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    Summary
    EudraCT Number:2013-001058-85
    Sponsor's Protocol Code Number:WOE_2013_SB
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-04-03
    Trial results View 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 number2013-001058-85
    A.3Full title of the trial
    EFFECTS OF BENFOTIAMINE ON INTRAEPIDERMAL NERVE FIBER DENSITY (IENFD) AND DIABETIC NEUROPATHY IN SUBJECTS WITH SENSORIMOTOR DIABETIC POLYNEUROPATHY: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP PILOT STUDY OVER 12 MONTHS
    Effekte der Behandlung mit Benfotiamin auf die intraepidermale Nervenfaserdichte und auf die diabetische Neuropathie bei Personen mit sensomotorischer diabetischer Polyneuropathie (SMDP): Eine doppel-verblindete, randomisierte, placebo-kontrollierte, 2-Gruppen Pilotstudie über 12 Monate
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effects of benfotiamine treatment over 12 months on variables of peripheral diabetic neuropathy
    Effekte der Behandlung mit Benfotiamin über 12 Monaten auf Variabeln der peripheren diabetischen Neuropathie
    A.4.1Sponsor's protocol code numberWOE_2013_SB
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1140-6958
    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 SponsorWörwag Pharma GmbH & Co. KG
    B.1.3.4CountryGermany
    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 supportWörwag Pharma GmbH & Co. KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationProfil Institut für Stoffwechselforschung
    B.5.2Functional name of contact pointOvidiu Alin Stirban
    B.5.3 Address:
    B.5.3.1Street AddressHellersbergstr. 9
    B.5.3.2Town/ cityNeuss
    B.5.3.3Post code41460
    B.5.3.4CountryGermany
    B.5.4Telephone number+4921314018486
    B.5.6E-mailalin.stirban@profil.com
    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 Milgamma mono 300
    D.2.1.1.2Name of the Marketing Authorisation holderWörwag Pharma GmbH & Co. KG
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 placeboTablet
    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
    Diabetic neuropathy
    Diabetische Neuropathie
    E.1.1.1Medical condition in easily understood language
    Nerve damage caused by diabetes
    Nervenschäden verursacht durch Diabetes mellitus (Zuckerkrankheit).
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10036113
    E.1.2Term Polyneuropathy in diabetes
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of the present study is to assess before, as well as 6 and 12 months following a therapy with benfotiamine the influence of therapy on intraepidermal nerve fiber density (an early marker of nerve damage) in 22 people with type 1 or 2 diabetes mellitus and diabetic sensorimotor polyneuropathy.
    Ziel der Studie ist den Einfluss einer Therapie mit Benfotiamin nach 6 und 12 Monaten auf die intraepidermale Nervenfaserdichte (ein Parameter der sensitiv Nervenschäden widergibt) bei 22 Personen mit Typ 1 oder Typ 2 Diabetes mellitus zu untersuchen.
    E.2.2Secondary objectives of the trial
    To investigate the effects of therapy on skin autofluorescence (a measure of accumulation of toxic compounds), as well as on neuropathic symptoms and deficits.
    Den Effekt der Therapie auf die Autofluoreszenz der Haut (ein Parameter der die Ansammlung toxischer Produkte widerspiegelt), sowie auf neuropathische Symptome und Defizite zu untersuchen.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed and dated written informed consent obtained before any study-related activities
    2. Have type 1 or type 2 diabetes mellitus based on the disease diagnostic criteria (WHO) classification on ongoing insulin or/and oral antidiabetic therapy with a stable regimen for the previous 3 months
    3. Male or female subjects aged between 18 and 75 years, inclusive
    4. Have an HbA1c level ≤ 9.5% without optimizing potential
    5. (mTCNS ≥ (above or equal to) 6) OR (a score on the MNSI questionnaire of ≥4 or a score on the MNSI examination ≥2.5)
    6. Medical history without major pathology (with the exception of type 2 diabetes) as judged by the investigator, especially no major peripheral artery disease.
    7. Body mass index (BMI) between 25 and 45kg/m2, both inclusive
    8. Ability and willingness to abstain from alcohol and from engaging in strenuous physical activity from 24 hours prior to each visit until discharge from the unit.
    1. Vorliegen einer unterschriebenen Einwilligungserklärung vor dem Durchführen jeglicher studienbezogenen Aktivitäten.
    2. Probanden mit einem Typ 1 oder Typ 2 Diabetes mellitus (Diagnosestellung nach WHO Kriterien) mit einer stabilen Diabetestherapie in den letzten 3 Monaten
    3. Männer oder Frauen zwischen 18 und 75 Jahre (beides inklusive)
    4. HbA1c ≤ 9.5% ohne Möglichkeit der Therapieintensivierung
    5. (mTCNS ≥ 6 Punkte) ODER (MNSI questionnaire ≥4 oder MNSI examination ≥2.5 Punkte)
    6. Anamnese frei von schwerwiegenden Erkrankungen (ausser Typ-2-Diabetes) nach Beurteilung des Investigators, insbesondere kein Vorliegen einer schwerwiegenden peripheren arteriellen Verschlusskrankheit.
    7. Body mass index (BMI) zwischen 25 und 45kg/m2 (beide inklusive)
    8. Bereitschaft zum Verzicht auf Alkoholgenuss und anstrengende körperliche Aktivität ab 24 h vor jedem Behandlungsbesuch bis zum Ende des Besuchs.
    E.4Principal exclusion criteria
    1. Subjects with secondary forms of diabetes such as due to pancreatitis.
    2. Current or previous treatment (less than 6 months) with benfotiamine, B-vitamins, vitamin B complex, alpha lipoic acid or actovegin.
    3. Have any contraindications, known allergy, or hypersensitivity to benfotiamine.
    4. Have any contraindications, known allergy, or hypersensitivity to local anesthetics.
    5. Neuropathy by other origin than diabetes.
    6. Other severe pain that might impair the assessment of neuropathic pain.
    7. Treatment with more than one of following: tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, anticonvulsants, class I antiarrhythmics with Na-channel inhibition (mexiletine, flecainid, propafenon and others) or neuroleptics in patients receiving these drugs for neuropathic pain.
    8. Have participated in an interventional medical, surgical, or pharmaceutical study within the last three months prior to entry into the study.
    9. Women of child-bearing age who are pregnant, lactating or plan a pregnancy within the next 24 months.
    10. Patients on systemic glucocorticoid treatment (except topic or inhalative preparations) within the last 3 months prior to screening.
    11. Subjects with any severe medical or surgical history of conditions likely to confound study assessments or study endpoints, for example but not limited to haemoglobinopathies, inflammatory bowel disease, cystic fibrosis, bariatric surgery and/or any surgery shortening the intestine, history of galactose intolerance, lactose- or glucose-galactose-malabsorption.
    12. Subjects with a suspicion for malignant diseases or a history of a malignant disease within the last 10 years.
    13. As judged by the investigator, serious and/or unstable coronary heart disease (unstable angina, myocardial infarction within the preceding 6 months), congestive heart failure of New York Heart Association Class III or worse, uncontrolled hypertension, history of congenital QT-syndrome within family, history of stroke (within the preceding 6 months) or serious peripheral vascular disease.
    14. Clinically significant vital signs including known bradycardia with pulse rate < 50/min.
    15. Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or coagulation screening tests, as judged by the Investigator.
    16. Clinical or laboratory evidence of hepatic dysfunction or disease; laboratory evidence defined as any of the following parameters: alkaline phosphatase, ALT, AST or bilirubin > 3x ULN. Isolated mild rise in bilirubin considered to be due to Gilbert’s condition is allowed.
    17. Chronic pancreatitis.
    18. Uncontrolled high blood pressure (DBP > 95 mmHg and/or SBP > 160 mmHg), unless clearly documented to be white-coat hypertension
    19. History of any psychiatric condition that might impair the subject’s ability to understand or to comply with the requirements of the study or to provide informed consent.
    20. Currently active or history of alcohol abuse (defined as an intake of more than 24 units of alcohol per week; one unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits) or drug addiction (including soft drugs like cannabis products).
    21. Use of concomitant medication which would be likely to interact with benfotiamine (according to the subject information leaflet).
    22. Subjects known to be positive for Hepatitis B surface antigen or Hepatitis C antibodies (or diagnosed with active hepatitis according to local practice).
    23. Subject who has donated or lost more than 500 mL blood within 3 months prior to screening.
    24. Veins unsuitable for repeated venepuncture.
    1. Andere Formen des Diabetes.
    2. Aktuelle oder in den letzten 6 Monaten vorangegangene Behandlung mit Benfotiamin, B-Vitaminen, Vitamin B- Komplex, Alpha-Liponsäure oder Actovegin.
    3. Vorliegen von Kontraindikationen oder bekannte Allergien gegen Benfotiamin.
    4. Vorliegen von Kontraindikationen oder bekannte Allergien gegen örtliche Betäubungsmittel.
    5. Neuropathie einer anderen Ursache als Diabetes.
    6. Behandlung mit mehr als einem der folgenden Arzneimittel: Trizyklische Antidepressiva, Serotonin-Norepinehphrin-Wiederaufnahmehemmer, Antikonvulsiva, Klasse I Antiarrhythmika mit Na-Kanal Inhibition (Mexiletin, Flecainid, Propafenon, etc.) oder Neuroleptika.
    7. Schwangere oder stillende Frauen. Frauen im gebärfähigen Alter die vorhaben, in den nächsten 24 Monaten schwanger zu werden.
    8. Patienten mit Verdacht auf maligne Erkrankung in den letzten 10 Jahren.
    9. Patienten die in den letzten 6 Monaten folgende Diagnosen hatten: Instabile Angina pectoris, Herzinfarkt, Herzinsuffizienz ab NYHA III, Schlaganfall, unkontrollierte arterielle Hypertonie, schwerwiegende periphere arterielle Verschlusskrankheit, QT-Verlängerungssyndrom in der Familienanamnese.
    10. Klinisch signifikante abnormale Vitalzeichen: Herzfrequenz < 50/min, Blutdruck diastolisch > 95 mmHg und/oder systolisch> 160 mmHg (außer Weißkittelhypertonie).
    11. Klinisch signifikant pathologische Laborwerte (alkalinische Phosphatase, ALT, AST oder Bilirubin > 3x ULN).
    12. Relevante psychiatrische Erkrankungen in der Vorgeschichte.
    13. Alkoholabusus aktuell oder in der Vorgeschichte.
    14. Bekannte Hepatitis B, C oder HIV Infektion.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in intraepidermal nerve fiber density (IENFD) after 6 months of benfotiamine treatment compared to placebo.

    Change from baseline in IENFD after 12 months of benfotiamine treatment compared to placebo.
    Veränderung der intraepidermalen Nervenfaserdichte (IENFD) nach 6 und nach 12 Monaten Therapie mit Benfotiamin.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, 6 months, 12 months.
    Zu Beginn der Studie, nach 6 und 12 Monaten Therapie.
    E.5.2Secondary end point(s)
    - Change from baseline in modified Toronto Clinical Neuropathy Score (mTCNS) after 3 months of benfotiamine treatment compared to placebo.
    - Change from baseline in Michigan Neuropathy Screening Instrument (MNSI) questionnaire after 3 months of benfotiamine treatment compared to placebo.
    - Change from baseline in MNSI examination after 3 months of benfotiamine treatment compared to placebo
    - Change from baseline in QoL after 3 months of benfotiamine treatment compared to placebo
    - Change from baseline in mTCNS after 6 months of benfotiamine treatment compared to placebo.
    - Change from baseline in MNSI questionnaire after 6 months of benfotiamine treatment compared to placebo.
    - Change from baseline in MNSI examination after 6 months of benfotiamine treatment compared to placebo
    - Change from baseline in QoL after 6 months of benfotiamine treatment compared to placebo
    - Change from baseline in mTCNS after 12 months of benfotiamine treatment compared to placebo.
    - Change from baseline in MNSI questionnaire after 12 months of benfotiamine treatment compared to placebo.
    - Change from baseline in MNSI examination after 12 months of benfotiamine treatment compared to placebo
    - Change from baseline in QoL after 12 months of benfotiamine treatment compared to placebo
    - Change from baseline in SAF after 3 months of benfotiamine treatment compared to placebo
    - Change from baseline in SAF after 6 months of benfotiamine treatment compared to placebo
    - Change from baseline in SAF after 12 months of benfotiamine treatment compared to placebo
    Veränderung nach 3, 6 bzw. 12 Monaten Therapie mit Benfotiamin folgender Parameter:
    • Symptome und Zeichen der DNP, erfasst mittels eines standardisierten Fragebogens, dem „modified Toronto Clinical Neuropathy Score“ (mTCNS).
    • Symptome der DNP, erfasst mittels eines standardisierten Fragebogens, dem „Michigan Neuropathy Screening Instrument (MNSI) Questionnaire“.
    • Zeichen der DNP, erfasst mittels eines standardisierten Fragebogens, dem „Michigan Neuropathy Screening Instrument (MNSI) Examination“.
    • Lebensqualität, gemessen mit einem standardisierten Fragebogen, dem „Neuro-Quality of Life“ (Neuro-QoL)
    • Autofluoreszenz der Haut (Skin Autofluorescence – SAF) als Parameter der Ansammlung von AGEs in der Haut.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, 3, 6 and 12 months.
    Zu Beginn der Studie, nach 3, 6 und 12 Monaten Therapie.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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
    Letzter Besuch des letzten Probanden.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    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: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2013-04-03. Yes
    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 state22
    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)
    During the participation in the trial and afterwards subjects will be treated by their diabetologist and/or their general practitioner according to existing guidelines for their disease.
    Während der Teilnahme an der Studie und danach werden die Probanden von ihrem Diabetologen und/oder ihrem Hausarzt entsprechend geltenden Leitlinien für ihre Erkrankung behandelt.
    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 Decision2013-07-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-06-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-09-07
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