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    Summary
    EudraCT Number:2014-001959-24
    Sponsor's Protocol Code Number:BoTN-Study
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-06-27
    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 number2014-001959-24
    A.3Full title of the trial
    BoTN: Onabotulinumtoxin A for the treatment of trigeminal neuralgia: Efficacy, safety and neurophysiological alterations under therapy – a prospective, controlled trial
    BoTN: Onabotulinumtoxin A zur Behandlung der Trigeminusneuralgie: Wirksamkeit, Sicherheit und neurophysiologische Veränderungen unter Therapie - eine prospektive, kontrollierte klinische Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Botox for the treatment of facial pain, provoked by an extremely painful irritation of the fifth cranial nerve
    Botox zur Behandlung des Gesichtsschmerzes, der durch einen äußerst schmerzhaften Reizungszustand des fünften Hirnnerven ausgelöst wird
    A.4.1Sponsor's protocol code numberBoTN-Study
    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 Essen
    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 supportAllergan Pharmaceuticals Ireland
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Essen
    B.5.2Functional name of contact pointPrincipal Investigator
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstrasse 55
    B.5.3.2Town/ cityEssen
    B.5.3.3Post code45122
    B.5.3.4CountryGermany
    B.5.4Telephone number00490201723-84385
    B.5.5Fax number00490201723-6962
    B.5.6E-mailmark.obermann@uk-essen.de
    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 Yes
    D.2.1.1.1Trade name BOTOX®
    D.2.1.1.2Name of the Marketing Authorisation holderAllergan Pharmaceuticals Ireland
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameBOTOX®
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOnabotulinumtoxin A
    D.3.9.1CAS number 93384-43-1
    D.3.9.3Other descriptive nameBOTULINUM TOXIN TYPE A
    D.3.9.4EV Substance CodeSUB13117MIG
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Trigeminal neuralgia
    Trigeminusneuralgie
    E.1.1.1Medical condition in easily understood language
    Extremely painful irritation of the fifth cranial nerve accompanied by recurrent and suddenly occurring, eletrifying exacerbation of pain
    äußerst schmerzhafter Reizungszustand des fünften Hirnnerven, der mit wiederkehrenden, plötzlich einschießenden, elektrisierenden Schmerzattacken über wenige Sekunden einhergeht
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assessment of the clinical efficacy and safety of local injection of Onabotulinumtoxin A compared to placebo in the therapy of classical trigeminal neuralgia
    Erfassung der klinischen Wirksamkeit und Sicherheit von lokaler Onabotulinumtoxin-A-Injektion im Vergleich zu Placebo bei der Behandlung der klassischen Trigeminusneuralgie
    E.2.2Secondary objectives of the trial
    Additional assessment of neurophysiological alterations of pain processing under BoTN-A therapy by pain-evoking potential and derivation of the nociceptive blink reflex
    Zur zusätzlichen Hypothesenbildung erfolgt die Erfassung neurophysiologischer Veränderungen der Schmerzverarbeitung unter BoNT-A-Therapie mittels schmerzevozierter Potenziale und Ableitung des nozizeptiven Blinkreflexes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Male and female patients of 18 years of age,
    • Patients of legal competence,
    • Sufficient knowledge of written and spoken German,
    • Diagnosis of classical trigeminal neuralgia according to the International Classification of Headache Disorders, third edition
    • Min. three bouts per day between Screening and Baseline
    • Unmodified prophylactic medication for TN (anti-epileptic drugs / Baclofen) during the last four weeks before study participation
    • Unmodified dosing of medication which may have an influence on the frequence and intensity of bouts of TN (tricyclic antidepressants, opiods)
    • Min. one therapeutic attempt of TN with Carbamazepin and in appropriate dose (min. 600 mg / d) either inadequate efficacy or intolerance during therapy
    • Patient willing and capable of attending regular examination and follow-up visits and completing patient questionnaires accurately
    • männliche und weibliche Patienten über 18 Jahre
    • geschäftsfähige Patienten
    • ausreichende Kenntnisse der deutschen Sprache in Wort und Schrift.
    • Diagnose einer klassischen Trigeminusneuralgie gemäß der International Classification of Headache Disorders, dritte Auflage.
    • min. drei Attacken täglich zwischen Screening und Baseline
    • unveränderte prophylaktische TN-Medikation (Antiepileptika / Baclofen) in den letzten vier Wochen vor Studienteilnahme.
    • unveränderte Dosierung von Medikamenten, welche einen möglichen Einfluss auf die Attackenfrequenz und -intensität der TN haben können (trizyklische Antidepressiva, Opiate)
    • min. ein stattgehabter Therapieversuch der TN mit Carbamazepin und entweder unter ausreichender Dosierung (min. 600 mg / d) unzureichende Wirksamkeit oder Unverträg-lichkeit im Therapieverlauf
    • Patient bereit und in der Lage, regelmäßig zu den Untersuchungs- bzw. Nachsorgeterminen zu erscheinen und die Patientenfragebögen sorgfältig auszufüllen
    E.4Principal exclusion criteria
    • Intolerance or contraindications against Botox® according to SmPC:
    o known intolerance/hypersensitivity against BoTN-A
    o local inflammation / sign of infection at allocated injection site
    • Pre-existing diseases with special warning notices according to SmPC:
    • Known periphal motor neuropathic disease (e.g. amyotrophic lateral sclerosis)
    • Known dysphagia, history of aspiration
    • Known corneal ulceration
    • History of neuromuscular disease (e.g. myasthenia gravis, Duchenne muscular dystrophy, Lambert-Eaton-Syndrome)
    • Severe allergic diathesis
    • Symptomatic cause of trigeminal complaints in terms of trigeminal neuropathic pain (e.g. associated with Herpes zoster, MSPlaque, post-traumatic or caused by local spherical mass)
    • Trigeminal autonomic syndroms (SUNCT/SUNA, paroxysmal hemicrania, cluster headache)
    • Ongoing substance/alcohol/medication abuse/dependence
    • Known dysfunction of haemostasis (anamnesis, laboratory)
    • Medical history, which induces an effective anticoagulation (e.g. atrial fibrillation)
    • Severe or terminal diesease (e.g. cancer or tuberculosis)
    • Chronic disease which causes impairment of absorption, metabolism, secretion of study medication
    • Chronic hepatic disease or 3 fold increase in transaminases above normal
    • Positive HIV-testing (anamnestic survey)
    • Nursing women
    • Pregnancy (pregnacy testing in fertile women)
    • Fertile women with insufficient contraception
    • Participation in a different clinical trial less than 30 days before inclusion
    • Previous inclusion into BoTN-study
    • Parallel participation in a different clinical trial

    • Kontraindikationen gegen Botox® gemäß Fachinformation:
    o bekannte Unverträglichkeit/Überempfindlichkeit gegen BoTN-A
    o Lokale Entzündung / Infektzeichen an vorgesehener Injektionsstelle
    • Vorerkrankungen, für welche gemäß Fachinformation besondere Warnhinweise bestehen:
    • bekannte motorisch-neuropathische Erkrankung (z.B. amyotrophe Lateralsklerose)
    • Bekannte Dysphagie, Aspiration in der Vorgeschichte
    • bekanntes Hornhautulkus
    • Erkrankungen, die die neuromuskuläre Transmission beeinträchtigen (Myasthenia gravis, Lambert-Eaton-Syndrom, fortgeschrittene Duchenne-Dystrophie).
    • schwere allergische Diathese
    • symptomatische Ursache trigeminaler Beschwerden im Sinne einer schmerzhaften Trigeminopathie (z.B. Herpes-zoster-assoziiert, MS-Plaque-assoziiert, post-traumatisch oder durch lokale Raumforderung bedingt)
    • Trigeminoautonome Syndrome (SUNCT/SUNA, Paroxysmale Hemikranie, Cluster Kopfschmerz)
    • bekannter Substanzmissbrauch
    • bekannte Störung der Hämostase (Anamnese, Labor)
    • Vorerkrankung bei der eine effektive Antikoagulation indiziert ist (z.B. Vorhofflimmern)
    • Alkoholiker, Medikamenten- oder Drogenabhängige
    • schwere chronische oder terminale Erkrankung (wie z.B. Krebs oder Tuberkulose)
    • jede chronische Krankheit, die Resorption, Metabolismus oder Ausscheidung des Präparates beeinflussen kann.
    • chronische Leberleiden oder Erhöhung der Transaminasen über das 3-fache der Normwerte
    • HIV-Test: positiv (anamnestische Erhebung)
    • Stillzeit
    • Schwangerschaft: Bei Patientinnen im gebärfähigen Alter ist eine Schwangerschaft mittels eines Schwangerschaftstests oder anderer geeigneter Methoden auszuschließen. Ein entsprechender Vermerk ist in das Krankenblatt aufzunehmen.
    • Frauen im gebärfähigen Alter ohne ausreichenden Konzeptionsschutz.
    • Teilnahme an einer klinischen Studie innerhalb der letzten 30 Tage
    • Teilnahme an dieser Studie zu einem früheren Zeitpunkt
    • gleichzeitige Teilnahme an einer anderen klinischen Prüfung
    E.5 End points
    E.5.1Primary end point(s)
    average number of cases of TN bouts during week four (= week 16 of therapy) after double-blind intervention in V2 of BoTN-A / Placebo injection
    durchschnittliche Anzahl an TN-Attacken innerhalb der vierten Woche ( = 16. Therapiewoche ) nach doppelblinder Intervention in V2 nach BoNT-A / Placebo- Injektion
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 16 of therapy
    16. Therapiewoche
    E.5.2Secondary end point(s)
    1. Alteration of average frequency of bouts in week 4 after double-blind intervention (week 16 of therapy) compared to Baseline (days 1-7 before V0) and week 12 of therapy.
    2. Alteration of average frequency of bouts in week 14, 18, 20 and 24 of therapy compared to Baseline and week 12 of therapy.
    3. Intensity of bouts on a numerical rating scale (NRS) in week 14, 16, 18, 20 and 24 of therapy compared to Baseline and week 12 of therapy.
    4. Cases of bouts compared to Baseline and V1.
    5. Adverse events
    6. Rescue-medication required compared to Placebo and run-in-phase
    7. Number of days with TN bouts after V2
    8. Therapy-Response (reduction of cases/day of bouts about ≥ 30 %) in week 4, 8, and 12 of therapy compared to Baseline and in week 16, 20 und 24 of therapy compared to Baseline and week 12 of therapy.
    9. Quality of life / Degree of impairment in daily living, scaled at V0, V2 and V4 by: a) SF-12, b) HIT-6, c) ADS
    10. Questionnaires for adverse events (documented continuously):
    •Results of neurological examination (diagnostic finding of effective pathological value (yes/no) at V1, V2, V3 and V4 (compared to Baseline);
    • Results of physical examination (diagnostic finding of effective pathological value (yes/no)) at V1, V2, V3 and V4
    • Clinical Global Impression at V1, V2, V3 and V4
    1. Veränderung der durchschnittlichen Attackenfrequenz in in der vierten Woche nach doppelblinder Intervention (16. Therapiewoche) im Vergleich zu Baseline (Tag 1-7 vor V0) und zu 12. Therapiewoche.
    2. Veränderung der durchschnittlichen Attackenfrequenz in 14. , 18. 20.und 24. Therapiewoche im Vergleich zur Baseline und 12. Therapiewoche
    3. Attackenintensität auf einer numerischen Rating Skala (NRS) im in 14.,16., 18., 20. und 24. Therapiewoche Vergleich zur Baseline und zur 12. Therapiewoche
    4. Attackenanzahl im Vergleich zur Baseline und V1.
    5. Unerwünschte Ereignisse.
    6. Benötigte Rescue-Medikation im Vergleich zu Placebo und zur Run-in-Phase
    7. Anzahl der Tage mit TN-Attacken nach V2
    8. Therapie-Response (Reduktion der Anzahl / Tag an Attacken um ≥ 30 %) in 4., 8., und 12. Therapiewoche im Vgl. zu Baseline und in 16., 20. und 24. Therapiewoche im Ver-gleich zu Baseline und 12. Therapiewoche
    9. Lebensqualität / Grad der Einschränkung im Alltag, gemessen an V0, V2 und V4 durch: a) SF-12, b) HIT-6, c) ADS
    10. Fragebögen zu unerwünschten Ereignissen (kontinuierlich dokumentiert):
    • Ergebnisse der neurologischen Untersuchung (Befund von aktuellem Krank-heitswert (ja/nein) an V1,V2, V3 und V4 (im Vergleich zur Baseline);
    • Ergebnisse körperlichen Untersuchung (Befund von aktuellem Krankheitswert (ja/nein)) an V1,V2, V3 und V4
    • Clinical Global Impression an V1, V2, V3 und V4
    E.5.2.1Timepoint(s) of evaluation of this end point
    see E.5.2
    siehe unter E.5.2
    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.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 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 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
    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 months0
    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: 20
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state20
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 20
    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 completion of the clinical trial, patients with treatment response may continue with an off-label therapy. An authorization for assumption of costs by the health insurance of the study participant will be requested individually.
    Im Anschluss an die Studie kann bei Therapieansprechen eine Off-Label-Therapie fortgeführt werden. Eine Genehmigung der Kostenübernahme durch die Krankenversicherung des Studienteilnehmers wird individuell beantragt.
    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 Decision2014-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-26
    P. End of Trial
    P.End of Trial StatusOngoing
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