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    Summary
    EudraCT Number:2010-021015-16
    Sponsor's Protocol Code Number:TFM-CL3-002
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-23
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2010-021015-16
    A.3Full title of the trial
    A Phase III, Double-Blind, Placebo Controlled, Parallel Group, International, Multicenter Study of 12 Weeks Treatment with Trafermin 0.01% Spray in Patients with Diabetic Foot Ulcer of Neuropathic Origin.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study comparing Trafermin 0.01% spray and placebo in patients with diabetic foot ulcer of neuropathic origin.
    A.3.2Name or abbreviated title of the trial where available
    The TRAfermin in Neuropathic diabetic foot ulcer Study - northern Europe. The TRANS-North study
    A.4.1Sponsor's protocol code numberTFM-CL3-002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01217476
    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 SponsorOlympus Biotech Europe SAS
    B.1.3.4CountryFrance
    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 supportOlympus Biotech Europe SAS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOLYMPUS BIOTECH EUROPE SAS
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address62 Quai Charles de Gaulle
    B.5.3.2Town/ cityLyon
    B.5.3.3Post code69006
    B.5.3.4CountryFrance
    B.5.4Telephone number+33472449627
    B.5.5Fax number+33953545362
    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 Fiblast Spray
    D.2.1.1.2Name of the Marketing Authorisation holderKaken Pharmaceutical Co. Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationJapan
    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 nametrafermin 0.01% spray
    D.3.2Product code OTD-101, KCB-1
    D.3.4Pharmaceutical form Cutaneous spray, solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtrafermin
    D.3.9.1CAS number 131094-16-1
    D.3.9.2Current sponsor codeOTD-101
    D.3.9.3Other descriptive namehuman basic fibroblast growth factor (recombinant); bFGF
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    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 Yes
    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.3.11.13.1Other medicinal product typerecombinant human basic fibroblast growth factor (rh-bFGF) produced with E. coli
    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 placeboCutaneous spray, solution
    D.8.4Route of administration of the placeboCutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Wound closure rate of diabetic foot ulcers (DFUs) of neuropathic origin.
    E.1.1.1Medical condition in easily understood language
    Wound closure rate of foot ulcer of neuropathic origin in diabetic patient.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level LLT
    E.1.2Classification code 10012664
    E.1.2Term Diabetic foot ulcer
    E.1.2System Organ Class 100000004858
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate a superior wound closure rate of DFUs of neuropathic origin after a maximum of 12 weeks topical daily application of trafermin 0.01% spray compared with placebo, in addition to best local care. Wound closure is defined as 100% reepithelialization of the target DFU (i.e. the target wound only), without exudates.
    E.2.2Secondary objectives of the trial
    • To determine the time to reach complete wound closure.
    • To determine absolute and relative wound area regression and wound edge migration based on planimetry tracing.
    • To determine the occurrence rate of clinical infection related to the target DFU.
    • To evaluate the safety of trafermin 0.01% spray.
    • To determine the rate of amputations on the target DFU.
    • To determine the frequency of local surgical procedures.
    • To determine the maintenance of wound closure/time to re-opening up to 3 months after observed reepithelialization.
    • To determine DFU new occurrence/recurrence up to 12 months.
    • To explore biomarkers from target wound fluid (selected centers only).
    • To assess high sensitivity C-Reactive Protein (hs CRP) level variations.
    • To explore the correlation of absolute and relative wound area regression and wound edge migration based on photography in comparison with planimetry tracing.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provide written informed consent to participate.
    2. Male or female patients age 18 years or older.
    3. Type 1 or 2 diabetes.
    4. A single full-thickness DFU that has been present for at least 2 weeks.
    5. DFU surface area ≥0.9 cm2 and ≤20 cm2 confirmed by the investigator’s measurement, and its surface area not decreased by more than 40% compared to the selection value.
    6. No exposure of bone in the target DFU.
    7. Neuropathy confirmed by loss of protective sensation to monofilament test.
    8. Non-infected target foot DFU of confirmed neuropathic origin with:
    - ABPI on the target leg (>0.9; ≤1.3) or if ABPI is >1.3 or is not assessable66, TBPI on target foot ≥0.7,
    OR
    - ABPI on target leg (≥0.7 - ≤0.9) or if ABPI is >1.3 or is not assessable66, TBPI on target foot <0.7, AND a toe blood pressure >40 mmHg
    9. Completed the 2-week placebo run-in period during which they were compliant to off-loading and to daily application of placebo spray, without major protocol violation. Compliance with the placebo run-in treatment regimen must be “excellent” or “acceptable”.
    10. Glycosylated hemoglobin (HbA1c) ≤10% (from a blood sample taken during the placebo run-in period).
    11. Target DFU appropriately debrided (<10% black and at least 50% of red/pink on a colorimetric scale).
    12. Target DFU of grade A1 or A2 on the University of Texas Wound Classification System or of Grade 1 or 2 of the Wagner classification.
    E.4Principal exclusion criteria
    1. Active Charcot foot, or inactive Charcot foot, if the target DFU cannot be properly offloaded.
    2. Ulcers of non-neuropathic origin (e.g., rheumatoid, radiation-related, vasculitis-related ulcers).
    3. Presence of any foot ulcer (whether or not on the target foot) for which local or systemic antibiotic treatment is required.
    4. Evidence of skin cancer within or adjacent to the target ulcer.
    5. Any infected ulcers, defined as any problem such as (but not limited to) cellulitis, osteomyelitis, gangrene, or deep tissue infection requiring local or systemic antibiotic therapy.
    6. Another wound on the same foot as the target DFU. (i.e. Patients with another wound on the same limb as the target DFU are eligible for the study provided the concomitant wound is not infected and is above the ankle of the target foot).
    7. Any known active malignancy that requires general, local, surgical or radiation therapy either ongoing or within the previous 6 months; or patients whose treatment has been suspended for compassionate reasons, or who are not considered as cured from any malignancy.
    8. Morbid obesitywith body mass index (BMI) ≥45 kg/m2
    9. Clinically significant medical conditions, in the investigator’s opinion, that could impair wound healing (e.g. hepatic impairment, immunocompromised patients).
    10. Severe renal failure, defined as requirement for hemodialysis or peritoneal dialysis.
    11. Females who are pregnant or breastfeeding, or who are of childbearing potential and not practicing a medically approved method of contraception.
    12. Concomitant treatment with high dose oral or parenteral corticosteroids, defined as a daily dose of at least 7.5 mg prednisone or equivalent.
    13. Participation in another clinical study within the previous 3 months.
    14. Current participation in another clinical study with any drug or device.
    15. History of drug or alcohol abuse within the previous year.
    16. Concurrent severe psychiatric disease (including severe depressive disorder).
    17. Known intolerance to the IMP or to any of its excipients.
    18. Known to be uncooperative or noncompliant.
    19. Outpatients who are unable to comply with the requirement for daily spray application at home (either application by a family member or by a visiting nurse).
    20. Any other condition which, in the opinion of the investigator, would render the patient unsuitable for the study.
    E.5 End points
    E.5.1Primary end point(s)
    Wound closure is defined as observed 100% reepithelialization of the target DFU, without exudates, confirmed by a second medical evaluation after two weeks.
    The wound closure rate is the number of patients achieving wound closure at the specified timepoint during the 12-week double blind treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At intervals of 2 weeks during the double-blind treatment period.
    E.5.2Secondary end point(s)
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of the time to reach complete wound closure.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of absolute and relative wound area regression and of wound edge migration of target DFU (using Gilman's formula see Section 11.6.2) over 12 weeks and over 24 weeks, based on planimetry tracing.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of clinical infection occurrence related to the target DFU.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of amputation rate on the target foot.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups on the frequency of local surgical procedures.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of reopening rates of closed wounds at 1, 2 and 3 months after confirmed reepithelialization.
    • Maintenance of wound closure/time to re-opening up to 3 months after confirmed reepithelialization.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of new wound occurrence up to 6 months after randomization.
    • Comparative evaluation of the trafermin 0.01% spray and placebo groups of new wound occurrence/wound recurrence up to 12 months after randomization.
    • Comparative evaluation of variation in hs CRP levels between the trafermin 0.01% spray and placebo groups after the 12-week double blind treatment period.
    • Exploratory biomarker analysis from target wound fluid collected from a subgroup of patients (selected centers only).
    • Exploratory evaluation of wound area regression based on photography in comparison to planimetry tracing
    E.5.2.1Timepoint(s) of evaluation of this end point
    At intervals of 2 weeks during the double blind treatment period , and at 3, 6 and 9 months after the end of treatment period during the primary and secondary follow-up periods.
    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) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Bulgaria
    Croatia
    Denmark
    Germany
    Hungary
    Netherlands
    Poland
    Slovakia
    Sweden
    E.8.7Trial has a data monitoring committee Yes
    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
    End of Trial is defined as last patient last visit in accordance with the protocol. After the double-blind treatment period (max. 12 weeks), patients will be followed up for a total of 9 months from the last treatment application.
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial 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: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 195
    F.4.2.2In the whole clinical trial 210
    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)
    The general care for the patients’ health will continue after they have ended their participation in the study. The investigators will take care to advice the participants and to provide them the most suitable treatment.
    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 Decision2011-11-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-03-27
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