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    The EU Clinical Trials Register currently displays   38185   clinical trials with a EudraCT protocol, of which   6272   are clinical trials conducted with subjects less than 18 years old.
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    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
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2016-002743-41
    A.3Full 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.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Cineole in acute non-purulent rhinosinusitis
    A.3.2Name or abbreviated title of the trial where available
    Cineole in acute non-purulent rhinosinusitis
    A.4.1Sponsor's protocol code numberEA-15-01-996
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEngelhard Arzneimittel GmbH & Co. KG
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEngelhard Arzneimittel GmbH & Co. KG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEcron Acunova GmbH
    B.5.2Functional name of contact pointFrankfurt Office
    B.5.3 Address:
    B.5.3.1Street AddressHahnstrasse 70
    B.5.3.2Town/ cityFrankfurt
    B.5.3.3Post code60528
    B.5.4Telephone number0049696680300
    B.5.5Fax number00496966803029
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCineole 200 mg, Sinupan forte
    D.3.4Pharmaceutical form Gastro-resistant capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN1,8-cineole
    D.3.9.1CAS number 470-82-6
    D.3.9.3Other descriptive nameCINEOLE
    D.3.9.4EV Substance CodeSUB20486
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D. medicinal product type1,8-cineole is isolated from eucalyptus oil as its main constituent
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGastro-resistant capsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute, non-purulent rhinosinusitis
    E.1.1.1Medical condition in easily understood language
    Acute, non-purulent rhinosinusitis
    E.1.1.2Therapeutic area Diseases [C] - Ear, nose and throat diseases [C09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10052106
    E.1.2Term Rhinosinusitis
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    Day 7 (EOT, V3);
    Day 3 (Interim visit, V2)
    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 235
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state250
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-11-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-26
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