Clinical Trials Register

Summary
EudraCT Number:	2019-000060-20
Sponsor's Protocol Code Number:	2018-08-EFT-1
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-07-29
Trial results	View results

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

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2019-000060-20

A.3

Full title of the trial

Efficacy and safety of acetylcysteine for the treatment of acute uncomplicated rhinosinusitis: a prospective, randomized, double-blind, placebo-controlled trial

Ефикасност и безопасност на ацетилцистеин при лечение на остър неусложнен риносинуит: проспективно, рандомизирано, двойно-сляпо, плацебо-контролирано изпитване

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and safety of acetylcysteine for the treatment of acute uncomplicated rhinosinusitis

A.3.2

Name or abbreviated title of the trial where available

not availble

A.4.1

Sponsor's protocol code number

2018-08-EFT-1

A.5.4

Other Identifiers

Name:

CRO trial No.

Number:

C1018001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Hexal AG
B.1.3.4	Country	Slovenia
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	HEXAL AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Lek Pharmaceuticals d.d.
B.5.2	Functional name of contact point	Maja Radivojša Matanović
B.5.3	Address:
B.5.3.1	Street Address	Verovškova 57
B.5.3.2	Town/ city	Ljubljana
B.5.3.3	Post code	1526
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	+38615801326
B.5.6	E-mail	maja.radivojsa_matanovic@sandoz.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	AЦЦ 600 MG ЕФЕРВЕСЦЕНТНИ ТАБЛЕТКИ
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz Pharmaceuticals d.d., Ljubljana, SI
D.2.1.2	Country which granted the Marketing Authorisation	Bulgaria
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Acetylcysteine 600 mg effervescent tablet
D.3.2	Product code	ACC 600
D.3.4	Pharmaceutical form	Effervescent tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLCYSTEINE
D.3.9.1	CAS number	616-91-1
D.3.9.2	Current sponsor code	ACC 600
D.3.9.3	Other descriptive name	ACC 600
D.3.9.4	EV Substance Code	SUB05229MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Effervescent tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute rhinosinusitis

E.1.1.1

Medical condition in easily understood language

Inflammation of the nasal mucosa (called also “rhinitis“) and of the paranasal sinuses (“sinusitis”).

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10052106
E.1.2	Term	Rhinosinusitis
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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;
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.

E.4

Principal exclusion 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 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.

E.5 End points

E.5.1

Primary end point(s)

Mean change from baseline in the daily MSS over the entire treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

After the end of the clinical part of the trial, following database lock and unblinding.

E.5.2

Secondary end point(s)

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 (major symptom score) development over the course of the study;
SNOT-22 (sino-nasal outcome test) 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.

The safety endpoints 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.

E.5.2.1

Timepoint(s) of evaluation of this end point

After the end of the clinical part of the trial, following database lock and unblinding.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

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

Bulgaria

Germany

Moldova, Republic of

Russian Federation

E.8.7

Trial has a data monitoring committee

E.8.8

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

VISIT 6 on Day 15 (+3) is the last regular visit (LVLS).
A FOLLOW-UP PHONE CALL (within 7 days after Visit 6) is planned to be performed. 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 date of the last follow up call of the last patient in the trial will be defined as the end of the trial.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In the whole clinical trial

900

F.5

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

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-08-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-20

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