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
Link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001959-24/DE/

A. Protocol Information
A.1 Member State Concerned: Germany - BfArM
A.2 EudraCT number: 2014-001959-24
A.3 Full title of the trial: BoTN: Onabotulinumtoxin A for the treatment of trigeminal neuralgia: Efficacy, safety and neurophysiological alterations under therapy – a prospective, controlled trial
A.3 Full title of the trial (de): BoTN: Onabotulinumtoxin A zur Behandlung der Trigeminusneuralgie: Wirksamkeit, Sicherheit und neurophysiologische Veränderungen unter Therapie - eine prospektive, kontrollierte klinische Studie
A.3.1 Title 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
A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language (de): Botox zur Behandlung des Gesichtsschmerzes, der durch einen äußerst schmerzhaften Reizungszustand des fünften Hirnnerven ausgelöst wird
A.4.1 Sponsor's protocol code number: BoTN-Study
A.7 Trial is part of a Paediatric Investigation Plan: No
A.8 EMA Decision number of Paediatric Investigation Plan: 

B. Sponsor Information
Sponsor 1
B.1.1 Name of Sponsor: University Hospital Essen
B.1.3.4	Country: Germany
B.3.1 and B.3.2	Status of the sponsor: Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1 Name of organisation providing support: Allergan Pharmaceuticals Ireland
B.4.2 Country: Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1 Name of organisation: University Hospital Essen
B.5.2 Functional name of contact point: Principal Investigator
B.5.3 Address
B.5.3.1 Street Address: Hufelandstrasse 55
B.5.3.2 Town/ city: Essen
B.5.3.3 Post code: 45122
B.5.3.4 Country: Germany
B.5.4 Telephone number: 00490201723-84385 
B.5.5 Fax number: 00490201723-6962 
B.5.6 E-mail: mark.obermann@uk-essen.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: Yes
D.2.1.1.1 Trade name: BOTOX®
D.2.1.1.2 Name of the Marketing Authorisation holder: Allergan Pharmaceuticals Ireland
D.2.1.2 Country which granted the Marketing Authorisation: Germany
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: BOTOX®
D.3.4 Pharmaceutical form: Powder for solution for injection
D.3.4.1 Specific paediatric formulation: No
D.3.7 Routes of administration for this IMP:
Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8 INN - Proposed INN: Onabotulinumtoxin A
D.3.9.1 CAS number: 93384-43-1
D.3.9.3 Other descriptive name: BOTULINUM TOXIN TYPE A
D.3.9.4 EV Substance Code: SUB13117MIG
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: 50 
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
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: No
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: Solution for injection
D.8.4 Route of administration of the placebo: Subcutaneous use

E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1 Medical condition(s) being investigated: Trigeminal neuralgia
E.1.1 Medical condition(s) being investigated (de): Trigeminusneuralgie
E.1.1.1 Medical condition in easily understood language: Extremely painful irritation of the fifth cranial nerve accompanied by recurrent and suddenly occurring, eletrifying exacerbation of pain
E.1.1.1 Medical condition in easily understood language (de): äußerst schmerzhafter Reizungszustand des fünften Hirnnerven, der mit wiederkehrenden, plötzlich einschießenden, elektrisierenden Schmerzattacken über wenige Sekunden einhergeht
E.1.1.2 Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
MedDRA Classification
E.1.3 Condition being studied is a rare disease: Yes
E.2 Objective of the trial
E.2.1 Main 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
E.2.1 Main objective of the trial (de): Erfassung der klinischen Wirksamkeit und Sicherheit von lokaler Onabotulinumtoxin-A-Injektion im Vergleich zu Placebo bei der Behandlung der klassischen Trigeminusneuralgie
E.2.2 Secondary 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
E.2.2 Secondary objectives of the trial (de): Zur zusätzlichen Hypothesenbildung erfolgt die Erfassung neurophysiologischer Veränderungen der Schmerzverarbeitung unter BoNT-A-Therapie mittels schmerzevozierter Potenziale und Ableitung des nozizeptiven Blinkreflexes.
E.2.3 Trial contains a sub-study: No
E.3 Principal 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

E.3 Principal inclusion criteria (de): • 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.4 Principal 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 


E.4 Principal exclusion criteria (de): • 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.5.1 Primary 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
E.5.1 Primary end point(s) (de): durchschnittliche Anzahl an TN-Attacken innerhalb der vierten Woche ( = 16. Therapiewoche ) nach doppelblinder Intervention in V2 nach BoNT-A / Placebo- Injektion
E.5.1.1 Timepoint(s) of evaluation of this end point: week 16 of therapy
E.5.1.1 Timepoint(s) of evaluation of this end point (de): 16. Therapiewoche
E.5.2 Secondary 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

E.5.2 Secondary end point(s) (de): 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.5.2.1 Timepoint(s) of evaluation of this end point: see E.5.2
E.5.2.1 Timepoint(s) of evaluation of this end point (de): siehe unter E.5.2
E.6 and E.7 Scope of the trial
E.6 Scope of the Trial
E.6.1 Diagnosis: No
E.6.2 Prophylaxis: No
E.6.3 Therapy: Yes
E.6.4 Safety: Yes
E.6.5 Efficacy: Yes
E.6.6 Pharmacokinetic: No
E.6.7 Pharmacodynamic: No
E.6.8 Bioequivalence: No
E.6.9 Dose response: No
E.6.10 Pharmacogenetic: No
E.6.11 Pharmacogenomic: No
E.6.12 Pharmacoeconomic: No
E.6.13 Others: No
E.7 Trial type and phase 
E.7.1 Human pharmacology (Phase I): No
E.7.1.1 First administration to humans: No
E.7.1.2 Bioequivalence study: No
E.7.1.3 Other: No
E.7.1.3.1 Other trial type description: 
E.7.2 Therapeutic exploratory (Phase II): Yes
E.7.3 Therapeutic confirmatory (Phase III): No
E.7.4 Therapeutic use (Phase IV): No
E.8 Design of the trial
E.8.1 Controlled: Yes
E.8.1.1 Randomised: Yes
E.8.1.2 Open: No
E.8.1.3 Single blind: No
E.8.1.4 Double blind: Yes
E.8.1.5 Parallel group: Yes
E.8.1.6 Cross over: No
E.8.1.7 Other: No
E.8.2 Comparator of controlled trial
E.8.2.1 Other medicinal product(s): No
E.8.2.2 Placebo: Yes
E.8.2.3 Other: No
E.8.2.4 Number of treatment arms in the trial: 2
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.8.5 The trial involves multiple Member States: No
E.8.6 Trial involving sites outside the EEA
E.8.6.1 Trial being conducted both within and outside the EEA: No
E.8.6.2 Trial being conducted completely outside of the EEA: No
E.8.7 Trial 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.8.9.1 In the Member State concerned years: 2
E.8.9.1 In the Member State concerned months: 0
E.8.9.1 In the Member State concerned days: 0

F. Population of Trial Subjects
F.1 Age Range
F.1.1 Trial has subjects under 18: No
F.1.1.1 In Utero: No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks): No
F.1.1.3 Newborns (0-27 days): No
F.1.1.4 Infants and toddlers (28 days-23 months): No
F.1.1.5 Children (2-11years): No
F.1.1.6 Adolescents (12-17 years): No
F.1.2 Adults (18-64 years): Yes
F.1.2.1 Number of subjects for this age range: 20
F.1.3 Elderly (>=65 years): No
F.2 Gender
F.2.1 Female: Yes
F.2.2 Male: Yes
F.3 Group of trial subjects
F.3.1 Healthy volunteers: No
F.3.2 Patients: Yes
F.3.3 Specific vulnerable populations: No
F.3.3.1 Women of childbearing potential not using contraception : No
F.3.3.2 Women of child-bearing potential using contraception: No
F.3.3.3 Pregnant women: No
F.3.3.4 Nursing women: No
F.3.3.5 Emergency situation: No
F.3.3.6 Subjects incapable of giving consent personally: No
F.3.3.7 Others: No
F.4 Planned number of subjects to be included
F.4.1 In the member state: 20
F.4.2 For a multinational trial
F.4.2.2 In 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.
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) (de): 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 Decision: 2014-08-13
N. Ethics Committee Opinion of the trial application: Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion:
N. Date of Ethics Committee Opinion: 2014-08-26

P. End of Trial
P. End of Trial Status: Ongoing