Clinical Trials Register

Summary
EudraCT Number:	2016-002743-41
Sponsor's Protocol Code Number:	EA-15-01-996
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:	2016-08-22
Trial 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

2016-002743-41

A.3

Full title of the trial

Prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-center trial to evaluate the efficacy and safety of cineole vs. placebo in the treatment of acute non-purulent rhinosinusitis

A.3.1

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

Cineole in acute non-purulent rhinosinusitis

A.3.2

Name or abbreviated title of the trial where available

Cineole in acute non-purulent rhinosinusitis

A.4.1

Sponsor's protocol code number

EA-15-01-996

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	Engelhard Arzneimittel GmbH & Co. KG
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	Engelhard Arzneimittel GmbH & Co. KG
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	Ecron Acunova GmbH
B.5.2	Functional name of contact point	Frankfurt Office
B.5.3	Address:
B.5.3.1	Street Address	Hahnstrasse 70
B.5.3.2	Town/ city	Frankfurt
B.5.3.3	Post code	60528
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049696680300
B.5.5	Fax number	00496966803029

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	Cineole 200 mg, Sinupan forte
D.3.4	Pharmaceutical form	Gastro-resistant capsule, soft
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	1,8-cineole
D.3.9.1	CAS number	470-82-6
D.3.9.3	Other descriptive name	CINEOLE
D.3.9.4	EV Substance Code	SUB20486
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	200
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	Yes
D.3.11.13.1	Other medicinal product type	1,8-cineole is isolated from eucalyptus oil as its main constituent

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	Gastro-resistant capsule, soft
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, non-purulent rhinosinusitis

E.1.1.1

Medical condition in easily understood language

Acute, non-purulent rhinosinusitis

E.1.1.2

Therapeutic area

Diseases [C] - Ear, nose and throat diseases [C09]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
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

English The objective of this study is to evaluate the efficacy and tolerability of cineole in comparison to placebo, based on the clinical success in patients with acute non-purulent rhinosinusitis with an appearance of sinusitis symptoms not later than 5 days

Primary aim:
To establish the efficacy of cineole by demonstrating superiority compared to placebo by evaluating the change (difference) of the Major symptom score (MSS):
1. from baseline to day 7 (End-of-treatment, V3)
2. from baseline to day 3 (Interim, V2), (in case of significant result of 1).

E.2.2

Secondary objectives of the trial

– Change (difference) of the Major Symptom Score (MSS) from baseline (V1) to visit V4.
– Response to treatment defined as improvement of MSS by >=50% at day 7 (V3) as compared to baseline.
– Response to treatment defined as improvement of MSS by >=50% at day 3 (V2) as compared to baseline.
– Safety evaluation by comparison of the incidence of adverse events in the treatment groups.
– Number of drop-out patients requiring alternative therapy with antibiotics at interim visit at day 3.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subjects who are able to understand and are willing to comply to trial instructions.

2) Having given written informed consent.

3) Age 18 to 75 years (inclusively).

4) Diagnosis of acute non-purulent rhinosinusitis with an appearance of sinusitis symptoms
≤ 5 days confirmed by ultrasonography of paranasal sinuses.

5) Baseline investigator-evaluated major symptom score (MSS) of ≥8 and ≤12
(of maximal 15 score points), out of the 5 main rhinosinusitis symptoms at least 3 must be present. Among these the presence of nasal congestion and facial pain / pressure is mandatory.

6) Presence of nasal congestion (score of ≥ 1 on four-point rating scale).

7) Mild to moderate facial pain/pressure (score of ≥ 1 and ≤ 2 on four-point rating scale).

8) Satisfactory health condition except for the rhinosinusitis as determined by the investigator based on medical history and physical examination.

9) No clinical assumption of necessity for antibiotic indication or application within 3 days before treatment.

E.4

Principal exclusion criteria

1) Clinical assumption of necessity for antibiotic indication or application within 3 days before treatment.

2) History of hypersensitivity to any excipient of the applied drugs.

3) Concomitant treatment with antibiotics, decongestal nasal sprays, antacida and proton-pump inhibitors, secretolytic agents other than the trial medication or any other medication or treatment listed in the disallowed medication list.

4) Acute exacerbation of allergic or chronic rhinosinusitis within 30 days.

5) Surgery of paranasal sinuses within 6 weeks.

6) Polyposis nasi, Cystic fibrosis and anatomical deviations of the nasal septum that significantly impair nasal and paranasal ventilation / airflow.

7) Patients with bronchial asthma.

8) Underlying diseases leading to significant immune deficiency.

9) Signs or symptoms of fulminant bacterial sinusitis (e.g. fever > 38.5 °C, orbital complications, severe unilateral frontal headache or toothache).

10) Odontogenic sinusitis.

11) Drug or alcohol abuse in the opinion of the investigator.

12) Participation in a clinical trial within 30 days prior to the treatment phase of this study or concomitantly.

13) Pregnant or nursing (lactating) women.

14) Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) who are not using an acceptable method of contraception defined as:
• Surgical sterilization
• Hormonal contraception
• IUD
• Total abstinence throughout the trial at the discretion of the investigator

Periodic abstinence is NOT an acceptable method of contraception. An acceptable method of contraception must be maintained throughout the trial.

A woman who is post-menopausal must have a negative urine pregnancy test at screening but will not need to comply with an acceptable method of contraception. Women are considered post-menopausal and not of child-bearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

15) Subjects with significant diseases, defined as a disease which, in the opinion of the investigator, may either put the subject at risk because of participation in the trial or a disease which may influence the results of the trial or the subject’s ability to participate in the trial; includes subjects with a history of gastrointestinal bleeding, significant cardiovascular, liver or renal disease.

16) Subjects directly or indirectly involved in the execution of this protocol, including employees of the CRO and persons related to them.

17) Subject is in custody by order of an authority or a court of law.

18) Subjects with chronic obstructive pulmonary disease (COPD), pertussis or pseudocroup.

E.5 End points

E.5.1

Primary end point(s)

To establish the efficacy of cineole by demonstrating superiority compared to placebo by evaluating the change (difference) of the Major symptom score (MSS)
1. from baseline (V1) to day 7 (End-of-treatment, V3)
2. baseline (V1) to day 3 (Interim visit, V2) (in case of significant results of 1)

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 7 (EOT, V3);
Day 3 (Interim visit, V2)

E.5.2

Secondary end point(s)

1) Change (difference) of the Major Symptom Score (MSS) from baseline (V1) to visit V4.
2) Response to treatment defined as improvement of MSS by >=50% at day 7 (V3) as compared to baseline.
3) Response to treatment defined as improvement of MSS by >=50% at day 3 (V2) as compared to baseline.
4) Safety evaluation by comparison of the incidence of adverse events in the treatment groups.
5) Number of drop-out patients requiring alternative therapy with antibiotics at interim visit at day 3.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Day 14 (V4)
2) Day 7 (V3)
3) Day 3 (V2)
4) Day 14 (V4)
5) Day 3 (V2)

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

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

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

LVLS

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

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:

235

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

250

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)

None (Acute rhinosinusitis is a non-serious, self-resolving condition, which usually resolves completely within 14 days. The trial duration covers this period. Therefore, unless decided otherwise by the investigator, further treatment after trial participation will not be necessary. If necessary, the investigator may continue to treat the subject with other medications until the rhinosinusitis is resolved)

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

2016-11-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-06-26

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