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    Summary
    EudraCT Number:2016-004730-18
    Sponsor's Protocol Code Number:OSLER_TIMOLOL
    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:2017-06-30
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2016-004730-18
    A.3Full title of the trial
    The influence of Timolol Nasal Spray on Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
    Der Einfluss von Timolol Nasenspray auf Epistaxis bei Morbus Osler Patienten
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The influence of a special medicinal Nasal Spray on nasal bleeding in patients with a hereditary disease leading to vessel anomalies of the nasal mucosa
    Der Einfluss eines speziellen Medikamentes in Form von Nasenspray auf das Nasenbluten bei Patienten, die an einer Gefäßerbkrankheit leiden, welche zu Veränderungen der Nasenschleimhaut führt
    A.4.1Sponsor's protocol code numberOSLER_TIMOLOL
    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 SponsorUniversity Hospital Regensburg
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMorbus Osler Selbsthilfe Stiftung e.V.
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportPharmacy of the University Hospital Erlangen
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportZSER ( Zentrum für seltene Erkrankungen)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Regensburg
    B.5.2Functional name of contact pointKlinik für HNO Heilkunde
    B.5.3 Address:
    B.5.3.1Street AddressFranz-Josef-Strauss-Allee 11
    B.5.3.2Town/ cityRegensburg
    B.5.3.3Post code93053
    B.5.3.4CountryGermany
    B.5.4Telephone number00499419449410
    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 nameTimolol 0,5%
    D.3.4Pharmaceutical form Nasal drops, solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPNasal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTimolol
    D.3.9.3Other descriptive nameTIMOLOL
    D.3.9.4EV Substance CodeSUB11069MIG
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 No
    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 placeboNasal spray
    D.8.4Route of administration of the placeboNasal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    2) hereditary hemorrhagic telangiectasia
    2) Morbus Osler
    E.1.1.1Medical condition in easily understood language
    genetic disorder that leads to abnormal blood vessel formation
    Erbkrankheit die zu abnormalen Gefässformationen führt
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10031132
    E.1.2Term Osler-Weber-Rendu disease
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The clinicial trial shall proof if Timolol nasal spray twice daily (1mg/day) in addition to a TruBlue laser therapy every three months can improve the treatment of epistaxis in patients with HHT. The degree of effectiveness ist measured by duration and frequency of nasal bleeding and the Epistaxis Severity Score (ESS).
    Sie soll zeigen, ob sich die Effektivität der Behandlung von Epistaxis bei Morbus Osler Patienten durch eine additive Anwendung von Timolol Nasenspray 2mal täglich (in einer Dosierung von 1 mg/d) zuzüglich zur der in dreimonatigen Abständen erfolgenden TruBlue Lasertherapie steigern lässt. Maß für die Effektivität der Behandlung ist die Dauer und Häufigkeit der Epistaxis gemessen anhand des Epistaxis Severity Scores (ESS).
    E.2.2Secondary objectives of the trial
    - Compatibility and safety of the IMP for HHT patients during 3 months period of application (dosage 1mg/day).
    - Development of patients subjective satisfaction during the clinical trial based on a numeric ratins scale (NRS).
    - Development of blood values (hemoglobin/ferritin/transferrin) of the patients taking part in the clinical trial.
    - Development of the quality of life of the patients taking part in the clinical trial with EQ-5D questionnaire and SFB questionnaire.
    - Verträglichkeit und Sicherheit von Timolol Nasenspray in der Dosierung 1 mg/d über einen Anwendungszeitraum von 3 Monaten.
    - Entwicklung der subjektiven Zufriedenheit der von Epistaxis betroffenen Morbus Osler Patienten im Verlauf der klinischen Prüfung anhand einer numerischen Rating-Skala (NRS).
    - Veränderung der Blutwerte (Hämoglobin/ Ferritin/ Transferin) vor und nach dreimonatiger Applikation von Timolol Nasenspray.
    - Lebensqualität der an Epistaxis betroffenen Patienten mit Morbus Osler vor und nach Anwendung des Prüfpräparates anhand des EQ-5D und des SFB Fragebogens.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    o age ≥ 18 years
    o diagnosis of HHT according to the Curaçao-criteria
    o written consent to the clinical trial
    o intellectual and lingual ability to answer a questionnaire independently
    o at least 2 TruBlue laser treatment of the nasal mucosa in the medical history
    o at least weekly frequency of nose bleeds of which one nose bleed episode lasts longer than 5 minutes
    o Alter ≥ 18 Jahre
    o gesicherte Diagnose Morbus Osler anhand der Curaçao-Kriterien
    o schriftliche Einwilligung in die klinische Prüfung
    o Intellektuelle und sprachliche Befähigung einen Fragebogen selbstständig zu beantworten
    o Mindestens 2 TruBlue Laserbehandlungen im Bereich der Nasenschleimhaut
    o Blutungshäufigkeit häufiger als einmal pro Woche und davon mindestens einmal mehr als 5 Minuten
    E.4Principal exclusion criteria
    o pregnancy
    o patients taking part in another clinical trial
    o bronchial asthma or chronically obstructive lung disease (COPD)
    o sinusbradycardia, sick-sinus-syndrome, sinuatrial block second oder third degree, atrioventricular block withour pacemaker based on the patients past medical history and ECG
    o manifest heart failure, cardiogenic shock, angina pectoris in the patients past medical history
    o hypotension below 100/60 mmHg according to past medical history or measurements before inclusion in the clinical trial
    o bradycardia (less than 60 beats per minute) measured before inclusion in the clinical trial
    o patients with severe circulatory disturbances or illnesses(e.g. severe Raynaud-Syndrome) according to their past medical history
    o Diabetes mellitus in their past medical history
    o hyperthyroidism in past medical history
    o phaeochromocytoma in past medical history
    o muscle weakness/ myasthenia gravis in the patients medical history
    o patients with atopy or anaphylactic reactions on miscellaneous allergens according to the medical history
    o ongoing or planned hyposensitisation
    o hypersensitvity to betablockers or benzalkonium chloride
    o concomitant use of oral Calcium channel blockers (Diltiazem/Verapamil),
    antiarrhythmics (including Amiodaron), digitalis and
    parasympathomimetics in the patients medical history
    o concomitant use of CYP2D6 inhibitors (e.g. Chinidin, Fluoxetin, Paroxetin)
    o concomitant use of systemic or ophthalmic beta blocker
    o concomitant use of anticoagulants
    o Discontinuation of iron replacement therapy or start of iron replacement therapy one months before inclusion on the clinical trial to the end of the clinical trial
    o Nasal Surgery (e.g. cautery of the AV-shunts or the sphenopalatine artery) within 3 month before inclusion in the clinical trial.

    o Bestehende Schwangerschaft
    o Teilnahme an einer anderen klinischen Prüfung
    o Asthma bronchiale oder chronische obstruktive Lungenerkrankung (COPD)
    o Sinusbradykardie, Sick-Sinus-Syndrom, SinuatrialerBlock zweiten oder dritten Grades, AV-Block ohne Schrittmacher in der Anamnese sowie im EKG vor Beginn der klinischen Prüfung
    o manifeste Herzinsuffizienz, kardiogener Schock, Angina pectoris in der Anamnese
    o Hypotonie unterhalb von 100/60 mmHg in der Anamnese und bei der Untersuchung vor Beginn der klinischen Prüfung
    o Bradykardie (unter 60 Schläge pro Minute) im EKG vor Studieneinschluss
    o Patienten mit schweren peripheren Durchblutungsstörungen/Erkrankungen (z.B. schwere Formen der Raynaud-Krankheit oder Raynaud-Syndrom) in der Anamnese
    o Diabetes mellitus in der Anamnese
    o Schilddrüsenüberfunktion in der Anamnese
    o Phäochromozytom in der Anamnese
    o Muskelschwäche/ Myasthenia gravis in der Anamnese
    o Patienten mit Atopie oder schweren anaphylaktischen Reaktionen auf verschiedene Allergene in der Anamnese
    o Patienten, die aktuell eine Hyposensibilisierung durchführen oder planen
    o in der Anamnese Hypersensitivität gegenüber Betablockern oder Benzalkonium chlorid
    o gleichzeitige Einnahme von oralen Kalziumkanalblockern (Diltiazem/Verapamil), Antiarrhythmika (einschließlich Amiodaron), Digitalisglykosiden sowie Parasympathomimetika
    o gleichzeitige Anwendung mit CYP2D6-Hemmstoffen (z.B. Chinidin, Fluoxetin, Paroxetin)
    o gleichzeitige Einnahme systemischer oder opthalmologischer Betablocker
    o Einnahme oraler Antikoagulanzien
    o Abbruch der bestehenden Eisentherapie mit Eisentabletten oder Infusionen bzw Neubeginn einer Eisentherapie mit Eisentabletten oder Infusionen im Zeitraum einen Monat vor Beginn der klinischen Prüfung bis zum Abschluss der klinischen Prüfung
    o Operative Maßnahme im Bereich der Nase innerhalb der letzten 3 Monate vor Einschluss in die klinische Prüfung und während der klinischen Prüfung im Sinne einer operativen Unterbindung großer zuführender Gefäße oder Einnähen von Nasenseptumfolien

    E.5 End points
    E.5.1Primary end point(s)
    Epistaxis Severity Score (ESS) upon completion of treatment with Timolol nasal spray or Placebo
    Epistaxis Severity Score (ESS) nach Abschluss der Behandlung
    E.5.1.1Timepoint(s) of evaluation of this end point
    after a three months treatment with the IMP or the Placebo
    (visit 4/ visit 7)
    nach einer 3 monatigen Anwendung des Prüfpraparates oder des Placebos
    (Visite 4/ Visite 7)
    E.5.2Secondary end point(s)
    - Evaluation of compatibility and safety of the IMP for HHT patients by frequent measurement of pulse and blood pressure and documentation of AEs (adverse events).
    - Evaluation of patients subjective satisfaction during the clinical trial based on a numeric ratins scale (NRS).
    - Measurement of blood values (hemoglobin/ferritin/transferrin) of the patients taking part in the clinical trial.
    - Evaluation of the quality of life of the patients taking part in the clinical trial with EQ-5D questionnaire and SFB questionnaire.
    - Verträglichkeit und Sicherheit des Prüfpräparates für die an Epistaxis leidenden Morbus Osler Patienten durch regelmäßige Dokumentation von Puls und Blutdruck sowie Dokumentation von AEs (Adverse Events, unerwünschte Ereignisse).
    - Subjektive Zufriedenheit der an Epistaxis leidenden Morbus Osler Patienten aus beiden Gruppen vor, während und nach der Anwendung des Prüfpräparates anhand einer nummerischen Analogskala (NRS).
    - Blutwerte (Hämoglobin/ Transferrin/ Ferritin) der teilnehmenden Morbus Osler Patienten.
    - Lebensqualität der an Epistaxis betroffenen Morbus Osler Patienten anhand des EQ-5D Fragebogens sowie des SFB Fragebogens (Solotsch D. , Koller M. et al 2006).
    E.5.2.1Timepoint(s) of evaluation of this end point
    after a three months treatment with the IMP or the Placebo
    (visit 4/ visit 7)
    nach einer 3 monatigen Anwendung des Prüfpraparates oder des Placebos
    (Visite 4/ Visite 7)
    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 Yes
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.6Cross over Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    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)
    After study termination, patients with HHT continue to be adequately treated with various available treatment options. The Department of otorhinolaryngology at the University Hospital Regensburg will remain to be the main point of contact for the patients, even after the termination of the study.
    Nach Beendigung der klinischen Prüfung werden die Morbus Osler Patienten weiterhin an unserer Klinik adäquat weiter behandelt. Auch nach der Studie bleibt die Klinik und Poliklinik für Hals-Nasen und Ohrenheilkunde, Universitätsklinikum Regensburg Ansprechpartner der Patienten mit Morbus Osler.
    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 Decision2019-12-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-19
    P. End of Trial
    P.End of Trial StatusCompleted
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