pharmaceuticals d.d. for archiving in the TMF. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 48 of 82 
8.5.7 IMP Non-Conformances 
1. DEFINITIONS 
Non-conformances to the investigational medicinal product (Test product and 
Placebo) can include:  
1) Complaints connected to the quality of the product such as 
• 
any fault of quality and/or effectiveness e.g. change of visual 
appearance, change of amount, damaged tablets/capsules, 
presence of foreign matter. 
• 
any fault of the containers and outer packages e.g. surface 
imperfection, container leakage, missing contents. 
• 
any fault of the labelling e.g. missing or illegible label. 
• 
any falsification of the medicinal product e.g. suspected product 
mix-up, tampering or counterfeiting. 
2) Deviations connected to the transport of the product, such as damaged 
transport carton and/or damaged secondary package upon receipt of 
the shipment, missing drugs from the shipment package, unsuitable 
transport conditions. 
2. PROCESS 
In case any of the non-conformances listed above are detected or information 
about these non-conformances has been received, the completed Non-
conformance Report must be sent to the sponsor/its representative within 24 
hours.  
In parallel, the local CRAs of the study must be informed about the non-
conformance. If possible, a photo of affected material should be attached to the 
report. Affected material should be retained and stored according to the storage 
conditions label and/or returned to sponsor if requested by the sponsor/its 
representative. 
8.5.8 Prior and Concomitant Medication, Therapeutic Measures 
Any medication other than the IMPs (described in section 8.5.1) is defined as 
concomitant medication. Any concomitant medication will be carefully 
documented in the CRF specifying the substance (name of medication), reason 
for administration, administration scheme (regimen, no. of units, dose per unit) 
dosage form, route of administration, start and stop date of treatment or ongoing 
(if applicable) in context of the exclusion criteria listed in section 8.4.2. 
 
The following concomitant medication is NOT ALLOWED for the present 
trial: 
 Intranasal or systemic use of corticosteroids within 30 days prior to screening 
visit and during the trial; 
 Intranasal or systemic use of antibiotics within 30 days prior to screening visit 
and during the trial;


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 49 of 82 
 Use of nasal decongestants within 2 days prior to screening visit and during 
the trial; 
 Concomitant treatment within 7 days prior to screening visit of common cold-
like symptoms with any of the following: 
- 
Analgesics 
- 
Non-steroidal anti-inflammatory drugs 
- 
Antihistamines 
 Concomitant use of intranasal saline irrigation; 
 Use of immunosuppressive agents within 30 days prior to screening visit and 
during the trial. 
 
The following concomitant therapeutic measures available at home are NOT 
ALLOWED for the present trial: 
 Infrared light, hot and/or warm pads/compresses, and home remedies, e.g. 
fragrance lamps with essential oils like rosemary, thyme eucalyptus and mint 
oil etc.  
 
The following concomitant medication IS ALLOWED for the present trial: 
 Any other long-term therapy for any chronic disease (if expected to be 
maintained stable during the entire trial duration). 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 50 of 82 
9 
Trial Procedures 
The visit schedule and planned assessments for each visit in tabulated form are 
presented in section 2.1 and 2.2.  
The trial duration will last about 16 days for a single patient. A total number of 6 
ambulatory visits is planned for the present trial (see description below).  
VISIT 1 will be carried out 1 day before the start of treatment (Day 1) and 
includes the documentation of the following screening examinations: 
 date of signing the informed consent 
 date and time of examination (visit)  
 patient identification by means of national ID card or another national ID 
document 
 demographic data: birth date, ethnicity, gender, height, weight 
 life style and habits: consumption of alcohol, nicotine, history of drug abuse or 
use of illegal drugs 
 history of primary disease (acute, uncomplicated rhinosinusitis) 
 Major Symptom Score (MSS) assessment by the patient (transcribed by 
the investigator from the Trial Specific Source Form (TSSF) into the CRF) 
 medical and surgical history (anamnesis) for documentation of the following:  
− concomitant diseases and concomitant therapies/ medication(s) 
documented at Visit 1; 
− previous diseases and surgeries and previous therapies/ medication(s) 
within the last 6 months prior to screening Visit 1; 
− medical or other therapeutical measures/ actions used currently by the 
patient (e.g. sinus lavage, intranasal saline irrigation) 
− additional anamnestic information concerning:  
last participation in any clinical trial,  
last administration of any investigational drug,  
allergy (e.g. perennial or seasonal rhinitis),  
drug hypersensitivity or intolerance, 
hypersensitivity or intolerance to acetylcysteine or any of the excipients of 
the trial medication, 
check for hereditary fructose intolerance, galactose intolerance, lactase 
deficiency or glucose-galactose malabsorption. 
 for female patient of childbearing potential: information on use of any 
contraception, method of contraception used [e.g. oral, injectable or 
implantable contraceptives, intrauterine contraceptive devices (IUD), pre-
existing sterilization with date of sterilization, or sexual abstinence or 
vasectomized partner] and for postmenopausal female patient the date of last 
menstrual bleeding will be documented.  
Where a contraceptive medication is used, a specification of the drug name, 
dosage/route, start, ongoing and end of treatment is to be documented.  
 vital signs measurements of body temperature with documentation of the 
measuring method used, pulse rate, and blood pressure after 5 minutes rest in 
sitting position 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 51 of 82 
 physical examination per body system: general/nutritional sate, skin, 
head/neck, eyes, cardiovascular, respiratory, gastrointestinal, hepatic/biliary, 
endocrine/metabolic, lymph nodes, urogenital, neurological, psychiatric, 
musculoskeletal 
 ENT examination of nose (septum, mucosa, secretion, obstruction, polyps), 
ears (effusion and erythema), and mouth/ throat (anterior and posterior 
discharge, dental abnormalities and halitosis) 
 laboratory examination of blood (please see below) 
 serum pregnancy test (hCG) for female subjects (please see below) 
 check of inclusion criteria according to protocol 
 check of exclusion criteria according to protocol 
 investigator’s decision on patient’s enrolment. 
The blood specimen (30 mL) for the screening safety laboratory 
investigations will include the following parameters: 
Hematology: 
hemoglobin, hematocrit, leukocytes with differential count, 
erythrocytes, erythrocyte sedimentation rate, MCV, MCH, 
MCHC, and platelet count 
Blood chemistry: 
Electrolytes 
sodium, potassium, serum calcium, serum albumin, 
chloride 
Substrates 
creatinine, total protein, total bilirubin, blood glucose, 
urea, uric acid 
Enzymes 
ALT, AST, γ-GT, ALP 
The investigator will be provided with the original laboratory print-out(s) or 
certified copy (dated and signed by the laboratory staff) of the original laboratory 
print-out(s) for the individual patient health medical record file. The laboratory 
results have to be entered into the CRF. Any values out of range have to be 
assessed by the investigator as “not clinically relevant” (NCR) or “clinically 
relevant” (CR). For implausible laboratory values e.g. due to technical error or 
print-out error, the investigator will use the assessment “implausible value” (IPV).  
If medically required, a separate blood draw will be taken for follow-up of CR or 
IPV parameters. 
Serum pregnancy test (hCG) in all female patients. The result will be 
documented in the CRF. In case of a positive test result, this patient cannot be 
included in the trial. 
All laboratory blood tests will be carried out in a certified local laboratory. A 
signed and dated list of the normal ranges and units of the laboratory blood and 
parameters and the certificate of the laboratory will be provided to 
 
before the start of the trial. Also updates of the laboratory reference ranges/ 
certificates (if any) will be provided to 
. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 52 of 82 
VISIT 2 (Day 1 – between 7 and 9 a.m.) 
The following procedures will be performed and documented in on this day: 
 date and time of examination 
 patient identification by means of national ID card or other national ID 
document 
 vital signs measurements of body temperature with documentation of the 
measuring method used, pulse rate, and blood pressure after 5 minutes rest in 
sitting position 
 documentation of any changes in the concomitant therapy(ies)/ medication(s) 
or use of other therapeutic measures/ actions 
 adverse event questioning 
 check of exclusion/withdrawal criteria and further patient eligibility 
 Major Symptom Score (MSS) assessment by the patient (transcribed by 
the investigator from TSSF into the CRF, and constituting the baseline 
value) 
 dispensation of the patient diary 
 SNOT-22 questionnaire on Day 1 (documented by patient in the diary during 
the visit in the clinical site) 
 dispensation of a patient study identification card 
 Randomization to double-blind treatment 
 dispensation of the Patient Kit (box) containing the double-blinded 
trial medication for 14 days and including the separate 
Replacement/Reserve medication box with 3 Daily Kits 
 first intake of 2 tablets solved in 200 mL of water (morning dose of 
Daily Kit 1) in the presence of the investigator during the intake of 
breakfast. A pre-packed snack (e.g. croissant or similar) and a small 
beverage will be provided to the patient for breakfast. 
 patient instructions for further intake of medication at home with the 
breakfast and lunch, for daily documentation of MSS in the diary and for 
correct storage of medication at home 
 patient instructions for return of the diary and the used medication at next 
visit for investigator’s check. 
 
VISIT 3 (Day 4) 
The following procedures will be performed and documented in on this day: 
 date and time of examination (visit) 
 patient identification by means of national ID card or other national ID 
document 
 vital signs measurements of body temperature with documentation of the 
measuring method used, pulse rate, and blood pressure after 5 minutes rest in 
sitting position 
 documentation of any changes in the concomitant therapy(ies)/ medication(s) 
or use of other therapeutic measures/ actions 
 adverse event questioning 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 53 of 82 
 check of exclusion/ withdrawal criteria and further patient eligibility 
 review of the Patient Diary entries and compliance check; check of the 
correct documentation of Major Symptom Score (MSS) recorded by the 
patient once a day before intake of the morning dose 
 detach the originals of the completed patient diary pages (top pages) 
and retain in the ITF until the final shipment of the complete diary to 
 for data entry in the clinical database. The no-carbon copy 
paper diary pages remain in the ITF of the clinical center. 
 assessment of the overall response to treatment (investigator) 
 check of the returned used Daily Kits 
 patient instructions for further intake of medication at home with the breakfast 
and lunch, for daily documentation of MSS and SNOT-22 (on Day 7) in the 
diary and for correct storage of medication at home 
 patient instructions for return of the diary and the used medication at next visit 
for investigator’s check. 
 
VISIT 4 (Day 7) 
The following procedures will be performed and documented in on this day: 
 date and time of examination (visit) 
 patient identification by means of national ID card or other national ID 
document 
 vital signs measurements of body temperature with documentation of the 
measuring method used, pulse rate, and blood pressure after 5 minutes rest in 
sitting position 
 documentation of any changes in the concomitant therapy(ies)/ medication(s) 
or use of other therapeutic measures/ actions 
 adverse event questioning 
 check of exclusion/withdrawal criteria and further patient eligibility 
 ENT examination of nose (septum, mucosa, secretion, obstruction, polyps), 
ears (effusion and erythema), and mouth/ throat (anterior and posterior 
discharge, dental abnormalities and halitosis) 
 review of the Patient Diary entries and compliance check; check of the 
correct documentation of Major Symptom Score (MSS) recorded by the 
patient once a day before intake of the morning dose and check of the 
correct documentation of SNOT-22 questionnaire on Day 7 (by patient, in 
the diary) 
 detach the originals of the completed patient diary pages (top pages) 
and retain in the ITF until the final shipment of the complete diary to 
 for data entry in the clinical database. The no-carbon copy 
paper diary pages remain in the ITF of the clinical center. 
 assessment of the overall response to treatment (investigator) 
 assessment of the overall tolerability (investigator and patient) 
 check of the returned used Daily Kits


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 54 of 82 
 patient instructions for further intake of medication at home with the breakfast 
and lunch, for daily documentation of MSS in the diary and for correct storage 
of medication at home 
 patient instructions for return of the diary and the used medication at next visit 
for investigator’s check. 
 
VISIT 5 (Day 10) 
The following procedures will be performed and documented in on this day: 
 date and time of examination (visit) 
 patient identification by means of national ID card or other national ID 
document 
 vital signs measurements of body temperature with documentation of the 
measuring method used, pulse rate, and blood pressure after 5 minutes rest in 
sitting position 
 documentation of any changes in the concomitant therapy(ies)/ medication(s) 
or use of other therapeutic measures/ actions 
 adverse event questioning 
 check of exclusion/ withdrawal criteria and further patient eligibility 
 review of the Patient Diary entries and compliance check; check of the 
correct documentation of Major Symptom Score (MSS) recorded by the 
patient once a day before intake of the morning dose 
 detach the originals of the completed patient diary pages (top pages) 
and retain in the ITF until the final shipment of the complete diary to 
 for data entry in the clinical database. The no-carbon copy 
paper diary pages remain in the ITF of the clinical center. 
 assessment of the overall response to treatment (investigator) 
 check of the returned used Daily Kits 
 patient instructions for further intake of medication at home with the breakfast 
and lunch, for daily documentation of MSS and SNOT-22 (on Day 14) in the 
diary and for correct storage of medication at home 
 patient instructions for return of the diary and the used medication at next visit 
for investigator’s check. 
 
END OF TREATMENT on Day 14 
In case of delayed final visit (Visit 6), the patient can voluntarily take reserve 
study medication for a maximum of 3 additional days. 
 
VISIT 6 (Day 15 (+3)) 
The following procedures will be performed and documented in on this day: 
 date and time of examination (visit) 
 patient identification by means of national ID card or other national ID 
document 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 55 of 82 
 vital signs measurements of body temperature with documentation of the 
measuring method used, pulse rate, and blood pressure after 5 minutes rest in 
sitting position 
 documentation of any changes in the concomitant therapy(ies)/ medication(s) 
or use of other therapeutic measures/ actions 
 adverse event questioning 
 physical examination per body system: general/nutritional state, skin, 
head/neck, eyes, cardiovascular, respiratory, gastrointestinal, hepatic/biliary, 
endocrine/metabolic, lymph nodes, urogenital, neurological, psychiatric, 
musculoskeletal 
 ENT examination of nose (septum, mucosa, secretion, obstruction, polyps), 
ears (effusion and erythema), and mouth/ throat (anterior and posterior 
discharge, dental abnormalities and halitosis) 
 laboratory examination of blood (please see below) 
 serum pregnancy test (hCG) for female subjects (please see below) 
 review of the Patient Diary entries and compliance check; check of the 
correct documentation of Major Symptom Score (MSS) recorded by the 
patient once a day before intake of the morning dose and for the correct 
documentation of the last SNOT-22 questionnaire reported by the patient 
in the diary on Day 14 
 detach the originals of the completed patient diary pages (top pages) 
and retain in the ITF until the final shipment of the complete diary to 
for data entry in the clinical database. The no-carbon copy 
paper diary pages remain in the ITF of the clinical center. 
 last Major Symptom Score (MSS) reported by the patient during the visit 
on Day 15(+3) and transcribed from TSSF by the investigator into the 
CRF 
 assessment of the overall response to treatment (investigator) 
 assessment of the overall tolerability (investigator and patient) 
 check of the returned used Daily Kits and the used or not used 
Replacement/Reserve Daily Kits (1, 2, 3). 
The blood specimen (30 mL) for the final safety laboratory investigations 
will include the following parameters: 
Hematology: 
hemoglobin, hematocrit, leukocytes with differential count, 
erythrocytes, erythrocyte sedimentation rate, MCV, MCH, 
MCHC, and platelet count 
Blood chemistry: 
Electrolytes 
sodium, potassium, serum calcium, serum albumin, 
chloride 
Substrates 
creatinine, total protein, total bilirubin, blood glucose, 
urea, uric acid 
Enzymes 
ALT, AST, γ-GT, ALP 
Serum pregnancy test (hCG) in all female patients.  
The result will be documented in the CRF. In case of a positive test result, the 
investigator must report it immediately (within 24 hours) of awareness to the 
Country Patient Safety Head and in copy to the Study Managers (see 9.3.7). 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 56 of 82 
The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, inborn abnormalities, or maternal and/or newborn 
complications. 
Any values out of range have to be assessed by the investigator as “not clinically 
relevant” (NCR) or “clinically relevant” (CR). For implausible laboratory values 
e.g. due to technical error or print-out error, the investigator will use the 
assessment “implausible value” (IPV). If medically required, a separate blood 
draw can be taken for follow-up of CR or IPV parameters. 
 
FOLLOW-UP PHONE CALL (within 7 days after Visit 6 or earlier in case of 
premature termination) 
 date of phone call 
 check of adverse events after Visit 6. 
During the phone call the investigator will check if any AE occurred after Visit 6 
and if medically required the patient can be invited for additional (not trial related) 
visits. The results of these additional examinations and treatments will remain in 
the individual medical health records/ files of the clinical center(s) only. The date 
of the last follow up call of the last patient in the trial will be defined as the end of 
the trial. 
In case that the investigator cannot reach the patient for the final follow-up call, 
he/she will document this in the CRF.  
9.1 
Trial Specific Efficacy Assessments 
The following trial specific efficacy assessments will be performed by the 
PATIENT: 
 
 Major Symptom Score (MSS) 
The MSS combines the 5 most relevant symptoms of rhinosinusitis based on 
expert clinician recommendations1, 21, 22 (rhinorrhea/ anterior discharge, 
postnasal drip, nasal congestion, headache, and facial pain/pressure as 
reported by the group of Meltzer21 and Revicki et al.22) and has been employed 
as primary efficacy criterion in several clinical trials1. 
Assessment of symptom severity. The patient will rate the severity of each of the 
five symptoms of the MSS using a four-point rating scale of increasing severity 
( = none/not present,  = mild,  = moderate,  = severe).  
The MSS will be assessed by the patient at screening (Visit 1) and 
immediately before randomization (Visit 2; this will constitute the baseline 
value). The investigator will transcribe both patient’s MSS assessments 
into the CRF.  
Thereafter, the patient will document the MSS in the patient diary once a 
day before intake of the morning dose, starting with Day 2 until Day 14 (last 
day of treatment or earlier in case of drop-out). 
The last MSS will be assessed by the patient during Visit 6 and transcribed 
into the CRF. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 57 of 82 
 Sino-Nasal Outcome Test (SNOT-22) questionnaire 
SNOT-22 will be assessed by the patient in the patient diary on Day 1, Day 7 
and Day 14.  
SNOT-22 will be part of the patient diary printed on no-carbon copy paper (one 
top page and a second no-carbon copy page). The patient must complete the first 
SNOT-22 in the patient diary during Visit 2, after the investigator explained 
unclear terms and answered all patient’s questions. 
The following trial specific efficacy assessments will be performed and 
documented by the INVESTIGATOR: 
 
 Investigator’s assessment of the overall response to treatment 
The investigator will assess the overall response to treatment at each visit after 
baseline: on days 4 (Visit 3), 7 (Visit 4), 10 (Visit 5), and 15 (Visit 6). 
The investigator will rate the response to treatment using a five-point rating scale: 
 = major deterioration,  = minor deterioration,  = no change,  = minor 
improvement,  = major improvement. 
9.2 
Trial Specific Safety Assessments 
Overall assessment of tolerability by the patient and by the investigator on 
days 7 (Visit 4) and Day 15 (Visit 6). 
 Patient’s assessment of the overall tolerability 
The patient will assess the overall tolerability during the visit on days 7 (Visit 4) 
and 15 (Visit 6).  
The patient will rate the tolerability using a five-point rating scale:  = very poor, 
 = poor,  = medium,  = good,  = very good. The investigator will document 
the patient assessment of overall tolerability in the CRF.  
 Investigator’s assessment of the overall tolerability 
The investigator will assess the overall tolerability on days 7 (Visit 4) and 15 (Visit 
6). 
The investigator will rate the tolerability using a five-point rating scale:  = very 
poor,  = poor,  = medium,  = good,  = very good. 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs): AEs will be 
recorded by the investigator at each visit until the end of the double-blind phase 
inclusive the follow-up phone call (within 7 days after Visit 6 or earlier in case of 
premature termination). AEs will be assessed for seriousness, severity and drug-
event relationship (details are provided in section 9.3). 
Vital signs: Blood pressure, pulse rate, and body temperature will be recorded at 
each visit: at screening (Visit 1), immediately before randomization (Visit 2; this 
will constitute the baseline value), and on days 4 (Visit 3), 7 (Visit 4), 10 (Visit 5), 
and 15 (Visit 6). 
ENT examination of nose (septum, mucosa, secretion, obstruction, polyps); 
ears (effusion and erythema), mouth/ throat (anterior and posterior discharge, 
dental abnormalities and halitosis) will be recorded at screening (Visit 1), on Day 
7 (Visit 4) and on Day 15 (Visit 6). 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 58 of 82 
Safety laboratory examination of blood at screening (Visit 1) and end of 
treatment (Visit 6) for the following: 
Hematology: 
hemoglobin, hematocrit, leukocytes with differential count, 
erythrocytes, erythrocyte sedimentation rate, MCV, MCH, 
MCHC, and platelet count 
Blood chemistry: 
Electrolytes 
sodium, potassium, serum calcium, serum albumin, 
chloride 
Substrates 
creatinine, total protein, total bilirubin, blood glucose, 
urea, uric acid 
Enzymes 
ALT, AST, γ-GT, ALP 
Pregnancy test: In all women a serum pregnancy test for measurement of 
human chorionic gonadotropin (hCG) will be performed at screening (Visit 1) and 
at Visit 6. 
9.3 
Adverse Events 
9.3.1 Definitions 
An Adverse Event / Experience (AE) is any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product 
and which does not necessarily have to have a causal relationship with this 
treatment. 
An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any 
dose: 
 results in death 
 is life-threatening 
 requires inpatient hospitalization or prolongation of existing inpatient 
hospitalization 
 results in persistent or significant disability/ incapacity  
 is a congenital anomaly/ birth defect 
 is medically significant: Medical and scientific judgment 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 hospitalization but may jeopardize the subject (patient) or 
may require intervention to prevent one of the other outcomes listed above. 
These should also usually be considered serious. 
These characteristics/consequences have to be considered at the time of the 
event. For example, regarding a life-threatening event, this refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 59 of 82 
A (Serious) Adverse Drug Reaction ((S)ADR) is any (S)AE for which the 
investigator or sponsor assess a reasonable possibility for a causal relationship 
to a medicinal product, see 9.3.3 below. 
A (Serious) Unexpected Adverse Reactions is defined as a (serious) adverse 
drug reaction, the nature or severity of which is not consistent with the Reference 
Safety Information (SmPC).  
The term ‘severity’ is used here to describe the intensity of a specific event. This 
has to be distinguished from the term ‘serious’. Reports which add significant 
information on the specificity, increase of occurrence, or severity of a known, 
already documented serious adverse reaction constitute unexpected events. 
Information about common side effects already known about the Investigational 
Medicinal Product (IMP) can be found in the Reference Safety Information 
(SmPC) or will be communicated in the form of Investigator Notifications. This 
information will be included in the subject information and should be discussed 
with the subject. 
For further details, please refer to the Quick Reference Guide for completing the 
Serious Adverse Event Form. 
9.3.2 Severity of Adverse Events 
The term ‘severity’ is used here to describe the intensity of a specific event. This 
has to be distinguished from the term ‘serious’. In the course of the trial, the 
investigator will determine whether any AE have occurred and will grade their 
severity as follows: 
− Mild 
Usually transient in nature and generally not interfering with 
normal activities 
− Moderate 
Sufficiently discomforting to interfere with normal activities 
− Severe 
Prevents normal activities 
 
9.3.3 Relationship to the IMP 
The investigator should evaluate all AEs considering all accessible data, at any 
time new information becomes available. The definition of IMP includes the test 
product under evaluation or the placebo that is given during any phase of the 
trial. 
The investigator should assess whether or not, in his/her expert opinion, the AE 
is suspected to the drug. Suspected means that a causal relationship between 
the drug and an adverse event is at least a reasonable possibility, i.e. the 
relationship cannot be ruled out. 
Causality assessments are critical and must be provided for each unique AE in 
relation to each IMP, non-investigational medicinal product (NIMP) or other 
concomitant medication, if applicable. Missing causality assessments will be 
handled as suspected to IMP by the sponsor. 
AEs with a suspected relationship to NIMP or other concomitant medication (for 
both Sandoz and non-Sandoz products), even if non-serious, need to be reported 
by the investigator to the respective Country Patient Safety Head (see section 
9.3.5 for contact details). 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 60 of 82 
9.3.4 Adverse Events Documentation 
Any AE (non-serious and serious) occurring after the subject has provided study-
specific informed consent and until the last study visit of the subject, has to be 
recorded on the AE pages of the Case Report Form (CRF). 
The occurrence of AEs should be sought by non-directive questioning of the 
subject at each visit during the study. AEs also may be identified when they are 
volunteered by the subject during or between visits or during physical 
examination, laboratory test or other assessments. All AEs should be given 
appropriate medical care. Treatment may include one or more of the following: no 
action taken (i.e. further observation only); IMP dosage adjusted/temporarily 
interrupted; IMP permanently discontinued due to this AE; concomitant 
medication given; non-drug therapy given, patient hospitalized / patient’s 
hospitalization prolonged. The treatment of the AE should be documented in the 
CRF. In addition, the action taken with the IMP should be documented, and 
should be assigned to one of the following categories: not changed, withdrawn, 
reduced, increased, interrupted, unknown and not applicable.  
Concomitant medication, other treatments or changes in the administration of the 
IMP should be specified and documented. 
Medical conditions/diseases present before starting IMP are only considered AEs 
if they worsen after enrolment. Abnormal laboratory values or test results 
constitute AEs only if they induce clinical signs or symptoms, are considered 
clinically relevant, or require therapy. 
Once an AE is identified, the investigator should follow-up as specified below. 
Each time, the outcome should be documented and assigned to one of the 
following categories: not recovered/unchanged, condition deteriorating, 
recovered/resolved, improving/recovering, recovered/resolved with sequelae, 
fatal or unknown. The assessment of an AE should be made at each planned 
visit (or more frequently, if necessary). The investigator should document in the 
CRF any changes in seriousness, severity, the suspected relationship with the 
IMP, the interventions required to treat it, and the outcome.  
Adverse events occurring between informed consent and the last visit  
The investigator should follow up on all AEs which occurred from signature of 
study-specific informed consent until the last visit of the subject, at which point 
the outcome assessment is documented in the CRF.  
Ongoing serious adverse events at the time of last visit 
For any SAEs still ongoing at the time of last visit, the investigator should 
continue to follow-up until the SAE has resolved or has stabilized / is judged 
permanent for SAEs considered to be related to IMP (SADRs), and for up to 30 
days after the last visit of subject for non-related SAEs. The investigator should 
send SAE follow-up reports to recipients as per the ‘SAE Reporting’ section 9.3.5 
below.  
Serious adverse events occurring after the last visit 
Any SAEs experienced after the last visit should only be reported to sponsor if 
the investigator suspects a causal relationship to study treatment. The 
investigator must report the SADR to recipients as per the ‘SAE Reporting’ 
section 9.3.5 below. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 61 of 82 
9.3.5 SAE Reporting 
It is vitally important that the investigator reports immediately, i.e., no later than 
24 hours after awareness, any SAEs, or updates to previously reported SAEs, 
even if the investigator does not consider the AE to be drug-related. 
The investigator should send SAE reports on the “Serious Adverse Event Report 
Form”, as initial or follow-up reports, via fax or email to the Country Patient Safety 
Head, and in copy to the project management (Lek Pharmaceuticals d.d.), to the 
addresses provided on the next page. 
The investigator should also send all updates / new information on a new SAE 
Report Form as a follow-up to the previously reported SAE. The follow-up 
information should describe whether the event has resolved or continues, if a 
diagnosis is available, if and how it was treated, and whether the subject 
continued or withdrew from study participation. 
Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode, regardless of when the event 
occurs.  
Any new SAE (that is considered completely independent of a previously 
reported SAE) should be reported as a new and separate initial SAE report. 
Any queries from the Country Patient Safety Head, Contract Research 
Organization (CRO) or sponsor/its representative regarding SAE reports should 
be answered by the investigator within 24 hours. 
For more detailed information refer to the “Quick Reference Guide for Completing 
the SAE Form”.  
The investigator should retain a delivery confirmation of the SAE reports 
for all recipients in the investigator study file. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 62 of 82 
TT 1 
Addresses for SAE reporting 
Country Patient Safety Head, for Bulgaria: 
email:
fax: 
Country Patient Safety Head, for Germany: 
email: 
fax: 
 
Country Patient Safety Head, for Moldova: 
email:
fax: 
 
Country Patient Safety Head, for Russia: 
email:
fax: 
 
 (Lek Pharmaceuticals d.d.):  
PhD 
email: 
Dipl. Biol. 
email:
 
The responsible contact persons for questions are: 
(Lek Pharmaceuticals d.d.) 
Phone 
 
(Lek Pharmaceuticals d.d.) 
 PhD 
Phone: 
, MD, PhD 
Phone: 
 
 
Investigator Notification and 6 monthly line listings 
If a SADR is not listed in the Reference Safety Information (SmPC), the sponsor 
may urgently require further information from the investigator for Health Authority 
reporting. 
The sponsor may, if applicable, issue Investigator Notifications and 6 monthly line 
listings of Suspected Unexpected Serious Adverse Reactions (SUSARs) to all 
investigators concerned with any study with the same IMP. 
The submission of these Investigator Notifications and 6-monthly line listings, if 
applicable, to local IRBs / Ethics Committees is the responsibility of the 
investigator (supported by the CRO) as stipulated in the study contract. The 
submission of Investigator Notifications and 6-monthly line listings to national 
Ethics Committee is the responsibility of the CRO, if applicable. 
 
Health authority reporting 
The sponsor/its representative will submit all reportable cases within the 
requested timelines to all concerned health authorities. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 63 of 82 
9.3.6 Emergency Unblinding for the Treatment of SAEs 
The investigator should unblind the treatment (with the emergency envelope) for 
an individual case only in emergency situations, and only if relevant to the 
subsequent treatment of the subject (see also section 8.5.5 on unblinding). 
9.3.7 Pregnancies 
The investigator must report any cases of pregnancy of subjects in the course of 
a study immediately (within 24 hours) of awareness to the Country Patient 
Safety Head and in copy to the Study Managers (Sponsor/its representative and 
), as described in section 9.3.5. Pregnancies are only reported 
from the time of first IMP dose. 
The investigator should immediately withdraw the subject from the study, and 
should follow-up each case of pregnancy, and report the outcome, including 
spontaneous or voluntary termination, details of the birth, and any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.  
Cases of pregnancy are reported on a “Drug Exposure in Pregnancy Form” 
(Novartis form). Pregnancy follow-up are reported on the same form, and should 
include an assessment of the relatedness of any untoward pregnancy outcome to 
the IMP. 
Any SAE during pregnancy of a subject must be reported on the SAE Report 
Form and reported as described in section 9.3.5. 
The investigator should retain a delivery confirmation of the “Drug Exposure in 
Pregnancy Form” for all recipients in the investigator study file. 
For more detailed information refer to the “Quick Reference Guide for Completing 
the Drug Exposure in Pregnancy Form” (Novartis document). 
9.3.8 IMP Related Complaints 
In case of quality complaints related to the IMP, the investigator within 24 hours 
of learning of its occurrence informs the sponsor/its representative as described 
in section 9.3.5.  
Any AE associated with a quality complaint needs to be documented and 
reported in addition by the investigator as described in section 9.3.4 and 9.3.5. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 64 of 82 
9.3.9 Special Case Scenarios 
Special case scenarios can be serious or non-serious (see table below), and they 
should be reported like AE cases as described in section 9.3.4 and 9.3.5, even if 
no (other) AEs are associated with their occurrence. 
Special case scenario 
Reportable within 24 hours 
from investigator to 
Country Patient Safety 
Head 
Drug exposure during breastfeeding 
x 
Intentional Overdose by patient (including 
suicide attempts, suicide attempt is always 
serious) 
Only if associated with SAE 
Drug / drug interactions 
Only if associated with SAE 
Withdrawal syndrome/ reaction 
Only if associated with SAE 
Drug dependence, misuse, abuse or 
addiction (always serious) 
x 
Suspected Transmission of infectious 
agents (always serious) 
x 
Death (incl. without other event, always 
serious) 
x 
 
9.3.10 
Reconciliation 
Reconciliation between the safety database of the sponsor and the clinical 
database at the CRO will be done periodically as described in a reconciliation 
plan (part of Data Management Plan generated by 
) by comparing 
line listings from the safety database with the data in the clinical database. 
The data management will review the CRFs / the clinical database for potentially 
unreported cases. For any reportable case, the following parameters need to 
match exactly between the clinical and the safety database: trial number, center 
number, subject/patient screening number, randomization number, investigational 
drug, seriousness, date of death (if applicable) and investigator causality. All 
other parameters only need to be plausibly and medically consistent. For any 
reportable case assessed as suspected or for other events of special interest (if 
applicable), a more detailed reconciliation should be conducted, including also 
treatment dates, outcome, medical history and concomitant therapy. 
9.3.11 
Investigator Training 
By his/ her signature of the trial protocol, the principal investigator and the sub-
investigator certifies that he/she has been trained in the Sponsor AE/SAE and 
pregnancy reporting obligations by the CRO as defined in the trial protocol. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 65 of 82 
9.3.12 
Abnormal Clinical Laboratory Values 
For abnormal clinical laboratory results the investigator must indicate in the CRF 
if the value is clinically relevant (CR) or not clinically relevant (NCR) or 
implausible (IPV). 
Control laboratory investigations can be performed at any time during the trial. In 
case of unexplained or unexpected laboratory abnormalities with clinical 
relevance, the tests must be followed up until the results return to normal range 
or baseline value, and/ or adequate explanation for the abnormality is found. The 
results of control laboratory investigations must be documented in a separate 
CRF laboratory control page. 
9.3.13 
Safety Assessment 
All patients screened and randomized in the trial will be included in the listing of 
safety data in the final study report. The reason for withdrawal and date of any 
withdrawal will be reported in the final study report. All adverse experiences will 
be listed and tabulated by severity, treatment and causal relationship to the IMP 
in final study report. 
9.4 
Premature Trial Discontinuation 
The conditions for premature discontinuation of the trial in particular cases or in 
general are summarized below. 
9.4.1 Withdrawal of Patients 
Subjects may be withdrawn: 
 at their own request with or without giving reasons, 
 at the discretion of the investigator for reasons of medical prudence. 
In either event, the sponsor/its representative will be immediately notified and the 
date and reasons for the withdrawal will be clearly stated in the patient's CRF. 
Patients can also be withdrawn by the investigator for several reasons. These 
include: 
- 
safety reasons 
- 
if adverse event (including intercurrent disease) develop, which rule 
out continuation of the trial medication, or the AE could impair the 
validity of the results, or the AE makes further patient participation in 
this trial inadvisable, 
- 
non-compliance, 
- 
if circumstances, defined as withdrawal criteria are registered. 
Exclusion criteria defined in section 8.4.2 which are not present at 
screening but develop or are registered during the course of the trial 
are defined as withdrawal criteria.


HEXAL AG 
Trial Protocol 
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Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 66 of 82 
For each patient withdrawn from the trial before the defined trial end, for whatever 
reason, a complete final examination must be performed as far as possible 
regarding the patient's availability and health condition. In case of withdrawal, the 
time, date and reasons for the withdrawal will be documented in the CRF. 
9.4.2 Replacement of Drop-Outs 
Drop-outs will not be replaced. 
9.4.3 Premature Termination of the Trial 
The sponsor/its representative may discontinue the trial at any time. 
The ethics committees or the regulatory authorities involved might revoke their 
positive opinion regarding the trial which will lead to termination of the trial. 
If, in the opinion of the coordinating investigator, the clinical observations in the 
trial suggest that it might not be justifiable for medical reasons to continue, he 
may terminate the trial after consultation with the sponsor/its representative or the 
sponsor/its representative may terminate the trial for safety, administrative or 
other reasons.  
Reasons for discontinuation must be documented appropriately and provided to 
the sponsor/its representative, the ethics committees and regulatory authorities 
involved (if applicable). 
The trial can also be terminated at single clinical center(s) due to any of the 
following reasons: 
- 
on request of the center, or 
- 
if results of an audit or regulatory inspection reveal critical findings 
which preclude further participation on the trial. 
9.5 
Data Quality Assurance 
9.5.1 Monitoring 
The sponsor will contract the monitoring of this clinical trial to
 The 
monitoring visits in the present trial will be performed by
(for the 
centers in Germany) or its local subcontractors (see details in section 1.7).  
A Monitoring Plan will be generated by
in accordance with
SOP 2406. 
Monitoring of this study will be performed according to the standard operating 
procedures developed by
in order to check the adherence to the 
protocol in compliance with GCP guidelines and to ensure international 
acceptability of the study data. It is the responsibility of the investigator to assure 
that the study is conducted in accordance with the protocol, ICH-GCP and that 
valid data are entered into the CRF. Therefore, the investigator will make the 
records available to
or to the sponsor/its representative co-monitor 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 67 of 82 
upon request at reasonable times. Case report forms will be checked by the 
CRA(s) for completeness and clarity. 
Data verification is legally required and will be done by direct comparison with 
source documents in case of subject's respective consent or by cross-checking 
with source documents in the presence of the investigator - always giving due 
consideration to data protection and medical confidentiality. In this respect the 
investigator assures 
 to support at all times. 
The investigator will permit representatives of 
 and the sponsor/its 
representative to monitor/co-monitor the study as frequently as necessary to 
determine that data recording and protocol adherence are satisfactory. The CRFs 
and related documents will be reviewed by the CRA(s) in detail in accordance 
with the 
 and the GCP regulation. 
Visits may be conducted also by representative of 
 or the sponsor/its 
representative at suitable intervals throughout the study. These visits will be 
carried out for the purposes of verifying adherence to the protocol and the 
completeness and exactness of the data entered in the CRFs. The sponsor/its 
representative can have any information on the state of the study.  
The original (top) pages of the CRF and the patient diary will be transferred to 
 after completion of the trial for the individual patient(s) for data entry 
in the clinical database. The transport of the completed CRFs/diaries to 
 
will be organized in several shipments. The original CRF pages and the 
original patient diary pages (top page) will be transferred with the final clinical 
study report to the Sponsor/its representative. The no-carbon copy paper page 
(2nd page) of the CRFs and the diaries remain in the ITF at the clinical center. 
It is the investigator's obligation to assure documentation of all relevant trial data 
in the subject's health medical file, such as medical history/concomitant diseases, 
date of study enrolment, visit dates, results of examinations, administrations of 
medication and AEs. 
 will affirm and uphold the principle of the subject's right to protection 
against the invasion of privacy. Throughout the study, all data will only be 
identified by subject screening/ randomization number. The data will be kept 
blinded accordingly in all data analyses. 
All obtained data will be checked for plausibility and completeness by the 
monitors and in-house by qualified staff of 
 Further plausibility 
checks will be performed by means of special computer programs. Study protocol 
and final report will be additionally reviewed by the sponsor/its representative. 
9.5.2 Protocol Deviation Definition and Reporting 
A protocol deviation is any change, divergence, or departure from the study 
design or procedures defined in the protocol like missed evaluations, incorrect 
timing of evaluations, non-compliance with study medications and intake of 
medications not allowed or any non-adherence to the protocol that impacts 
patient’s rights, safety or welfare. After a patient has been enrolled, it is the 
investigator’s responsibility to make a reasonable effort to correct any protocol 
deviations and to continue the patient’s participation in the study. Protocol 
deviations do not themselves constitute a justification for withdrawal of a patient 
from the study (see section 9.4.3). 
Deviations from the protocol including violations of inclusion/exclusion criteria will 
be assessed as “minor” or “major” in cooperation with the Sponsor/its 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 68 of 82 
representative. Major deviations from the protocol will lead to the exclusion of a 
patient from the Per Protocol Set (PPS). 
Protocol deviations will be reported to the project management of Lek 
Pharmaceuticals d.d. during the course of the study in the Monitoring Reports. 
The handling of these deviations will be defined in the Monitoring Plan. 
All protocol deviations will be listed and the impact on the evaluability of the 
patients concerned will be discussed in the Blind Data Review meeting prior to 
database closure and any statistical analysis. Major Protocol Deviations leading 
to exclusion of patients from the per protocol analysis will be decided by the 
sponsor/its representative. 
Protocol deviation notifications and reports are submitted to health authority and/ 
or relevant IEC/IRB according to applicable requirements/ guidelines/ law. 
9.5.3 Data Management 
The results from screening and data collected during the trial will be recorded in 
the CRF and in the patient diaries which will be designed and printed by 
 
. Each CRF page will be signed and dated by the investigator. 
All data concerning the study will be documented in the CRFs and patient diaries 
designed especially for this study and in data clarification forms issued by the 
data management. 
The CRFs and patient diaries will consist of an original (1st page) and one 
second page (no-carbon copy paper). The 1st page will be sent to 
 
for data entry in the clinical database. The no-carbon copy paper page 
will remain in the ITF of the clinical center. 
SAE and Pregnancy forms will consist of one original only. The filled in 
SAE and/or Pregnancy reports should be submitted via fax or email to the 
Country Patient Safety Head and in copy to the Study Managers (Lek 
Pharmaceuticals d.d. 
), as described in section 9.3.5 and the 
original document is filed in the ITF at the clinical center. 
The Data Management Department of 
 will check the CRFs for 
completeness and plausibility (manually and computer-supported) and data 
clarification forms will be generated.  
All corrections in the CRF are to be made legibly and signed by the investigator in 
accordance with GCP principles. All CRF pages (as described above) will be 
delivered thereafter to 
. 
 is responsible for the first step of 
data validation, receiving the results from the investigator. Each subject will be 
identified in the database by the respective screening/ randomization number. 
Description of the data entry procedure, the data handling (including data checks, 
coding of AEs, query procedure) and the software used for data management will 
be given in the Data Management Plan. Study specifics will be described in the 
Data Management Plan/ Data Validation Plan before the start of the data 
management process. The Data Management and Validation Report will be 
written after database closure. 
The database for data capture will be created by 
 using Oracle 
Clinical 5.1.0 (or higher) for Oracle Database 12c & Oracle Thesaurus 
Management System 5.1.0 or higher. After locking the database, the files will be 
exported to SAS and handed over to the sponsor/its representative. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 69 of 82 
Regarding the data entry, a study specific data capture mask will be generated 
which allows a consecutive CRF-based data entry. 
The data will be entered 2 times by 2 independent persons of the data 
management department (DMD). During the second data entry, the typist has to 
decide in case of discrepancies between both entries, which entry is correct. 
Concerning non-defined cases, the problem will be documented and clarified 
together with the data/project manager. 
Each complete CRF input will be documented on a specific form (data 
management record). At the same time, the name of the data typist as well as 
date and daytime of each of the 2 data entries per CRF will be documented in the 
Oracle Clinical database. 
After double data entry the data set will be checked for implausible entries, 
violations of inclusion/exclusion criteria, or other violations of the study protocol. 
After the data entry all data changes/additions or corrections will be documented 
on query forms according to GCP. 
Coding of AEs, prior and concomitant medications and prior and concomitant 
diseases will be done according to last available versions of MedDRA (The 
Medical Dictionary for Regulatory Activities) and of WHO/ATC. 
The data management and the statistical evaluation of the clinical study are done 
on a PC running Windows 10 operating system, using the statistical software 
package SAS, Version 9.4 (or higher). 
9.5.4 Auditing 
To guarantee that the performance of the trial is in accordance with the GCP 
provisions, in-house and, if needed, on-site audits may be carried out. The 
auditor will be independent from the staff involved in the proceedings of this trial.  
The investigator agrees to give the auditor access to all relevant documents for 
review. The same applies in case of an inspection by authorities. In the case of 
any inspection of 
 by an authority the sponsor/its representative will 
be consulted before the inspectors are permitted access to any of the project 
records.  
After each on-site audit the investigator will receive an audit confirmation by the 
auditor. This confirmation has to be filed together with the trial documentation and 
made available to the authorities in case of supervision. At the end of the trial, the 
audit certificate will be included in the final report. 
9.5.5 Quality Assurance System 
The 
 quality management department will conduct regular internal 
audits of the trial documents. A report will be prepared documenting the result of 
audits on the final trial protocol and related documents (e.g. CRF and patient 
information/ informed consent form) and the study report including appendices. A 
certificate confirming the audit performed will be included in the final study report. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 70 of 82 
10 Biometrics and Statistical Aspects 
The biostatistical evaluation will be carried out by 
 by means of the 
statistical software package SAS for Windows (Statistical Analysis System, SAS-
Institute, Cary NC, USA). 
10.1 
Statistical Analysis Plan 
The statistical analysis plan (SAP) will be finalized prior to database lock. All 
relevant points related to the statistical analysis will be defined in the SAP. The 
main points are described in the following sections. In addition to these points the 
SAP will contain information on further topics (e.g., evaluation of baseline 
comparability of groups, different types of sensitivity analysis, handling of missing 
data, wrong treatment assignment, etc.). 
10.2 
Endpoints 
10.2.1 
Primary Endpoint 
The primary endpoint is:  
• 
Mean change from baseline in the daily MSS over the entire treatment 
period: 
1
14
෍൫𝑥𝑥𝑖𝑖−𝑥𝑥 𝐷𝐷𝐷𝐷𝐷𝐷 1 (𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏)൯ 
𝐷𝐷𝑎𝑎𝑎𝑎 15
𝑖𝑖=𝐷𝐷𝐷𝐷𝐷𝐷 2
 
10.2.2 
Secondary Endpoints 
Secondary endpoints are:  
• 
Time to onset of action defined as first day of active treatment on which 
MSS shows statistically significant difference from placebo 
• 
MSS development over the course of the study 
• 
SNOT-22 by visit and changes versus baseline 
• 
Percentage of responders and non-responders to treatment based on the 
assessment of overall response to treatment by the investigator.


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 71 of 82 
10.2.3 
Safety Endpoints 
The safety endpoints in this trial are: 
• 
Incidence and severity of adverse events 
• 
Incidence and severity of drug-related adverse events 
• 
Clinically relevant changes in laboratory parameters, vital signs, physical 
and ENT examination parameters from Visit 1 to Visit 6 (or early 
termination)  
• 
Overall assessment of tolerability by patient and by investigator. 
10.3 
Populations for Analysis 
Statistical analysis will be performed on three different patient populations: 
• 
Safety Set (SS), 
• 
Full-Analysis Set (FAS), 
• 
Per-Protocol Set (PPS). 
10.3.1 
Safety Set 
The Safety Set (SS) is defined as all randomized patients who receive at least 
one dose of the trial medication. This will be the primary dataset for the 
evaluation of safety. 
10.3.2 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized patients who receive 
at least one dose of the trial medication and who have at least one post-baseline 
assessment of MSS during the double-blind treatment period. This will be the 
primary dataset for comparison of the primary endpoint. 
If any subject terminates the trial before completing the 14 days of double-blind 
treatment the last available post-baseline assessment of the MSS will be carried 
forward until the virtual last observation point (Last Observation Carried 
Forward or LOCF). 
The LOCF will also be used for calculating the secondary endpoints, if relevant. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 72 of 82 
10.3.3 
Per Protocol Set 
The Per Protocol Set (PPS) is defined as all FAS-evaluable patients who 
complete the double-blind treatment period without major protocol violations that 
could affect the efficacy evaluation. The latter will be prospectively defined before 
unblinding the trial.  
Protocol violations will be documented in the Protocol Deviation Report. 
Individuals having any major violations will not be included in the per protocol set. 
All decisions regarding major deviations will be discussed and agreed between 
the statistician/medical team and the sponsor/its representative in the Blind Data 
Review Meeting, prior to unblinding and commencing the final analysis on the 
locked database. 
10.4 
Statistical Tests 
 will write the Statistical Analysis Plan (SAP) for the present trial. 
Efficacy: 
Efficacy of the test product will be shown by testing superiority of the three 
different doses in a hierarchical test procedure from the highest to the lowest 
dose compared to placebo. 
Hierarchical ordered hypotheses will be tested at the type I error rate of α=0.05 
(two-sided) until the first non-rejection. No error rate adjustment is required. 
The set of hypotheses is as follows: 
H01: µ2400 = µPL 
H11: µ2400 ≠ µPL 
 
H02: µ1200 = µPL 
H12: µ1200 ≠ µPL 
 
H03: µ600 = µPL 
H13: µ600 ≠ µPL 
Where µ notes “mean change from baseline in the daily MSS over the entire 
treatment period” for the respective strength.  
Superiority of the Test treatment over placebo (PL) is confirmed if the p-value is 
< 0.05 and a positive treatment effect is shown. 
For the primary efficacy an endpoint, analysis of covariance (ANCOVA) will be 
carried out using treatment and center as factors and baseline MSS as a 
covariate.  
The trial will be powered to demonstrate superiority of the test product over 
placebo in the primary efficacy endpoint. 
The confirmatory analysis of the primary endpoint will be performed in the FAS.  
In addition, the analyses used for the primary efficacy endpoint will be performed 
in the PPS. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 73 of 82 
This analysis is intended to provide supportive evidence and will be considered 
descriptive. 
Safety: 
The Safety Set will be used for the analysis of the safety data. All safety data 
obtained in this trial will be tabulated descriptively with descriptive group statistics 
(mean, standard deviation, minimum, maximum, number of valid cases) where 
appropriate.  
AEs will be summarized by primary system organ class (SOC) and preferred term 
(PT). Severity and drug-event relationship of treatment emergent AEs are 
summarized separately. All adverse events will be listed. 
Vitals signs, including changes from baseline will be summarized. A frequency 
table will be presented for abnormal values of laboratory parameters. 
10.5 
Calculation of Sample Size 
The sample size is calculated in respect of the primary endpoint. For the 
calculation of sample size following parameters were taken into consideration 
based on data published by Jund et al. (2015)1: 
α 
 
 
 
 
= 0.05 (two-sided) 
ß 
 
 
 
 
= 0.20 (power = 80%) 
mean MSS change (test) 
 
= 5.4 
mean MSS change (placebo) 
= 4.5 
Standard deviation 
 
 
= 3.4 
Randomization ratio  
 
= 1 (1:1:1:1, 3 doses of test 
 
 
 
 
 
vs. placebo) 
Sample size per group: 
 
= 225 subjects 
The numbers above refer to the FAS. 
The resulting number of patients to be randomized in each of the groups is 
approximately 225. The total number of patients to be randomized is thus equal 
to 900. 
10.6 
Coding and Randomization 
The randomization code will be generated by a company subcontracted by the 
sponsor and otherwise not involved in the present trial (
, using the program
The randomization code will be kept confidential at the sponsor, in a sealed 
envelope with no access for personnel involved in the study conduct.  
The Blind Data Review Meeting (BDRM) will be held after closure of the database 
and before unblinding the trial. The decisions taken at this meeting will be 
documented in a respective protocol. Only after the BDRM protocol is signed by 
the parties involved and all database activities are completed, the unblinding will 
be possible. The sponsor/its representative will be asked to give an approval for 
the study unblinding. The randomization code will be included in the Trial Master 
File (TMF) along with correspondence concerning the study unblinding. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 74 of 82 
10.7 
Data Presentation 
The presentation of data will follow the ICH requirements for the structure and 
content of clinical study reports6. 
More details about the statistical analyses and the exact type of data presentation 
will be provided in the statistical analysis plan (SAP), which will be finalized prior 
to database lock. Any deviation from the original statistical plan will be described 
and justified in the final report, as appropriate. 
There will be a clear accounting for all patients who entered the trial, using 
figures and tables in the text of the report. The numbers of patients who were 
randomized, and who completed the trial will be provided, as well as the reasons 
for all discontinuations, grouped by treatment and by major reason (lost to follow-
up, adverse event, poor compliance etc.). 
All important deviations related to trial inclusion or exclusion criteria, conduct of 
the trial, patient management or patient assessment will be described. Protocol 
deviations will be appropriately summarized and grouped into different 
categories, e.g.: 
• 
patients who entered the trial even though they did not satisfy the entry 
criteria 
• 
patients who developed withdrawal criteria during the trial but were not 
withdrawn 
• 
patients who received the wrong treatment or incorrect dose 
• 
patients who received an excluded concomitant treatment. 
All patients planned for inclusion in the statistical analysis will be allocated to the 
respective patient population, e.g., all patients receiving any investigational 
products, all patients with any efficacy observation, all patients completing the 
trial with a specified degree of compliance, etc. 
The statistical analysis used will be described in the text of the report, with 
detailed documentation of statistical methods presented in appendix 16.1.9 of the 
study report. Important features of the analysis including the particular methods 
used, handling of drop-outs and missing data, adjustments for multiple 
comparisons, etc. will be discussed. Any changes in the analysis made after 
unblinding will be identified. 
10.8 
Interim Evaluation 
No interim evaluation is planned for the trial. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 75 of 82 
11 Trial Documentation 
11.1 
Source Documents 
All originals or certified copies (dated and signed by the investigator) of 
measurements using medical devices, which routinely produce an image or 
print-out of the respective results (e.g. safety laboratory), will be 
considered as source documents. 
All other data that cannot be derived from images/print-outs and are 
collected in the individual patient health medical record file in the clinical 
center will serve also as source data and will be transferred into the CRF as 
far as requested for the trial purposes.  
Should the investigator enter any data first into any other kind of a 
document before transferring the data into the CRF, this other document 
becomes the source for the respective type of data.  
A Trial Specific Source Form (TSSF) will be generated for the needs of the 
present trial and this document will be presented to the IEC/IRB and RA for 
approval. All TSSFs will be filed in the ITF and must be archived for at least 
25 years after the trial has been completed. 
According to Chapter 1.51 of ICH Topic E6 (R2)3 - source data must be 
original records or certified copies of original records. 
“Certified copy is a copy (irrespective of the type of media used) of the original 
record that has been verified (i.e., by a dated signature or by generation through 
a validated process) to have the same information, including data that describe 
the context, content, and structure, as the original. 3” 
As the 2nd page of CRFs and patient diaries is a duplex of the original (top) 
page of no-carbon copy paper signed and dated by the investigator, the 2nd 
page is considered as a certified copy. 
In addition, the following data, which is obtained on the patient’s informed 
consent form, is considered source data: 
 date of birth of patient, 
 screening number, 
 participation in present clinical trial with identification of sponsor, trial number, 
and trial medication, 
 date of signing informed consent. 
The original patient’s informed consent form (see also section 5.4) will be filed in 
the ITF and will remain at the investigational center for at least 25 years after the 
trial has been completed. 
Additionally, the investigator must record the patient’s trial participation in the 
subject medical health record/file. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 76 of 82 
11.2 
Case Report Form (CRF) 
A paper-based CRF will be used in this trial. 
 will design the CRF 
in close co-operation with the sponsor. The CRFs will be written in English.  
The CRFs will be printed on a double no-carbon copy paper (for details, 
please refer to section 9.5.3). 
The investigator will ensure that all data are entered promptly, completely, and 
accurately and conform to the source documents. This also applies to the data for 
screening failures, i.e. patients who have not fulfilled the eligibility criteria and 
thus are not enrolled into the trial. 
Even if there are no changes from a previous examination, the questions which 
are repeated in each CRF chapter should be fully answered for all patients 
continuing their study participation. 
11.3 
Patient Diary 
A paper-based patient diary containing the MSS and SNOT-22 
questionnaire will be used in this trial. 
 will design the diary in 
close co-operation with the sponsor.  
The diary template will be written in English and will then be translated into the 
local languages of the countries involved in the trial. The patients will always use 
the local version of the diary. 
The patient diary will be printed on a double no-carbon copy paper (for 
details, please refer to section 9.5.3). 
11.4 
Investigator's File 
 will provide each principal investigator with an investigator trial file 
specific to the trial and clinical center.  
As required according to ICH Topic E 63, all essential documents for the conduct 
of the clinical trial will be filed therein. These documents will serve to demonstrate 
the compliance of the clinical center personnel with the standards of GCP and all 
applicable regulatory requirements. The investigator trial file will be archived in 
the clinical center. 
11.5 
Trial Master File 
 will maintain and archive all essential documents for the conduct of the 
clinical trial in a trial master file as required according to ICH3.  
These documents will serve to demonstrate the compliance of all parties involved 
in the clinical trial with the standards of GCP and all applicable regulatory 
requirements. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 77 of 82 
11.6 
Final Report 
Prior to issuing the integrated final study report, 
 will prepare a draft 
report according to relevant ICH guidelines for approval by the sponsor/its 
representative. The draft report will be submitted to the QMD of 
, any 
findings will be considered in the final version. 
11.7 
Archiving 
The investigator must maintain all trial essential documents as specified in ICH 
Topic E 63 and as required by the applicable regulatory requirement(s). The 
investigator/ institution must take measures to prevent accidental or premature 
destruction of and inadmissible access to these documents.  
The investigator must make the 
 aware of the storage arrangements 
for the essential documents and conversely the 
 must inform the 
investigator/institution in writing of the need for record retention. The ultimate 
responsibility for the documents to be retained by the investigator/ institution 
resides with the investigator/institution.  
 must obtain the investigator's/institution's agreement to retain the 
trial related essential documents until the 
 informs the investigator/ 
institution these documents are no longer needed. If the investigator becomes 
unable to be responsible for their essential documents (e.g. relocation, retirement 
etc.), 
 must be notified in writing of this change and informed as to 
whom the responsibility has been transferred. 
Unless other law requires archiving for a longer period, the sponsor and the 
investigator shall archive the content of the clinical TMF/ ITF for at least 25 years 
after the end of the clinical trial. 
The medical files of subjects should be retained in accordance with national 
legislation. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 78 of 82 
12 Qualification of the Investigator and Agreements 
12.1 
Qualification of the Coordinating Investigator, Principal 
Investigator and Sub-Investigator(s) 
The coordinating investigator and the principal investigators must sign the 
protocol and any amendments. A signed and dated curriculum vitae (CV) 
showing the coordinating and principal investigator’s qualification and more than 
two years of experience in the conduct of clinical trials will be submitted to the 
sponsor/its representative. 
The investigator(s) must be qualified by education, language, training and 
experience to assume responsibility for the proper conduct of the trial. The 
investigators must meet all qualifications specified by the applicable regulatory 
requirements and must provide evidence of such qualifications throughout up-to-
date curriculum vitae and/or other relevant documentation requested. 
The investigators must be thoroughly familiar with the appropriate use of the 
investigational product(s), as described in the protocol, the current investigator’s 
brochure, in the product information and other sources of information provided by 
the sponsor. 
The investigators must be aware of and must comply with GCP and the 
applicable regulatory requirements. 
The investigators must maintain a list of appropriately qualified persons to whom 
the investigator has delegated significant trial related duties. 
12.2 
Agreements 
12.2.1 
Trial Initiation 
The investigator or delegated staff may not enroll any patients (i.e. start any 
trial-related activities) prior to sending the approval of the IEC/IRB and, if 
applicable, the approval of the regulatory authorities, to the sponsor/its 
representative and prior to the completion of a trial initiation visit, conducted by a 
representative of 
 (local CRA). 
The initiation visit will include an inventory of trial supplies and a detailed review/ 
explanation of the trial protocol and the CRF. 
12.2.2 
Confidentiality 
All information concerning trial medication, all trial material and trial drug shall 
remain the property of the sponsor. 
 and the investigator are obliged 
to keep all data and information of the trial confidential and to use that data only 
after permission of the sponsor. It is understood that no trial material or 
information developed by the sponsor of this trial in connection with 
Acetylcysteine 600 mg effervescent tablet shall be made available to third parties, 
except for official representatives, such as regulatory health authorities. 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 79 of 82 
Patients will be informed that all trial data will be stored on computer and handled 
strictly confidential. Patients will be identified throughout the documentation and 
evaluation procedures by the individual patient (screening/ randomization) 
number only, whereas all patient names will be kept secret by the investigator. 
12.2.3 
Investigator’s Signature 
By signing the trial protocol, the investigator takes responsibility that the trial is 
conducted according to the protocol, GCP and national drug laws and that the 
revised Declaration of Helsinki is observed in meaning and content to protect the 
participating persons. 
12.2.4 
Publication 
Any scientific publication of study results requires the consent of the sponsor. 
By signing the protocol, the investigator agrees that the trial results may be used 
for authorization purposes, for the compilation of information material and 
publication, including the statutory disclosure in publicly accessible databases, if 
applicable.  
12.2.5 
Investigator Fee 
 (or its local representatives - CRO) and the investigator(s) will 
conclude an agreement on trial fees. This agreement will consider the number of 
patients that are to be included and costs differentiated by the visits performed for 
each patient and for laboratory analyses. 
As this is a therapeutic trial the patients will receive remuneration of the traveling 
costs only and they are included in the investigator’s fees. 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 80 of 82 
13 References 
 
1 Jund R, Mondigler M, Stammer H, Stierna P, Bachert C. Herbal drug BNO 1016 
is safe and effective in the treatment of acute viral rhinosinusitis. Acta 
Otolaryngol. 2015 Jan;135(1):42-50 
2 WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical 
Principles for Medical Research Involving Human Subjects. Adopted by the 18th 
WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th 
WMA General Assembly, Tokyo, Japan, October 1975, 35th WMA General 
Assembly, Venice, Italy, October 1983, 41st WMA General Assembly, Hong 
Kong, September 1989, 48th WMA General Assembly, Somerset West, Republic 
of South Africa, October 1996, 52nd WMA General Assembly, Edinburgh, 
Scotland, October 2000, 53th WMA General Assembly, Washington 2002 (Note of 
Clarification on paragraph 29 added), 55th WMA General Assembly, Tokyo 2004 
(Note of Clarification on Paragraph 30 added), 59th WMA General Assembly, 
Seoul, October 2008, 64th WMA General Assembly, Fortaleza, Brazil, October 
2013 
3 GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2), Step 5, adopted by 
CHMP, 15 December 2016, issued as EMA/CHMP/ICH/135/1995 
4 ICH Topic E 8. General Considerations for Clinical Trials. Step 5. Note for 
Guidance on General Considerations for Clinical Trials (CPMP/ICH/291/95). 
March 1998 
5 ICH Topic E 9. Statistical Principles for Clinical Trials. Step 5. Note for 
Guidance on Statistical Principles for Clinical Trials (CPMP/ICH/363/96). 
September 1998 
6 ICH Topic E 3. Structure and Content of Clinical Study Reports. Step 5. Note for 
Guidance on Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95). July 1996 
7 Directive 2001/20/EC of the European Parliament and the Council of 4 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use 
8 Commission Directive 2005/28/EC of the European Parliament and the council 
of 8 April 2005 laying down principles and detailed guidelines for good clinical 
practice as regards investigational medicinal products for human use, as well as 
the requirements for authorization of the manufacturing or importation of such 
products 
9 EUROPEAN COMMISSION Communication from the Commission — Detailed 
guidance on the request to the competent authorities for authorisation of a clinical 
trial on a medicinal product for human use, the notification of substantial 
amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01). 
Official Journal of the European Union C 82/1 (EN);30.3.2010:1-19 
10 Communication from the Commission – Detailed guidance on the collection, 
verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’) (2011/C 172/01). 
Official Journal of the European Union 11.6.2011 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 81 of 82 
 
11 Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 
April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data, and repealing Directive 
95/46/EC (General Data Protection Regulation) (Text with EEA relevance). 
Official Journal of the European Union L119, 4 May 2016, p. 1–88. In force since 
25 May 2018 
12 Fokkens W, J et al.: European Position Paper on Rhinosinusitis and Nasal 
Polyps. Rhinology 2012;Suppl.23:1-299 
13 Rosenfeld R. M. et al.: Clinical Practice Guideline (Update): Adult Sinusitis. 
Otolaryngology–Head and Neck Surgery 2015;Vol.152(2S):S1–S39 
14 DEGAM, 2017: Rhinosinusitis. S2k-Leitlinie. AWMF-Register-Nr. 017/049 und 
053-012 
15 Summary of Product Characteristics for ACETYLCYSTEINE 100 MG 200 
MG 600 MG EFFERVESCENT TABLET (Sandoz: 1.3.1 spc-label-pl - common-
spc - 4,825, (DE/H/3625/001-003+ DE/H/3667/001 change 144214 + merg var 
001-var 002); 20141028:1-13 
16 Komet et al. A New Mucolytic Agent As A Therapeutic Adjunct in Nasal 
Sinusitis. The Eye, Ear, No5e and Throat Monthly 1965;Vol.44:47-50 
17 Boner A. L. et al. A combination of cefuroxime and N-acetylcysteine for the 
treatment of maxillary sinusitis in children with respiratory allergy. International 
Journal of Clinical Pharmacology, Therapy and Toxicology 1984,Vol. 22(9);511-
514 
18 Zeiger R. S.: Prospects for ancillary treatment of sinusitis in the 1990s. J 
Allergy Clin Immunol 1992;90:478-95 
19 Macchi A. et al.: Recurrent acute rhinosinusitis: A single blind clinical study of 
Nacetylcysteine vs Ambroxol associated to corticosteroid therapy. Int. J. 
Immunopathol. PharmacoI 2012;Vol. 25,No.1:207-217 
20 Bahtouee M. et al.: Acetylcysteine in the treatment of subacute sinusitis: A 
double blind placebo-controlled clinical trial. Ear Nose Throat J 2017; 
January;96(1):E7 
21 Meltzer E. O., Bachert C., Staudinger H.: Treating acute rhinosinusitis: 
Comparing efficacy and safety of mometasone furoate nasal spray, amoxicillin, 
and placebo. J Allergy Clin Immunol 2005;116:1298-1295 
22 Revicki D et al.: Major Symptom Score Utility Index for patients with acute 
rhinosinusitis. Am J Rhinol & Allergy 25,e99-e106, 2011;(doi: 
10.2500/ajra.2011.25.3575) 
23 Meyer, A., R. Buhl and H. Magnussen. The effect of oral N-acetylcysteine on 
lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir 1994;J 
7(3):431-436 
24 Demedts, M. et al.:. High-dose acetylcysteine in idiopathic pulmonary fibrosis. 
N Engl J Med 2005;353(21):2229-2242 
25 Behr, J., K. Maier, B. Degenkolb, F. Krombach and C. Vogelmeier. 
Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing 
alveolitis - Adjunctive therapy to maintenance immunosuppression. American 
Journal of Respiratory and Critical Care Medicine 1997;156(6):1897-1901 
 


HEXAL AG 
Trial Protocol 
Acetylcysteine 600 mg effervescent tablet 
 
Study No.: 2018-08-EFT-1 / C1018001 
 
EudraCT No.: 2019-000060-20 
 
Study Protocol Version Final 5.0, 14-Aug-2020  CONFIDENTIAL 
page 82 of 82 
 
26 Cazzola M, Calzetta L, Page C, Jardim J, Chuchalin AG, Rogliani P, Matera 
MG. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: 
a meta-analysis. Eur Respir Rev. 2015;24(137):451-461 
27 Smilkstein M.J., Knapp G.L., Kulig K.W., Rumack B.H.: Efficacy of oral N-
acetylcysteine in the treatment of acetaminophen overdose. Analysis of the 
national multicenter study (1976 to 1985). N Engl J Med.1988;319(24):1557-1562 
28 Richter, S. K. and A. J. Crannage: Evaluation of N-acetylcysteine for the 
prevention of contrast-induced nephropathy. J Community Hosp Intern Med 
Perspect 2015;5(3):27297 
29 Kang, X., D. Y. Hu, C. B. Li, Z. S. Ai and A. Peng: N-acetylcysteine for the 
prevention of contrast-induced nephropathy in patients with pre-existing renal 
insufficiency or diabetes: a systematic review and meta-analysis." Ren Fail 2015; 
37(10):297-303 
30 Trivedi, H., S. Daram, A. Szabo, A. L. Bartorelli and G. Marenzi: High-dose N-
acetylcysteine for the prevention of contrast-induced nephropathy. Am J Med  
2009;122(9):874.e9-874.e15 
31 Deepmala, J. Slattery, N. Kumar, L. Delhey, M. Berk, O. Dean, C. Spielholz 
and R. Frye: Clinical trials of N-acetylcysteine in psychiatry and neurology: A 
systematic review. Neurosci Biobehav Rev 2015;55:294-321 
32 Ooi S.L., Green R., Pak S.C.: N-Acetylcysteine for the Treatment of Psychiatric 
Disorders: A Review of Current Evidence. Biomed Res Int 2018;2469486 
33 Liu, X. H., C. Y. Xu and G. H. Fan: Efficacy of N-acetylcysteine in preventing 
atrial fibrillation after cardiac surgery: a meta-analysis of published randomized 
controlled trials. BMC Cardiovasc Disord 2014;14:52 
34 Lai, Z. W.et al.: N-acetylcysteine reduces disease activity by blocking 
mammalian target of rapamycin in T cells from systemic lupus erythematosus 
patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 
2012;64(9):2937-2946 
35 Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, Hartwell KJ, 
McRae-Clark AL, Brady KT. “A double-blind randomized controlled trial of N-
acetylcysteine in cannabis-dependent adolescents”. Am J Psychiatry 2012; 
169(8): 805-812 
36 Ghanizadeh A., Mohammadi M.R., Bahraini S., Keshavarzi Z., Firoozabadi A., 
Alavi Shoshtari A.: Efficacy of N-Acetylcysteine Augmentation on Obsessive 
Compulsive Disorder: A Multicenter Randomized Double Blind Placebo 
Controlled Clinical Trial. Iran J Psychiatry 2017;12(2):134-141 

SAP_001.pdf: 
Official Title: 
Efficacy and Safety of Acetylcysteine for the Treatment of Acute 
Uncomplicated Rhinosinusitis: a Prospective, Randomized, Double-blind, 
Placebo-controlled Trial 
NCT Number: 
NCT04123405 
Document Date: 
Statistical Analysis Plan Version 2: 07 October 2020 


Version Final 2.0, 07-Oct-2020 
page 1 of 34 
Efficacy and safety of acetylcysteine for the treatment of acute 
uncomplicated rhinosinusitis: a prospective, randomized, double-blind, 
placebo-controlled trial 
STATISTICAL ANALYSIS PLAN 
Version Final 2.0, date 07-Oct-2020 
Project No(s): 
EudraCT No. 
CRO: 
Sponsor: 
Project Management and 
Sponsor Representative: 
2018-08-EFT-1 (Sponsor) / C1018001 
(CRO) 2019-000060-20 
 
 
 
 
Phone: 
Fax:
HEXAL AG 
Industriestraße 25 
83607 Holzkirchen 
Germany 
Phone:
Fax: 
Verovškova 57 
1526 Ljubljana 
Slovenia 
Phone 
 
Mobile: 
 
Email: 
 


 
C1018001 
Statistical Analysis Plan 
Acetylcysteine 600 mg effervescent tablet 
EudraCT No.: 2019-000060-20 
1 
Signatures 
CONTRACT RESEARCH ORGANIZATION 
Author of Statistical Analysis Plan 
 Dipl. Math. 
Email:
 
Sig
 
 Dipl. Math. (FH) 
Email: 
 
Signature, Date 
Version Final 2.0, 07-0ct-2020 
HEXALAG 
2018-08-EFT-1 
page 2 of 34 


 
C1018001 
Statistical Analysis Plan 
Acetylcysteine 600 mg effervescent tablet 
EudraCT No.: 2019-000060-20 
 
, Dipl. Biol. 
Email: 
 
 
, MD, PhD 
Email: 
 
 
, Dipl. Biol., PhD 
Email:
 
Signature, Date 
Version Final 2.0, 07-0ct-2020 
HEXALAG 
2018-08-EFT-1 
page 3 of 34 


 
C1018001 
Statistical Analysis Plan 
Acetylcysteine 600 mg effervescent tablet 
EudraCT No.: 201 S-000060-20 
Project Management and Sponsor Representative 
 
Lek Pharmaceuticals d.d. 
 
02 . )0 , 2.020 
Si
 
Lek Pharmaceuticals d.d. 
, PhD 
Signature, Date 
Version Final 2.0, 07-0ct-2020 
HEXALAG 
2018-08-EFT-1 
page 4 of 34 


 
C1018001 
Statistical Analysis Plan 
Acetylcysteine 600 mg effervescent tablet 
EudraCT No.: 2019-000060-20 
Project Management and Sponsor Representative 
 
Lek Pharmaceuticals· d.d. 
 
Signature, Date 
 
Lek Pharmaceuticals d.d. 
, PhD 
Signature, Date 
Version Final 2.0, 07-0ct-2020 
HEXALAG 
2018-08-EFT-1 
page 4 of 34 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 5 of 34 
2 
Table of Contents 
TITLE PAGE .......................................................................................................................... 1 
1 
SIGNATURES .......................................................................................................... 2 
2 
TABLE OF CONTENTS ........................................................................................... 5 
3 
LIST OF ABBREVIATIONS ..................................................................................... 7 
4 
STATISTICAL ANALYSIS PLAN ............................................................................ 8 
5 
GENERAL STUDY INFORMATION ....................................................................... 10 
5.1 
OBJECTIVES ................................................................................................... 10 
5.1.1 
Primary Objective .......................................................................................... 10 
5.1.2 
Secondary Objective ..................................................................................... 10 
5.2 
STUDY DESIGN ............................................................................................... 10 
5.3 
STUDY POPULATION ........................................................................................ 10 
5.4 
STATISTICAL BASIS FOR SAMPLE SIZE .............................................................. 10 
5.5 
RANDOMIZATION ............................................................................................. 11 
6 
DEFINITION OF ENDPOINTS ............................................................................... 12 
6.1 
PRIMARY ENDPOINT ........................................................................................ 12 
6.2 
SECONDARY ENDPOINTS ................................................................................. 12 
6.3 
SAFETY ENDPOINTS ........................................................................................ 12 
7 
STATISTICAL ANALYSIS CONVENTIONS .......................................................... 13 
7.1 
POPULATION FOR ANALYSIS ............................................................................ 13 
7.1.1 
Safety Set ..................................................................................................... 13 
7.1.2 
Full Analysis Set (FAS) ................................................................................. 13 
7.1.3 
Per Protocol Set ............................................................................................ 13 
7.2 
STATISTICAL ANALYSIS METHODS .................................................................... 14 
7.2.1 
Listings and Descriptive Statistics ................................................................. 14 
7.2.2 
Rounding and Decimal Places ...................................................................... 14 
7.2.3 
Statistical Significance Level ......................................................................... 15 
7.2.4 
Software ........................................................................................................ 15 
7.2.5 
Missing Data ................................................................................................. 15 
7.2.6 
Interim Analysis ............................................................................................. 16 
7.2.7 
Protocol Deviations ....................................................................................... 16 
7.3 
ANALYSIS VARIABLES ...................................................................................... 17 
7.3.1 
Efficacy Variables .......................................................................................... 17 
7.3.1.1 
Major Symptom Score (MSS) ........................................................................ 17 
7.3.1.2 
Sino-Nasal Outcome Test (SNOT-22) Questionnaire .................................... 17 
7.3.1.3 
Investigator’s Assessment of the Overall Response to Treatment ................. 18 
7.3.2 
Demographic and Background Variables ...................................................... 18 
7.3.3 
Safety Variables ............................................................................................ 19 
7.3.3.1 
Adverse Events ............................................................................................. 19 
7.3.3.2 
Serious Adverse Events ................................................................................ 21 
7.3.3.3 
Assessment of Tolerability ............................................................................. 22 
7.3.3.4 
Vital Signs ..................................................................................................... 22 
7.3.3.5 
Physical Examination .................................................................................... 22 
7.3.3.6 
Examination of Nose, Ears, Mouth / Throat (ENT) ......................................... 22 
7.3.3.7 
Safety Laboratory Examination ..................................................................... 23 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
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7.3.4 
Compliance of patients .................................................................................. 23 
7.3.4.1 
Disposition of patients ................................................................................... 23 
7.3.4.2 
Protocol deviations ........................................................................................ 24 
7.3.4.3 
Compliance with IMP ..................................................................................... 24 
7.3.4.4 
Treatment duration and time intervals between visits .................................... 24 
7.4 
STATISTICAL ANALYSIS OF THE ENDPOINTS ...................................................... 25 
7.4.1 
Statistical Analysis of the Primary Endpoint ................................................... 25 
7.4.2 
Statistical Analysis of the Secondary Endpoints ............................................ 25 
7.4.2.1 
Time to onset of action defined as first day of active treatment on which MSS shows 
statistically significant difference from placebo .............................................. 25 
7.4.2.2 
MSS development over the course of the study ............................................ 26 
7.4.2.3 
SNOT-22 by visit and changes versus baseline ............................................ 26 
7.4.2.4 
Percentage of responders and non-responders to treatment based on the 
assessment of overall response to treatment by the investigator ................... 26 
8 
LIST OF TABLES, LISTINGS AND FIGURES ....................................................... 28 
8.1 
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT (CHAPTER 14) .......... 28 
8.2 
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT ............................... 31 
8.3 
LISTINGS (APPENDIX 16.2 OF THE CLINICAL STUDY REPORT) ............................ 31 
9 
REFERENCE LIST ................................................................................................ 34 
 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 7 of 34 
3 
List of Abbreviations 
ADAM 
Analysis Data Model 
AE 
Adverse event 
ANCOVA 
Analysis of Covariances 
 
 
CDISC 
Clinical Data Interchange Standards Consortium 
CEO 
Chief Executive Officer 
CHMP 
Committee for Medicinal Products for Human Use 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Coefficient of variation 
DMD 
Statistics and Data Management Department 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
(United States) Food and Drug Administration 
GLM 
General linear models (procedure in SAS) 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IMP 
Investigational medicinal product 
IQR 
Interquartile range 
LOCF 
Last Observation Carried Forward 
MSE 
Mean Sum of Squares of the error term (in ANCOVA) 
MSS 
Major Symptom Score 
OC 
ORACLE Clinical 
PPS 
Per-Protocol Set 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SDTM 
Study Data Tabulation Model 
SNOT 
Sino-Nasal Outcome Test (questionnaire) 
SOP 
Standard operating procedure 
TLF 
Tables, Listings, Figures 
TSSF 
Trial Specific Source Form 
WHO 
World Health Organization 
 
 
Note: Not all of the above-mentioned abbreviations are used in this document. 
 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 8 of 34 
4 
Statistical Analysis Plan 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in 
analyzing study data and outlines the statistical programming specifications for the 
Tables, Listings and Figures (TLFs). It describes the variables and populations, 
anticipated data transformations and manipulations and other details of the analyses 
not provided in the Trial Protocol. 
The analyses described are based on the following trial documents: 
 TRIAL PROTOCOL (Version Final 2.0, dated 24-Apr-2019) – GLOBAL as well as 
the latest country specific protocol versions as listed below: 
 TRIAL PROTOCOL AMENDMENT 1.0 (Version Final 1.0, dated 23-Aug-2019) 
with CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER 
AMENDMENT 1.0 (Version Final 3.0, dated 23-Aug-2019) - Valid for Germany 
only 
 TRIAL PROTOCOL AMENDMENT 2.0 (Version Final 1.0, dated 10-Sep-2019) 
with CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER 
AMENDMENT 2.0 (Version Final 4.0, dated 10-Sep-2019) - Valid for Bulgaria 
and Moldova only 
 TRIAL PROTOCOL AMENDMENT 3.0 (Version Final 1.0, dated 15-Oct-2019) 
with CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER 
AMENDMENT 3.0 (Version Final 5.0, dated 10-Oct-2019) - Valid for Russia 
only 
 TRIAL PROTOCOL AMENDMENT 4.0 (Version Final 1.0, dated 01-Nov-2019) 
with CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER 
AMENDMENT 4.0, (Version Final 6.0 dated 01-Nov-2019) - Valid for Moldova 
only. 
Due to internal restructuring, all project management responsibilities for the clinical trial 
shifted with effective date 19-Aug-2020 from Sandoz Development Center (SDC) 
Holzkirchen with address Industriestraße 25 in 83607 Holzkirchen, Germany to Sandoz 
Development Center (SDC) Slovenia, Lek Pharmaceuticals d.d., Verovškova 57, 1526 
Ljubljana, Slovenia. An amendment and new versions of the trial protocols valid for the 
four counties were generated (see below). 
 TRIAL PROTOCOL AMENDMENT 5.0 - GLOBAL (Version Final 1.0, dated 14-
Aug-2020) as well as the latest country specific protocol versions as listed 
below: 
 CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER AMENDMENT 
5.0 (Version Final 4.0, dated 14-Aug-2020) - Valid for Germany only 
 CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER AMENDMENT 
5.0 (Version Final 5.0, dated 14-Aug-2020) - Valid for Bulgaria only 
 CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER AMENDMENT 
5.0 (Version Final 6.0, dated 14-Aug-2020) - Valid for Russia only 
 CONSOLIDATED VERSION OF TRIAL PROTOCOL AFTER AMENDMENT 
5.0, (Version Final 7.0 dated 14-Aug-2020) - Valid for Moldova only. 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
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2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 9 of 34 
 
The following versions of the Case Report Forms and Patient Diary: 
 CASE REPORT FORM (Version Final 5.0 dated 10-Sep-2019), issued AFTER 
AMENDMENT 2.0 - Valid for Bulgaria only 
 CASE REPORT FORM (Version Final 6.0 dated 10-Oct-2019), issued AFTER 
AMENDMENT 3.0 - Valid for Russia only 
 CASE REPORT FORM (Version Final 7.0 dated 01-Nov-2019), issued AFTER 
AMENDMENT 4.0 - Valid for Moldova only 
 CASE REPORT FORM (Version Final 8.0 dated 28-Nov-2019) - Valid for 
Germany only 
 PATIENT DIARY (Version Final 3.0, 26-Apr-2019) 
 SOPs of CCDRD AG 
 GUIDELINE FOR GOOD CLINICAL PRACTICE E6 (R2), Step 5, adopted by 
CHMP, 15-December-2016, issued as EMA/CHMP/ICH/135/1995 
 ICH Topic E 9. Statistical Principles for Clinical Trials. Step 5. Note for Guidance on 
Statistical Principles for Clinical Trials (CPMP/ICH/363/96). September 1998 
 ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials, EMA/CHMP/ICH/436221/2017, 17 
February 2020 
Further references are listed in section 9. 
The SAP will be finalized prior to database lock and describes the statistical analysis as 
it is foreseen when the study is being planned. If circumstances should arise during the 
study rendering this analysis inappropriate, or if improved methods of analysis should 
arise, updates to the analyses may be made. Any deviations from the SAP after 
database lock, reasons for such deviations and all alternative or additional statistical 
analyses that may be performed, will be described in an SAP Addendum. 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 10 of 34 
5 
General Study Information 
5.1 
Objectives 
5.1.1 
Primary Objective 
The primary objective of the present trial is the assessment of the efficacy of three 
different total daily doses of the investigational product containing 600 mg 
acetylcysteine per effervescent tablet compared to placebo for the treatment of acute 
uncomplicated rhinosinusitis. 
5.1.2 
Secondary Objective 
The secondary objective of the present trial is the assessment of safety and tolerability 
of three different total daily doses of the investigational product containing 600 mg 
acetylcysteine per effervescent tablet compared to placebo for the treatment of acute 
uncomplicated rhinosinusitis. 
5.2 
Study Design 
The study will be conducted as a prospective, randomized, multinational, multicenter, 
double-blind study in 4 parallel groups of patients.  
5.3 
Study Population 
Approximately 900 patients with acute, uncomplicated rhinosinusitis will be 
randomized. 
A detailed complete list of inclusion and exclusion/withdrawal criteria is shown in the 
(country specific) Trial Protocol in chapter 8.4. 
5.4 
Statistical Basis for Sample Size 
The sample size is calculated in respect of the primary endpoint. For the calculation of 
sample size, the following parameters were taken into consideration based on data 
published by Jund et al. (2015)1: 
α 
 
 
 
 
= 0.05 (two-sided) 
ß 
 
 
 
 
= 0.20 (power = 80%) 
mean MSS change (test) 
 
= 5.4 
mean MSS change (placebo) 
= 4.5 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 11 of 34 
Standard deviation 
 
 
= 3.4 
Randomization ratio  
 
= 1 (1:1:1:1, 3 doses of test vs. placebo) 
Sample size per group: 
 
= 225 patients 
 
The numbers above refer to the FAS. 
The number of patients to be randomized in each of the groups is approximately 225. 
The total number of patients to be randomized is thus equal to 900.  
5.5 
Randomization 
Each of the patients will be randomly assigned to one of the following groups. 
 Group A: 600 mg acetylcysteine: one tablet test product plus three tablets placebo 
per day (to be taken as two tablets dissolved in a glass of water, twice daily) OR 
 Group B: 1200 mg acetylcysteine: two tablets test product plus two tablets placebo 
per day (to be taken as two tablets dissolved in a glass of water, twice daily) OR 
 Group C: 2400 mg acetylcysteine: four tablets test product per day (to be taken as 
two tablets dissolved in a glass of water, twice daily) OR 
 Group D: Placebo: four tablets placebo per day (to be taken as two tablets dissolved 
in a glass of water, twice daily). 


 
Statistical Analysis Plan 
HEXAL AG 
C1018001 
Acetylcysteine 600 mg effervescent tablet 
2018-08-EFT-1 
EudraCT No.: 2019-000060-20 
Version Final 2.0, 07-Oct-2020 
 
page 12 of 34 
6 
Definition of Endpoints 
6.1 
Primary Endpoint 
The primary endpoint is the mean change from baseline in the daily Major Symptom 
Score (MSS) calculated as  
𝑐ℎ𝑎𝑛𝑔𝑒𝑀𝑆𝑆
̂
= 1
14
∑(𝑀𝑆𝑆𝑖−𝑀𝑆𝑆 𝐷𝑎𝑦 1 (𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)) 
𝐷𝑎𝑦 15
𝑖=𝐷𝑎𝑦 2
, 
The MSS will be assessed by the patient and documented in the patients’ diaries (see 
section 7.4). 
6.2 
Secondary Endpoints 
 Time to onset of action defined as first day of active treatment on which MSS shows 
statistically significant difference from placebo 
 MSS development over the course of the study 
 SNOT-22 by visit and changes versus baseline 
 Percentage of responders and non-responders to treatment based on the 
assessment of overall response to treatment by the investigator. 
6.3 
Safety Endpoints 
 Incidence and severity of adverse events 
 Incidence and severity of drug-related adverse events 
 Clinically relevant changes in laboratory parameters, vital signs, physical and ENT 
examination parameters from Visit 1 to Visit 6 (or early termination)  
 Overall assessment of tolerability by patient and by investigator. 


 
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7 
Statistical Analysis Conventions 
7.1 
Population for Analysis 
7.1.1 
Safety Set 
The Safety Set (SS) is defined as all randomized patients who receive at least one 
dose of the trial medication. This will be the primary dataset for the evaluation of safety. 
7.1.2 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) is defined as all randomized patients who receive at least 
one dose of the trial medication and who have at least one post-baseline assessment 
of MSS during the double-blind treatment period. This will be the primary dataset for 
comparison of the primary endpoint. 
7.1.3 
Per Protocol Set 
The Per Protocol Set (PPS) is defined as all FAS-evaluable patients who complete the 
double-blind treatment period without major protocol violations (see Section 7.2.7) that 
could affect the efficacy evaluation, which include the availability of measurements of 
the primary endpoints. The latter will be prospectively defined before unblinding the 
trial.  


 
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7.2 
Statistical Analysis Methods 
7.2.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed.  
Data will be described using summary statistics as described in the following sections. 
For qualitative variables frequency tables (with absolute numbers and percentages) will 
be created. For quantitative variables descriptive statistics (number of non-missing 
observations [n], arithmetic mean, standard deviation, median, minimum and 
maximum) will be calculated. 
The standards used to support electronic data submission (e.g., clinic data, diagnostic 
lab data, efficacy data) will be based on the available version from the Clinical Data 
Interchange Standards Consortium (CDISC). The versions to be used during the course 
of this study will stay the same. The current versions are:  
 Study Data Tabulation Model (SDTM) v1.6, 
 Study Data Tabulation Model Implementation Guide (SDTM IG) v3.2,  
 CDISC SDTM Controlled Terminology, 2019-09-27 
 Analysis Data Model (ADaM) v2.1,  
 Analysis Data Model Implementation Guide (ADaM IG) v1.1,  
 The ADaM Basic Data Stucture for Time-to-Event Analyses v1.0 
 ADaM Structure for Occurrence Data (OCCDS) v1.0 
 CDISC ADaM Controlled Terminology, 2019-09-27 
 Define-XML v2.0. 
A Validation Report (using Pinnacle 21 Community, latest version) and respective 
Reviewer’s Guides (Study Data Reviewers Guide and Analysis Data Reviewers Guide) 
will be prepared. 
7.2.2 
Rounding and Decimal Places 
All raw data will be listed according to the number of decimal places presented in the 
source data (i.e. CRF, AE/SAE Report, SNOT diary). 
In general, the following rules regarding summary statistics will be applied, unless 
otherwise stated: 
• 
Mean and median will be tabulated to one more decimal place than the source 
data, 
• 
Minimum and maximum will be tabulated to the same number of decimal places 
as the source data, 


 
Statistical Analysis Plan 
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• 
Standard deviation will be tabulated to two more decimal places than the source 
data, 
• 
Coefficient of variation (CV)%, if applicable will be presented to one decimal 
place. 
The primary endpoint mean change will be rounded to 3 decimal places in listings and 
for further calculations (see section 7.4) 
7.2.3 
Statistical Significance Level 
All statistical tests and comparisons are evaluated at the 5% significance level (𝛼=
5%) if not stated otherwise. 
7.2.4 
Software 
All statistical analysis will be performed using Statistical Analysis Software (SAS) 
Version 9.4 or higher.  
7.2.5 
Missing Data 
In principle there will be no imputation of missing data. 
For evaluation of the primary endpoint in the FAS population the last observation 
carried forward (LOCF) - principle will be applied. 
If any patient terminates the trial before completing the 14 days of double-blind 
treatment, the last available post-baseline assessment of the MSS will be carried 
forward until the virtual last observation point, that means the last available post-
baseline MSS (i.e. the respective rating of each of the symptoms) will be carried 
forward for the calculation of the mean change of the MSS. 
For missing assessments of single symptoms which are missing between non-missing 
assessments, the same will be applied. I.e. the last non-missing score will be kept 
(which implies non-improvement). 
With respect to the evaluation of the secondary endpoints in the FAS the following will 
be applied: 
SNOT-22 score - in case of missing item values for the calculation of the score the 
worst item category will be used if not more than two item values are missing, 
otherwise the score will be regarded as missing. 
Percentage of responders and non-responders: Missing values for the investigator’s 
assessment of the overall response to treatment will be set to the worst case (1-major 
deterioration, i.e. considered as non-responder) 


 
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7.2.6 
Interim Analysis 
Not applicable. 
7.2.7 
Protocol Deviations 
All protocol deviations will be listed by patient and will be discussed with the sponsor 
during the Blind Data Review Meeting before unblinding and database lock. Depending 
on the severity of protocol deviations (minor/major) the patients will be assigned to the 
respective statistical population.  
Possible protocol deviations are discussed in a separate Protocol Deviation 
Management Plan. 
The following categories of protocol deviations were defined in the Protocol Deviation 
Management Plan: 
• 
Eligibility deviation, 
• 
Withdrawal deviation 
• 
Dosing deviation, 
• 
Prohibited medication and therapies deviation 
• 
Operational deviation 
The final decisions regarding the severity of protocol deviations will be documented in a 
separate Protocol Deviation Report. 
The occurred protocol deviations will be assessed by means of frequency tables, see 
Section 7.3.4.2. 


 
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7.3 
Analysis Variables 
7.3.1 
Efficacy Variables 
7.3.1.1 
Major Symptom Score (MSS) 
The MSS combines the following symptoms of rhinosinusitis based on expert clinician 
recommendations 
 rhinorrhea/ anterior discharge,  
 postnasal drip,  
 nasal congestion,  
 headache, and  
 facial pain/pressure. 
Assessment of symptom severity. The patient will rate the severity of each of the five 
symptoms of the MSS using a four-point rating scale of increasing severity ( = 
none/not present,  = mild,  = moderate,  = severe).  
The MSS is then the sum of the single ratings. 
The MSS will be assessed by the patient at screening (Visit 1) and immediately before 
randomization (Visit 2; this will constitute the baseline value). The investigator will 
transcribe both patient’s MSS assessments from TSSF into the CRF.  
Thereafter, the patient will document the MSS in the patient diary once a day before 
intake of the morning dose, starting with Day 2 until Day 14 (last day of treatment or 
earlier in case of drop-out). 
The last MSS will be assessed by the patient during Visit 6 and transcribed from TSSF 
into the CRF. 
Statistical evaluation of the MSS is described in section 7.4.  
7.3.1.2 
Sino-Nasal Outcome Test (SNOT-22) Questionnaire 
SNOT-22 will be assessed by the patient in the patient diary on Day 1, Day 7 and Day 
14.  
SNOT-22 will be part of the patient diary printed on no-carbon copy paper (one top 
page and a second no-carbon copy page). The patient must complete the first SNOT-
22 in the patient diary during Visit 2, after the investigator explained unclear terms and 
answered all patient’s questions. 
All individual SNOT questionnaire results of the Safety Set will be listed by patient. 
Further statistical evaluation is described in section 7.4.2. 


 
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7.3.1.3 
Investigator’s Assessment of the Overall Response to Treatment 
The investigator will assess the overall response to treatment at each visit after 
baseline: at Visit 3 (Day 4), Visit 4 (Day 7), Visit 5 (Day 10), and at Visit 6 (Day 15 or up 
to 3 additional days). 
The investigator will rate the response to treatment using a five-point rating scale:  = 
major deterioration,  = minor deterioration,  = no change,  = minor improvement, 
 = major improvement. 
All individual assessments of overall response of the Safety Set will be listed by patient. 
Further statistical evaluation is described in section 7.4.2 
7.3.2 
Demographic and Background Variables 
The following demographic and anthropometric information will be recorded: 
 Date of informed consent 
 Date of birth (in Germany only the year of birth will be recorded) 
 Age in years at date of informed consent (derived, whereas age for patients from 
Germany cannot be derived exactly from the CRF, Discrepancy Clarification Forms 
will be used to obtain the age of the patients from the investigator) 
 Ethnicity (Caucasian, Hispanic, Black, Asian, Unknown or other) 
 Gender/ Sex 
 Height without shoes (cm) 
 Body weight inclusive indoor clothing without shoes (kg) 
 Body mass index (BMI) calculated as [weight/height²] (kg/m²) 
 Life Style and Habits (alcohol consumption, smoking status and drug abuse history) 
 Anamnestic information (last participation in any clinical trial, allergies, …) 
 Anamnesis on Acute Uncomplicated Rhinosinusitis 
 Method of contraception (additional anamnesis for female patients only) 
 Medical and surgical history (including previous and concomitant diseases) 
 Previous medication (drug history)/ therapies (within 6 months prior to screening 
which stopped before screening) 
 Concomitant medication (recorded at screening visit and/or during the trial) 
 Medical or therapeutic measures (recorded at screening visit and/or during the trial) 
All demographic data and background variables of the Safety Set will be listed by 
patient, except for the anamnestic information. The anamnestic information is only 
collected in order to document the eligibility of the patients. Additionally, demographic 
data of the patients which were only screened but not treated will be listed by patient. 
Descriptive statistics for the quantitative data (age, height, weight, BMI) and absolute 
and relative frequencies of the quantitative data (sex, ethnic group) will be presented 
for the safety set, the FAS and for the PPS. 


 
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The concomitant medication (drug name, indication, administration scheme, dosage 
form, route of administration, start date and end date of medication) will be listed by 
patient. The end date will be substituted by the term ‘ongoing’ if the medication did not 
stop before termination of the trial. The listings contain the WHO Drug B3 coding up to 
level 4 for the used drugs, as well as MedDRA (Version 22.1 or higher) for the 
respective indications. 
Frequency tables will be presented for medical and surgical history (including previous 
and concomitant diseases) and for the previous and concomitant medication. 
The medical history will be displayed as incidences (number of findings and number of 
patients affected) for diseases and surgery which ended before start of the trial (Visit 2) 
by SOC, PT and treatment group for the safety set. 
The concomitant diseases will be displayed as incidences (number of findings and 
number of patients affected) for diseases and surgery which are present at start of the 
trial (Visit 2) SOC, PT and treatment group for the safety set. 
The previous medication, i.e. medication which stopped before the start of the trial 
(Visit 2) will be tabulated as numbers of findings and numbers of patients affected by 
WHO Drug B3 term Level 3, Preferred Name and by treatment group for the safety set. 
The concomitant medication which is present at the start of the trial (Visit 2) and which 
starts during the trial, will be tabulated as numbers of findings and numbers of patients 
affected by WHO Drug B3 term Level 3, Preferred Name and by treatment group for 
the safety set. 
7.3.3 
Safety Variables 
All evaluations of the safety variables will be performed in Safety Set. 
7.3.3.1 
Adverse Events 
An adverse event or adverse experience (AE) is any untoward medical occurrence in 
a patient or clinical investigation patient administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with this treatment. 
An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medical product, whether or not considered related to the medical 
product. 
Existing concomitant diseases are not considered AEs, except if they have 
worsened/adversely progressed during the study. 
The Medical Dictionary for Regulatory Activities (MedDRA, Version 22.1 or higher) is 
used for coding adverse events. 
All AEs with start date/time prior to first intake of IMP are pre-treatment AEs and will be 
assigned to screening. 
Any adverse events with missing start date/time or the end date/time are treated as 
follows: 


 
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 If the date is known but the time is unknown, the time will be imputed with a time 
0:00 h for the start and with 23:59 for the end. In the listings the unknown time will 
be displayed as NK. If the start date is a treatment date, then the AE will be 
assigned to the treatment of that date. 
 If the start date is incomplete: 
 Missing day: will be imputed with the 1st of the month unless month is the 
same month of first dose of study drug; then it will be imputed with first dose 
date 
 Missing day and month: will be imputed with 1st January unless year is the 
same as first dose date; then it will be imputed with first dose date  
 Completely missing: impute first dose date unless the end date suggests it 
could have started prior to this in which case the 1st January of the same year 
will be imputed as the start date  
 If the end date is incomplete: 
 Missing day: will be imputed with the last day of the month unless month is 
same as month of first dose of study drug; then it will be imputed with the last 
dose date  
 Missing day and month: will be imputed with 31st December unless year is the 
same as first dose date; then it will be imputed with last dose date 
 Completely missing (and not ONGOING): if the AE started prior to 1st dose 
date then it will be imputed the 1st dose date. If the AE started after 1st dose 
date then it will be imputed with the last dose date 
The pre-treatment adverse events which occurred before intake of the first dose of IMP 
(between screening visit (Visit 1) on Day -1 and Visit 2 on Day 1) will be presented in 
listings. 
The adverse events will be analyzed by means of frequency tables. For an overview a 
frequency table with numbers of patients affected will be presented by treatment for the 
categories (Summary of adverse events): total, adverse events leading to 
discontinuation, serious adverse events, and (serious) adverse events with outcome 
death. 
Further frequency tables will be classified by system organ class (SOC), preferred term 
(PT) derived from MedDRA and by treatment. The numbers of adverse events as well 
as the numbers of patients affected will be presented. 
Moreover, tables for incidences of adverse events and patients with respect to the 
following parameters will be created: 
 Severity (mild, moderate, severe), 
 Relationship between study medication and adverse event (suspected, not 
suspected), 
 Outcome (not recovered / not resolved / unchanged; recovered / resolved, 
improving/ recovering/ resolving; recovered with sequelae; fatal; condition 
deteriorating; unknown). 
All adverse events will be listed, these listings will be split into three parts containing 
the following columns: 


 
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Part I: Rnd. No. , Report No., Observed AE (in verbatim), Seriousness, Action taken 
with IMP; Severity, Outcome, Relationship to IMP, Relationship to NIMP 
The report number is an identifier for the single adverse events within one patient 
(chronologically). 
This part I will be displayed in two versions:  
• 
first version is sorted by treatment group (where pre-treatment adverse events 
will be pooled as additional group), random number and report number,  
• 
in the second version the adverse events are sorted by random number and 
report number. 
The second and third part will only be displayed sorted by random number and report 
number with the following information: 
Part II: Rnd. No., Report No., MedDRA Coding: Preferred Term (with Code), Date/Time 
of onset, Date/Time of end, Last date/time of dose before onset, Last treatment. 
Part III: Rnd. No, Report No, Event treatment, Specification of event treatment. 
These adverse events will be listed for the safety set. If patients experience adverse 
events who were not randomized, or had no intake of IMP then further listing for these 
events will be displayed. 
7.3.3.2 
Serious Adverse Events  
A serious adverse event (SAE) or serious adverse reaction (SAR) is any untoward 
medical occurrence that at any dose: 
 results in death, 
 is life-threatening, 
 requires inpatient hospitalization or prolongation of existing inpatient 
hospitalization, 
 results in persistent or significant disability/incapacity, 
 is a congenital anomaly/birth defect, or 
 is medically significant: Medical and scientific judgment 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 hospitalization but may jeopardize the subject (patient) or 
may require intervention to prevent one of the other outcomes listed above. 
The serious adverse events will be presented in listings.


 
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7.3.3.3 
Assessment of Tolerability 
The tolerability will be assessed by the investigator and by the patient at Visit 4 and 
Visit 6. It is rated using a five-point rating scale:  = very poor,  = poor,  = medium, 
 = good,  = very good. 
The assessments will be listed by patient. 
The results will be presented by means of frequency tables by visit and treatment. 
7.3.3.4 
Vital Signs 
The following vital sign measurements will be obtained according to the schedule of 
assessments in chapter 9 of the Trial Protocol on each visit and evaluated as normal or 
abnormal and judged regarding clinical relevance 
 Blood pressure, systolic and diastolic [mmHg] 
 Pulse rate [beats/min] 
 Body temperature [°C] 
The vital signs will be listed by patient.  
A separate listing for only abnormal results including the assessment of clinical 
relevance will be presented. 
Descriptive statistics for the values and for individual changes (absolute changes) to 
the baseline (measurement from screening visit) will be presented by measuring time 
point, parameter and treatment. 
7.3.3.5 
Physical Examination 
A physical examination is performed at the entry and final examination per body 
system (general state; nutritional state; skin; head, neck; eyes; cardiovascular; 
respiratory; gastrointestinal; hepatic, biliary; endocrine, metabolic; lymph nodes; 
urogenital; neurological; psychiatric; musculoskeletal) 
The findings, if any, will be listed by patient, abnormal findings will be listed separately. 
The results for the examination by body system (normal, abnormal) and for the 
changes from entry to final will be presented by means of frequency tables. The 
changes will be displayed as shift for Visit 6 against Visit 1. 
7.3.3.6 
Examination of Nose, Ears, Mouth / Throat (ENT) 
An examination of Nose (septum, mucosa, secretion, obstruction, polyps), Ears 
(effusion and erythema) and Mouth/Throat (anterior and posterior discharge, dental 
abnormalities and halitosis) will be performed at screening (Visit 1), at Visit 4 and at 
Visit 6. 


 
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The results will be listed by patient. The results per item and the findings 
(normal/abnormal) per system will be presented by means of frequency tables. The 
changes will be displayed as shift tables for Visit 4 against Visit 1 and for Visit 6 against 
Visit 1. 
7.3.3.7 
Safety Laboratory Examination 
The safety laboratory examination will be performed at Visit 1 (screening) and Visit 6 
(end of treatment) for the following: 
Hematology: 
hemoglobin, hematocrit, leukocytes with differential count, 
erythrocytes, erythrocyte sedimentation rate, MCV, MCH, 
MCHC, and platelet count 
Blood chemistry: 
Electrolytes 
sodium, potassium, serum calcium, serum albumin, chloride 
Substrates 
creatinine, total protein, total bilirubin, blood glucose, urea, uric 
acid 
Enzymes 
ALT, AST, -GT, ALP 
 
The individual values of the clinical laboratory tests (hematology, blood chemistry) will 
be listed by patient.  
Out-of-range values are marked with an assessment of clinical relevance (NCR = not 
clinically relevant, CR = clinically relevant). The course of out-of-range values is listed 
separately. 
Descriptive statistics for each parameter will be presented by visit and treatment. 
Further descriptive statistics for individual changes (from Visit 1 to Visit 6) will be 
presented by treatment. 
Frequency tables for the assessment of clinical relevance (normal, abnormal NCR, 
abnormal CR) will be presented by treatment. The changes of the assessment will be 
displayed as shift tables from Visit 1 to Visit 6. 
In addition, a serum pregnancy test in all female patients is performed at Visit 1 and 
Visit 6. The results will be listed by patient. 
7.3.4 
Compliance of patients 
7.3.4.1 
Disposition of patients 
The number of patients per site are presented by treatment group and population for 
analysis (screened, safety set, FAS, PPS). 
The disposition of patients according to their presence at the corresponding visit 
(performed, not-performed, drop-out) will be presented by means of frequency tables 
by treatment group. 


 
Statistical Analysis Plan 
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The documented main reason for drop-out (adverse event, inclusion criteria not met, 
exclusion criteria met, non-compliance, on patient’s request, contact to patient lost or 
other) will be presented by means of frequency tables by treatment group. 
7.3.4.2 
Protocol deviations 
The protocol deviations will be summarized by means of frequency tables by treatment 
group with respect to the category (eligibility deviation, withdrawal deviation, dosing 
deviation, prohibited medication deviation, operational deviation) and the assessment 
(minor/major). 
7.3.4.3 
Compliance with IMP 
The dispensation and return of IMPs is documented by the investigator in the Study 
Medication Logbook, which is part of each patients’ CRF. The daily intake of the IMPs 
(in the morning and at noon) is documented by the patients in their diaries. 
In total it is expected that each patient takes 56 of the dispensed tablets (14 days, 2 
tablets in the morning and 2 tablets at noon each day).  
Compliance (in %)  will therefore be calculated as the number of tablets which were 
taken, as documented in the diary, divided by 56. 
Further the ratio of returned (not used) tablets to dispensed tablets will be assessed as 
a measure of drug accountability. 
These measures of compliance and drug accountability will be analyzed descriptively 
with mean, standard deviation, minimum and maximum by treatment group. 
7.3.4.4 
Treatment duration and time intervals between visits 
The total duration of treatment will be calculated as the number of days between first 
and last intake of the IMP; these dates are documented in the CRF as start of 
treatment (date and time) and end of treatment (date and time). 
𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛= 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑒𝑛𝑑 𝑜𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑠𝑡𝑎𝑟𝑡 𝑜𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ 1 
This duration will be analyzed descriptively (mean, standard deviation, minimum and 
maximum) by treatment group for the safety set, the FAS and the PPS. 
The time intervals between Visit 1 and Visit 2, Visit 2 and Visit 3, Visit 2 and Visit 4, 
Visit 2 and Visit 5 and between Visit 2 and Visit 6 will be assessed descriptively (mean, 
standard deviation, minimum and maximum) by treatment group for the safety set, the 
FAS and the PPS. 
The start of treatment (month and year) is analyzed by means of frequency tables by 
treatment group for the safety set. 


 
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7.4 
Statistical Analysis of the Endpoints 
7.4.1 
Statistical Analysis of the Primary Endpoint 
Efficacy of the test product will be shown by testing superiority of the three different 
doses in a hierarchical test procedure from the highest to the lowest dose compared to 
placebo. 
Hierarchical ordered hypotheses will be tested at the type I error rate of 𝛼= 0.05 (two-
sided) until the first non-rejection. No error rate adjustment is required. 
The set of hypotheses is as follows: 
𝐻01: µ𝐴 = µ𝐷 versus 𝐻11: µ𝐴 ≠ µ𝐷,  
𝐻02: µ𝐵 = µ𝐷 versus  𝐻12: µ𝐵 ≠ µ𝐷, 
𝐻03: µ𝐶 = µ𝐷 versus 𝐻13: µ𝐶 ≠ µ𝐷. 
Where 𝜇𝑔𝑟𝑜𝑢𝑝 denotes “mean change from baseline in the daily MSS over the entire 
treatment period” in treatment group (Group A, B, C or D) for the respective strength.  
Superiority of the Test treatment over placebo (PL) is confirmed if the p-value is  below 
5% and a positive treatment effect is shown. 
For the primary endpoint, analysis of covariance (ANCOVA) will be carried out using 
treatment and center as factors and baseline MSS as a covariate.  
The SAS procedure PROC GLM will be used for that purpose. 
Basically, the following code will be used: 
proc glm data=primary; 
class treatment center; 
model mss=treatment center baseline_mss; 
estimate 'Group X vs D' treatment 1 -1 ; 
where treatment='X' or treatment='D'; 
run; 
The analysis will be performed for each hypothesis separately, i.e. only data of one 
active treatment group and the placebo group are included for the respective 
comparison.  
The confirmatory analysis of the primary endpoint will be performed in the FAS.  
In addition, the analyses used for the primary efficacy endpoint will be performed in the 
PPS. This analysis is intended to provide supportive evidence and will be considered 
descriptive. 
7.4.2 
Statistical Analysis of the Secondary Endpoints 
7.4.2.1 
Time to onset of action defined as first day of active treatment on 


 
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which MSS shows statistically significant difference from placebo 
This endpoint will be determined as follows: 
For each day of assessment (Day 2 until Day 14) of MSS a two-sample t-test (by 
means of an ANCOVA with factors treatment, center and baseline MSS as covariate) 
comparing the mean MSS in one active treatment group versus placebo group will be 
performed. The following hypotheses will be tested: 
𝐻0,𝑔,𝑣: 𝑀𝑆𝑆𝑔,𝑣= 𝑀𝑆𝑆𝐷,𝑣 vs. 𝐻1,𝑔,𝑣:𝑀𝑆𝑆𝑔,𝑣 ≠𝑀𝑆𝑆𝐷,𝑣 
For the active treatment groups 𝑔 (Groups A, B or C) and visits 𝑣 (from Day 2 to Day 
14). 
For each hypothesis to test only the data related to the hypothesis will be used.  
The earliest day showing a significant difference at level 𝛼= 5% will then be defined as 
the time to onset of action. 
This analysis is deemed to be descriptive and will be performed in FAS and in the PPS. 
7.4.2.2 
MSS development over the course of the study 
For each day of assessment (Day 1 until Day 15, or up to 3 days later) descriptive 
statistics (mean, standard deviation, median, minimum and maximum) for the MSS per 
treatment group will be determined and displayed for the FAS and the PPS. 
The mean values will be presented in a graphic containing the curves for all four 
treatment groups. 
7.4.2.3 
SNOT-22 by visit and changes versus baseline 
The total scores (sum of all single assessments per subject) will be analyzed 
descriptively by treatment group and assessment day (Day 1 - Baseline, Day 7 and 
Day 14). 
The change versus baseline will be determined individually as  
𝑐ℎ𝑎𝑛𝑔𝑒𝑆𝑁𝑂𝑇,𝑑𝑎𝑦= 𝑆𝑁𝑂𝑇𝑑𝑎𝑦−𝑆𝑁𝑂𝑇𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
𝑆𝑁𝑂𝑇𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
∗100%, 
where 𝑆𝑁𝑂𝑇𝑑𝑎𝑦 denotes the SNOT Score on Day 7 or Day 14. 
The percent change will be analyzed descriptively by treatment group and visit for the 
FAS and the PPS. 
The mean SNOT values by treatment and visit will be presented in a graphic containing 
the curves for all four treatment groups.  
7.4.2.4 
Percentage of responders and non-responders to treatment based on 


 
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the assessment of overall response to treatment by the investigator 
Based on the assessment of overall response responders are defined as patients who 
were cured by the treatment, i.e. with ratings 4 (minor improvement) and 5 (major 
improvement). 
Accordingly, patients whose disease was unchanged or deteriorated, i.e. with rating 1 
(major deterioration), 2 (minor deterioration) and 3 (no change) are defined as non-
responders. 
The mean percentages per treatment group and visit are presented. Differences 
between the active treatment groups and the placebo group will be investigated by 
means of two sided Chi-square tests (at significance level 5%) in the FAS and in the 
PPS. 
The SAS procedure PROC FREQ with basically the following code will be used: 
proc freq data=responders; 
   tables treatment*response /chisq; 
   where treatment='X' or treatment='D'; 
run; 
For the group of non-responders frequency tables for month of inclusion and country 
will be displayed. 
Additionally a Mantel-Haenszel will be performed using the month of inclusion as third 
control variable. This test is considered as sensitivity analysis to rule out the possibility 
that patients with seasonal rhinitis have an impact on the result. 
The SAS procedure PROC FREQ with basically the following code will be used: 
proc freq data=responders; 
   tables incl_month*treatment*response /cmh; 
   where treatment='X' or treatment='D'; 
run; 
This sensitivity analysis will be performed in the FAS and in the PPS. 
Bar charts of the relative number of the responders will be created per treatment group 
and by visit (Day 1, Day 7 and Day 14). 


 
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8 
List of Tables, Listings and Figures 
8.1 
Tables to be included in the Clinical Study Report 
(Chapter 14) 
Section 
Table titles 
14.1 Demographic data 
Numbers of patients per site by analysis population 
Randomization list, safety set 
Documented reason for drop-out, safety set 
Disposition of patients, safety set 
Start of treatment, safety set 
Treatment duration, safety set 
Treatment duration, FAS 
Treatment duration PPS 
Time intervals between Visit 2 and all other visits, safety 
set 
Time intervals between Visit 2 and all other visits, FAS 
Time intervals between Visit 2 and all other visits, PPS 
Compliance with IMP, safety set 
Occurrence of protocol deviations, safety set 
Medical history - Diseases, surgeries which ended 
before start of treatment (Visit 2) by SOC, PT and 
treatment, safety set 
Concomitant diseases which are present at start of 
treatment (Visit 2) by SOC, PT and treatment, safety set 
Previous medication (ended before start of treatment, 
Visit 2) incidences by WHO Drug B3 term level 3, 
Preferred Name and treatment, safety set 
Concomitant medication (at start of treatment, Visit 2) 
incidences by WHO Drug B3 term level 3, Preferred 
Name and treatment, safety set 
Summary of demographic data, safety set 
Summary of demographic data, FAS 
Summary of demographic data, PPS 
 
 


 
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14.2 Efficacy data 
Evaluation of the primary endpoint - Mean change from 
baseline in daily MSS ANCOVA and superiority test, 
Treatment A vs D, FAS  
Evaluation of the primary endpoint - Mean change from 
baseline in daily MSS ANCOVA and superiority test, 
Treatment A vs D, PPS  
Evaluation of the primary endpoint - Mean change from 
baseline in daily MSS ANCOVA and superiority test, 
Treatment B vs D, FAS  
Evaluation of the primary endpoint - Mean change from 
baseline in daily MSS ANCOVA and superiority test, 
Treatment B vs D, PPS  
Evaluation of the primary endpoint - Mean change from 
baseline in daily MSS ANCOVA and superiority test, 
Treatment C vs D, FAS  
Evaluation of the primary endpoint - Mean change from 
baseline in daily MSS ANCOVA and superiority test, 
Treatment C vs D, PPS  
Evaluation of secondary endpoint - Time to onset of 
action, FAS 
Evaluation of secondary endpoint - Time to onset of 
action, PPS 
Evaluation of secondary endpoint - MSS development 
of the course of the study, FAS 
Evaluation of secondary endpoint - MSS development 
of the course of the study, PPS 
Evaluation of secondary endpoint - SNOT-22 by visit 
and change to baseline, FAS 
Evaluation of secondary endpoint - SNOT-22 by visit 
and change to baseline, PPS 
Evaluation of secondary endpoint - Percentage of 
responders and non-responders, FAS 
Evaluation of secondary endpoint - Percentage of 
responders and non-responders, PPS 
Frequency table for month of inclusion and country in 
the group of non-responders, FAS 
Sensitivity analysis - Percentage of responders and 
non-responders controlled by month of inclusion, FAS 
Sensitivity analysis - Percentage of responders and 
non-responders controlled by month of inclusion, PPS 


 
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14.3 Safety 
 
Vital signs - Descriptive statistics by treatment and visit, 
safety set 
Vital signs - Descriptive statistics of individual changes 
to baseline by treatment and visit, safety set 
Findings in the physical examination by treatment and 
visit, safety set 
Examination of ENT by treatment and visit, safety set 
Safety laboratory, hematology -Descriptive statistics by 
treatment and visit, safety set 
Safety Laboratory, hematology- Value classification by 
treatment and visit, safety set 
Safety laboratory, hematology - Changes in the value 
classification (entry to final) by treatment, safety set 
Safety laboratory, blood chemistry - Descriptive 
statistics by treatment and visit, safety set 
Safety laboratory, blood chemistry - Value classification 
by treatment and visit, safety set 
Safety laboratory, blood chemistry - Changes in the 
value classification (entry to final) by treatment, safety 
set 
14.3.1 Adverse Events 
(per treatment / per 
patient) 
Summary of adverse events, safety set 
Listing of pre-treatment adverse events, safety set 
Listing of serious adverse events, safety set 
Numbers of patients with adverse events by SOC, PT 
and treatment, safety set 
Incidence of adverse events by SOC, PT and treatment, 
safety set 
Numbers of patients with adverse events by SOC, PT, 
treatment and severity, safety set 
Incidence of adverse events by SOC, PT, treatment and 
severity, safety set 
Numbers of patients with adverse events by SOC, PT, 
treatment and causality, safety set 
Incidence of treatment events by SOC, PT, treatment 
and causality, safety set 
Numbers of patients with adverse events by SOC, PT, 
treatment and outcome, safety set 
Incidence of adverse events by SOC, PT, treatment and 
outcome, safety set 


 
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14.3.2 Abnormalities in 
Vital Signs, Laboratory, 
Physical Examination, etc.  
Abnormalities in vital signs, safety set 
Abnormalities in physical Examination, safety set 
Abnormalities in ENT examination, safety set 
Time course of laboratory test results out of reference 
range, blood chemistry, safety set 
Time course of laboratory test results out of reference 
range, hematology, safety set 
8.2 
Figures to be included in the Clinical Study Report 
MSS development of the course of study, mean curves, Full Analysis Set 
MSS development of the course of study, mean curves, Per-Protocol Set 
SNOT development of the course of study, mean curves, Full Analysis Set 
SNOT development of the course of study, mean curves, Per-Protocol Set 
Percentage of responders - bar charts by visit and treatment group, Full Analysis Set 
Percentage of responders - bar charts by visit and treatment group, Per-Protocol Set 
8.3 
Listings (Appendix 16.2 of the Clinical Study Report) 
Section 
Table titles 
16.2.1 Discontinued patients 
Patients not treated with trial medication (only 
screened) 
Listing of drop-outs (withdrawal criteria / 
premature discontinuation), randomized and 
treated patients 
Disposition of patients treated with trial 
medication per study phase 
Inclusion criteria not met 
Exclusion criteria met 
16.2.2 Protocol deviations 
Protocol deviations 
16.2.3 Patients excluded from 
the efficacy analysis 
Patients excluded from the efficacy analysis (Per 
Protocol Set) 
Patients excluded from the efficacy analysis (Full 
Analysis Set) 
16.2.4 Demographic data 
Demographic data of patients treated with trial 
medication 


 
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Section 
Table titles 
Demographic data of patients not treated with trial 
medication 
Life style and habits - Alcohol consumption, safety 
set 
Life style and habits - History of drug abuse or 
use of illegal drugs, safety set 
Life style and habits - Smoking status, safety set 
Anamnesis on acute uncomplicated rhinosinusitis, 
Major Symptom Score, safety set 
Medical and surgical history, safety set 
Previous medication, safety set 
Concomitant medication, safety set 
Medical or other therapeutic measures, safety set 
Method of contraception, safety set 
Vital signs, safety set 
Physical examination, safety set 
ENT examination, safety set 
Assessment of tolerability by patient, safety set 
Assessment of tolerability by investigator, safety 
set 
16.2.5 Compliance and / or drug 
concentration data 
Visit dates, safety set 
Dispensation of blinded medication 
Return and check of used blinded medication 
16.2.6 Individual efficacy 
response data 
Major Symptom Score (MSS) assessed by the 
patient 
Sino-nasal outcome test (SNOT-22) assessed by 
the patient 
Assessment of overall response to treatment by 
the investigator 
16.2.7 Adverse event listings 
Display of adverse events, part I, sorted by 
treatment group, safety set 
Display of adverse events, part I, safety 
Display of adverse events, part II, safety set 
Display of adverse events, part III, safety set 
(Specification of Event treatment) 


 
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Section 
Table titles 
Display of serious adverse events, part I, safety 
set 
Display of serious adverse events, part II, safety 
set 
Display of serious adverse events, part III, safety 
set (Specification of event treatment) 
16.2.8 Listing of Individual 
Laboratory Measurements by 
Patient 
Laboratory test results - Abbreviation of test 
codes 
Laboratory test results of blood chemistry, safety 
set 
Laboratory test results of hematology, safety set 
Serum pregnancy test, safety set 


 
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9 
Reference List 
 
1 Jund R, Mondigler M, Stammer H, Stierna P, Bachert C. Herbal drug BNO 1016 is safe and effective in the 
treatment of acute viral rhinosinusitis. Acta Otolaryngol. 2015 Jan;135(1):42-50