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    The EU Clinical Trials Register currently displays   42758   clinical trials with a EudraCT protocol, of which   7042   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2016-004505-13
    Sponsor's Protocol Code Number:TOFFIFE
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-08-21
    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 - PEI
    A.2EudraCT number2016-004505-13
    A.3Full title of the trial
    Tocilizumab for the Treatment of Familial Mediterranean Fever – A randomized, doubleblind, phase II proof of concept study-TOFFIFE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Tocilizumab for the Treatment of Familial Mediterranean Fever
    Tocilizumab zur Behandlung des Familiären Mittelmeerfiebers – Eine randomisierte, doppelblinde Phase II Studie - TOFFIFE
    A.3.2Name or abbreviated title of the trial where available
    Tocilizumab for the Treatment of Familial Mediterranean Fever
    Tocilizumab zur Behandlung des Familiären Mittelmeerfiebers
    A.4.1Sponsor's protocol code numberTOFFIFE
    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 Tuebingen
    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 supportRoche
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportUniversity Hospital Tuebingen
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Tuebingen
    B.5.2Functional name of contact pointDepartment of Internal Medicine II
    B.5.3 Address:
    B.5.3.1Street AddressOtfried-Müller-Str. 10
    B.5.3.2Town/ cityTuebingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number+497071292980681
    B.5.5Fax number+497071294398
    B.5.6E-mailjoerg.henes@med.uni-tuebingen.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 RoActemra® 20mg/ml Konzentrat Tocilizumab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Pharma AG
    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
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNINN-Tocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal antibody against interleukin-6
    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 placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adult patients with Familial Mediterranean Fever, who have active disease
    E.1.1.1Medical condition in easily understood language
    Familial Mediterranean Fever
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10016207
    E.1.2Term Familial mediterranean fever
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of Tocilizumab in patients with active FMF in a randomized, placebo controlled setting


    Efficacy: measured by Physician’s Global Assessment of disease activity (PGA) at week 16
    Primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR and/or CRP (the one that led to inclusion must be normalized) + normalized SAA
    E.2.2Secondary objectives of the trial
    - To evaluate the safety of TCZ in subjects with FMF
    - To evaluate the proportion of patients achieving a Physician Global assessment of disease activity (PGA) ≤ 2 (minimal or none) at week 16
    - To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP < 0.5 mg/dl)
    - To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA < 10mg/l)
    - To evaluate the possibility of reducing intake of ibuprofene, diclofenac or paracetamol
    - To evaluate health related quality of live assessed by FFbH, FACIT Fatigue
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age ≥ 18 years and written informed consent
    - FMF according to the Tel Hashomer Criteria (Appendix); with at least one heterozygous or homozygous mutation of the MEFV gene
    - Inadequate response or intolerance to colchicine
    - Attack during the last 12 weeks, defined as episodes of fever and/or pericarditis and/or serositis and/or testis involvement and/or arthritis and/or erysipelas-like rash and
    - CRP >0.5mg/dl and/or ESR >20mm/h and/or SAA >10mg/dl
    - Physician Global Assessment (PGA) >2
    - Able and willing to provide written informed consent and to comply with the study protocol
    E.4Principal exclusion criteria
    Subjects presenting with any of the following criteria will not be included in the trial:
    - Age < 18 years
    - Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after randomization
    - Transplanted organs (except corneal transplant performed more than 3 months prior to screening)
    Exclusions Related to Prior or Concomitant Therapy
    - Previous treatment with TCZ
    - Treatment with glucocorticosteroide > 10mg/day within 1 week; prednisolone ≤ 10mg/day can be given on a stable dose throughout the study
    - Analgesic medication other than paracetamol or ibuprofen or diclofenac, which can be used at a stable dose and for treatment of FMF attacks.
    - Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
    - Treatment with Anakinra within the last 1 week prior to baseline (ptb), Canakinumab within the last 8 week prior to baseline
    - Treatment with etanercept within 2 weeks; certolizumab pegol, abatacept or adalimumab within 6 weeks; golimumab and infliximab within 8 weeks ptb
    - Rituximab within 24 weeks ptb
    - Leflunomide within 12 weeks ptb (washout possible),
    - azathioprine, cyclophosphamide within 12 weeks ptb
    - Immunization with a live/attenuated vaccine within ≤ 4 weeks ptb
    - Previous treatment with cell-depleting therapies, including investigational agents or approved therapies: anti-CD33, anti-CD52, anti-CD4, anti-CD5, anti- CD3 and anti-CD19
    - Treatment with intravenous gamma globulin within 6 months of baseline
    - Treatment with plasmapheresis within 6 months of baseline
    - Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation
    Exclusions Related to General Safety
    - History of severe allergic or anaphylactic reactions to human, humanized, or murine antibodies
    - Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, psychiatric or GI disease
    - History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
    - Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
    - Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
    - Active TB requiring treatment within the previous 3 years; Patients should be screened for latent TB and, if positive, treated according to local practice guidelines prior to initiating TCZ treatment; Patients treated for TB with no recurrence within 3 years and patients treated for latent TB within 3 years are eligible.
    - Primary or secondary immunodeficiency (history of or currently active)
    - Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured)
    - Females of childbearing potential who are not willing to use an effective method of contraception, such as condom, sterilization, or true abstinence throughout study and for a minimum of 6 months after study drug therapy and females who are breastfeeding
    - Pregnant women
    - Males of reproductive potential who are not willing to use an effective method of contraception, such as condom, sterilization, or true abstinence throughout study and for a minimum of 6 months after study drug therapy
    - History of alcohol, drug, or chemical abuse within 1 year prior to screening
    Laboratory Exclusions (at Screening)
    - Serum creatinine > 1.4 mg/dL in female patients and > 1.6 mg/dL (in male patients
    - ALT or AST > 2 ×ULN
    - Total bilirubin > 2 x ULN
    - Platelet count < 100 × 109/L
    - Hemoglobin < 8.5 g/dL
    - White blood cells < 3.0 ×109/L
    - Absolute neutrophil count < 2.0 × 109/L
    - Absolute lymphocyte count < 0.5 × 109/L
    - Positive hepatitis B surface antigen, anti-HBc, HIV or hepatitis C antibody
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy: measured by Physician’s Global Assessment of disease activity (PGA) at week 16
    Primary endpoint will be the number of patients achieving an adequate response to treatment at week 16, defined as: PGA ≤ 2 + normalized ESR and/or CRP (the one that led to inclusion must be normalized) + normalized SAA
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 16
    E.5.2Secondary end point(s)
    - To evaluate the safety of TCZ in subjects with FMF
    - To evaluate the proportion of patients achieving a Physician Global assessment of disease activity (PGA) ≤ 2 (minimal or none) at week 16
    - To evaluate the proportion of patients with the serological remission at week 16 + 28 (defined as CRP < 0.5 mg/dl)
    - To evaluate the proportion of patients with normalized SAA level at week 16 + 28 (defined as SAA < 10mg/l)
    - To evaluate the possibility of reducing intake of ibuprofene, diclofenac or paracetamol
    - To evaluate health related quality of live assessed by FFbH, FACIT Fatigue
    E.5.2.1Timepoint(s) of evaluation of this end point
    disease activity (PGA) ≤ 2 (minimal or none) at week 16
    serological remission at week 16 + 28
    proportion of patients with normalized SAA level at week 16 + 28
    To evaluate the possibility of reducing intake of ibuprofene, diclofenac or paracetamol at week 16 and 28
    To evaluate health related quality of live assessed by FFbH, FACIT Fatigue at week 16 and 28
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    Proof-of-Concept
    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 concerned4
    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
    In case of the following situations, a premature termination of the trial has to be considered:
    • Serious adverse drug reactions / not justifiable toxicity
    • Substantial changes in risk-benefit considerations
    • New insights from other trials
    • Insufficient efficacy
    • Insufficient recruitment rate

    For further information see chapter 6.10 to 6.12 of the submitted protocol
    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: 30
    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 state30
    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 Termination of the study, those patients with good response to treatment will be followed up regularly at the centers for signs of flaring disease. In case of disease flare patient will be treated according to local standard.
    The Sponsor will offer post-trial access to the study drug (TCZ) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product,
    For further information, please see Protocol Section 6.13.1.
    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 Decision2017-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-06-17
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