Clinical Trials Register

Summary
EudraCT Number:	2011-003623-35
Sponsor's Protocol Code Number:	CRS-02
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-07-24
Trial results	View results

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

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2011-003623-35

A.3

Full title of the trial

A multicentre, randomized, double-blind, placebo-controlled, parallel group study to assess efficacy and safety of two dosages of a herbal medicinal product (dry extract BNO 1016) in patients with chronic rhinosinusitis

A.3.1

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

study to assess the efficacy and safety of a herbal medicine (dry extract BNO-1016) in patients with chronic rhinosinusitis

A.3.2

Name or abbreviated title of the trial where available

BNO-1016 Chronic Rhinosinusitis

A.4.1

Sponsor's protocol code number

CRS-02

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	Bionorica SE
B.1.3.4	Country	Germany
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	Bionorica SE
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	Bionorica SE
B.5.2	Functional name of contact point	Senior Clinical Research Manager
B.5.3	Address:
B.5.3.1	Street Address	Kerschensteinerstr. 11-15
B.5.3.2	Town/ city	Neumarkt
B.5.3.3	Post code	92318
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4909181231283
B.5.5	Fax number	+49091812316283
B.5.6	E-mail	martin.mondigler@gmx.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Dry extract BNO-1016 Coated Tablets
D.3.2	Product code	BNO-1016
D.3.4	Pharmaceutical form	Coated 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.3.9.1	CAS number	8000040-68-8
D.3.9.3	Other descriptive name	PRIMULA FLOWERS
D.3.9.4	EV Substance Code	SUB15012MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	GENTIAN ROOT
D.3.9.4	EV Substance Code	SUB11986MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	8000043-47-2
D.3.9.3	Other descriptive name	RUMICIS ASETOSA
D.3.9.4	EV Substance Code	SUB15163MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	8000043-48-3
D.3.9.3	Other descriptive name	VERBENA HERB
D.3.9.4	EV Substance Code	SUB15693MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	ELDER FLOWERS
D.3.9.4	EV Substance Code	SUB31786
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
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	Coated 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

Chronic Rhinosinusitis

E.1.1.1

Medical condition in easily understood language

inflammation of the mucosa of the nose and paranasal sinuses of at least 12 weeks duration

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of two dosages (240 mg and 480 mg per day) of a herbal medicinal product (BNO 1016) compared with placebo in the treatment of chronic rhinosinusitis in adults.

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of 240 mg and 480 mg BNO 1016 compared with placebo during the 12-week treatment phase and the 8-week follow-up observation period.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Signed informed consent including data protection declaration
2.Male and femaleA) outpatients aged ≥18 and ≤75 years
3.Diagnosis of bilateral chronic rhinosinusitis without nasal polyps confirmed by:
-nasal endoscopy during the screening period (nasal endoscopy results not older than 2 months will be accepted) to confirm inflammation, mucopurulent discharge and/or oedema/mucosal obstruction primarily in middle meatus without nasal polyps being present
-at the discretion of the investigator a historic CT (before screening and not older than 24 months) will be considered additionally for confirmation of bilateral involvement of middle meatus and paranasal sinuses without resolution of symptoms (mucosal changes within the ostiomeatal complex and/or sinuses
4.Bilateral chronic rhinosinusitis characterized by (V1 and V2):
-presence of chronic rhinosinusitis symptoms for at least 12 weeks without complete resolution of symptoms prior to enrolment (V1)
-a MSS ≥6 points and ≤12 points for each of the screening days observed by diary entries (MSS Pat) and on the days of Visit 1 and Visit 2 (MSS Inv)
-on 5 random days of the screening period (or at least at days -5 to -1) assessed by MSSPAT and on the days of Visit 1 and Visit 2 assessed by MSSINV: rhinorrhoea (anterior or posterior) and pain (facial pain or headache) of at least moderate intensity (score ≥2)
A)Women will be considered for inclusion if they are not pregnant (as confirmed by urine pregnancy test), not breastfeading, or if menopause is ensured (at least 12 months without menstrual bleeding). Women of childbearing potential must use a highly effective (failure rate less than 1% per year, i.e. Pearl Index <1) method of contraception two weeks prior to trial inclusion and during the screening / treatment period of the clinical trial (vasectomised partner, sexual abstinence - the lifestyle of the female has to be such that there is complete abstinence from intercourse from two weeks prior to the first dose of trial medication until at least 72 hours after treatment -, implants, injectables, combined oral contraceptives, hormonal intrauterine devices or double-barrier methods, i.e. any double combination of intrauterine device, condom with spermicidal gel, diaphragm, sponge, and cervical cap).

E.4

Principal exclusion criteria

Medical history and medications:
1.Sinus surgery within the last 2 years (solitary sinus puncture is allowed)
2.Nasal concha surgery within the last 3 months
3.Presence of history of uni-or bilateral nasal polyps
4.Presence of moderate to severe co-morbid asthma, including allergic asthma
5.Patients with mild asthma having exacerbations within 30 days prior to trial inclusion
6.Patients with cystic fibrosis
7.Patients with a positive skin prick test at V1 against allergens to which the patient might be exposed to during the expected individual trial duration, if clinically relevant (results not older than 12 months will be accepted) if clinically relevant
8.Clinically relevant perennial (e.g. patients with actual clinical symptoms of allergic rhinitis against house dust/-mite antigen) or actual seasonal allergic rhinitis
9.Rhinitis medicamentosa (drug induced rhinitis)
10.Aspirin-Exacerbated Respiratory Disease [AERD] (Aspirin sensitivity)
11.Dentogenic sinusitis or otherwise unilateral sinusitis
12.Presence of anatomical deviations of the nasal septum that significantly impair nasal and paranasal ventilation / airflow
13.Known hypersensitivity to trial medication or excipients
14.Patients with rare hereditary problems of fructose intolerance, galactose intolerance, lactase deficiency or glucose-galactose malabsorption or sucrase-isomaltase insufficiency
15.Signs or symptoms of acute bacterial sinusitis (e.g. fever > 38.5°C, orbital complications, severe unilateral frontal headache or toothache)
16.Treatment with systemic or nasal antibiotics or corticosteroids within the last 4 weeks prior to V1
17.Treatment with decongestant preparations (α-sympathomimetics), analgesics (including systemic Non-Steroidal Inflammatory Drugs [NSAIDs], including paracetamol), mucolytics / secretolytics, antihistamines, or alternative medicine preparations for treatment of common cold like symptoms or with immunomodulating properties within the last 7 days prior to V1
18. Patients with gastric or duodenal ulcer
19.Other diseases within 5 years prior to V1, which in the opinion of the investigator disqualifies the patient for trial enrolment (e.g. liver or kidney disease, severe somatopathic, neurological and /or psychiatric diseases, history of malignancy or alcohol or drug abuse or immunodeficiency)
General:
19.Parallel participation in another clinical trial, participation in a different trial within less than 6 weeks prior to trial entry, or previous randomization into this clinical trial
20.Known to be, or suspected of being unable to comply with the clinical trial protocol, which in the opinion of the investigator disqualifies the patient for trial enrolment (e.g. no permanent address, known to be non-compliant or presenting an unstable psychiatric history)
21.Legal incapacity and / or other circumstances rendering the patient unable to understand the nature, scope and possible impact of the trial
22.Patients in custody by juridical or official order
23.Evidence of an uncooperative attitude
24.Patients who have difficulties in understanding the language in which the patient information is given
25.Patients who are members of the staff of the clinical trial site, staff of the sponsor or involved CRO, the investigator him- / herself or close relatives

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is defined as the average of investigator’s MSS ratings [score points] at V5 and V6 (arithmetic mean of 2 ratings):
Investigator rated MSS - average over V5 and V6 [score points]; CRF data

Major Symptom Score [MSS] (sum of rating scores for five individual rhinosinusitis symptoms, namely rhinorrhoea = anterior and posterior, nasal congestion, headache and facial pain / pressure) assessed by the investigator (MSSINV)

E.5.1.1

Timepoint(s) of evaluation of this end point

average MSS at Visit 5 and Visit 6 (CRF data)

E.5.2

Secondary end point(s)

Efficacy (MSS), Quality of Life (QoL), Pharmacoeconomy, Tolerability. For detailed information please refer to the trial protocol chapter 3.3 (page 24)

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the trial protocol chapter 3.3 (page 25).

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LV-LS

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 months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

796

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

601

F.4.2

For a multinational trial

F.4.2.1

In the EEA

885

F.4.2.2

In the whole clinical trial

885

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)

During treatment a reduction of severity of symptoms should be achieved. If, during treatment period, the severity of symptoms deteriorates, the patient does not respond to therapy or prematurely terminates the trial a standard of care treatment for CRS is initiated at the discretion of the physician. If, during or after the post-treatment observation period the CRS symptoms reappear or deteriorate, a standard of care treatment for this disease is initiated at the discretion of the physician.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-08-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-04-03

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