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    Summary
    EudraCT Number:2013-002248-98
    Sponsor's Protocol Code Number:TN-10
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2021-01-28
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-002248-98
    A.3Full title of the trial
    Anti-CD3 MAB (Teplizumab) for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
    ANTI-CD3 MAB (TEPLIZUMAB) per la prevenzione del diabete in PARENTI a rischio di sviluppare diabete di tipo 1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Preventing Diabetes with an Antibody in Relatives at Risk for the Disease
    Prevenire il diabete con un anticorpo in parenti a rischio per la malattia
    A.3.2Name or abbreviated title of the trial where available
    TN-10
    TN-10
    A.4.1Sponsor's protocol code numberTN-10
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01030861
    A.5.4Other Identifiers
    Name:Investigational New Drug (IND)Number:102629
    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 SponsorTRAILNET COORDINATING CENTER AT THE UNIVERSITY OF SOUTH FLORIDA
    B.1.3.4CountryUnited States
    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 supportNational Institute of Diabetes and Digestive and
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTrialNet Coordinating Center
    B.5.2Functional name of contact pointJulie Martin
    B.5.3 Address:
    B.5.3.1Street Address3650 Spectrum Boulevard Suite 100
    B.5.3.2Town/ cityTampa, Florida
    B.5.3.3Post code33612
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 813 396 9122
    B.5.5Fax number+1 877 777 7847
    B.5.6E-mailJulie.Martin@epi.usf.edu
    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 No
    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 nameteplizumab
    D.3.2Product code MGA031
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboSolution for infusion
    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
    Anti-CD3 mAb is to be used for the prevention of type 1 diabetes mellitus in relatives at risk for developing the disease.
    prevenzione del diabete di tipo 1
    E.1.1.1Medical condition in easily understood language
    prevention of type 1 diabetes mellitus
    Diabete di tipo 1
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10067584
    E.1.2Term Type 1 diabetes mellitus
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to assess the safety,
    efficacy, and mode of action of teplizumab for prevention of T1DM and to determine whether
    intervention with teplizumab will prevent or delay the development of T1DM in high risk autoantibody positive non-diabetic
    relatives.
    L¿obiettivo primario ¿ quello di valutare la sicurezza, l¿efficacia, e la modalit¿ di azione di teplizumab
    nella prevenzione del diabete di tipo 1 e di determinare se il trattamento con teplizumab impedir¿ o ridurr¿ lo sviluppo di T1DM in
    parenti non diabetici ad alto rischio positivi agli autoanticorpi.
    E.2.2Secondary objectives of the trial
    Secondary objectives will determine whether treatment with teplizumab is superior to placebo with respect to C-peptide responses to oral glucose, as obtained from timed collections during longitudinal tests. To compare the safety and tolerability of teplizumab to placebo and to assess the effects of treatment on mechanistic outcomes.
    Obiettivi secondari determineranno se il trattamento con teplizumab ¿ superiore al placebo per
    quanto riguarda le risposte C-peptide al glucosio orale, come ottenuto da raccolte temporizzate durante i test longitudinali.
    Confrontare la sicurezza e la tollerabilit¿ di teplizumab con il placebo e valutare gli effetti del trattamento sui risultati
    meccanicistici.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participant in TrialNet Natural History Study (TN01) and thus a relative of a proband** with T1DM.
    2. Between the ages of 1-45 years at the time of enrollment in TN01 and age = 8 at time of randomization in this trial
    3. Subject (or parent or legal guardian if the subject is a minor) is willing to provide Informed Consent.
    4. Individuals <18 years of age at time of randomization must have had a TrialNet conducted OGTT demonstrating abnormal
    glucose tolerance*
    within 7 weeks (52 days) of the baseline visit (visit 0).
    5. Individuals =18 years of age at time of randomization must have had two consecutive TrialNet conducted OGTT's demonstrating
    abnormal
    glucose tolerance, the most recent of which must have been within 7 weeks (52 days) of the baseline visit (visit 0).
    6. The participant must be positive for two or more diabetes-related autoantibodies on two occasions. The second occasion must
    occur within the six months prior to study drug administration, but does not need to involve the same two autoantibodies as were
    found on the first occasion.
    The autoantibodies that are to be confirmed are anti-GAD65, anti-ICA512, anti-insulin (MIAA), ZnT8 and/or ICA.
    7. Weigh at least 26 kg at randomization.
    8. If participant is female with reproductive potential, she must have a negative pregnancy test on Day 0 and be willing to avoid
    pregnancy for at least one year from randomization.
    9. If participant is male, he must be willing to avoid pregnancy in any partners for at least one year from randomization.
    10. Willing and medically acceptable to postpone live vaccine immunizations for one year after treatment.
    11. Willing to forego other forms of experimental treatment during the study.
    1. Partecipazione allo studio di storia naturale TrialNet (TN01) e quindi un parente di un probando ** con T1DM.
    2. Età compresa tra 1 e 45 anni al momento dell'arruolamento nello studio TN01 e età = 8 anni al momento della randomizzazione
    in questo studio.
    3. Soggetto (o il genitore o tutore legale, se il soggetto è minore) disponibile a fornire il consenso informato.
    4. I soggetti con età <18 anni al momento della randomizzazione devono aver avuto un OGTT condotto da TrialNet dimostrando
    anormale tolleranza al glucosio* entro 7 settimane (52 giorni) della visita basale (visita 0).
    5. Individui =18 anni di età al momento della randomizzazione devono aver effettuato
    due test OGTT consecutivi condotti da TrialNet che dimostrano anormale tolleranza al glucosio, il più recente dei quali deve essere
    stato entro 7 settimane (52 giorni) della visita basale (visita 0).
    6. Il partecipante deve essere positivo a due o più autoanticorpi correlati al diabete in due occasioni. La seconda occasione deve
    avvenire entro sei mesi precedenti la somministrazione del farmaco, ma non ha bisogno di coinvolgere gli stessi due autoanticorpi
    come nella prima occasione.Gli autoanticorpi che devono essere confermati sono anti-GAD65, anti-ICA512, anti-insulina (MIAA),
    ZnT8 e / o ICA.
    7. Pesare almeno 26 kg al momento della randomizzazione.
    8. Se partecipante è di sesso femminile con un potenziale riproduttivo, lei deve avere un test di gravidanza negativo il giorno 0 ed
    essere disposti a evitare la gravidanza per almeno un anno dalla randomizzazione.
    9. Se partecipante è maschio, egli deve essere disposto a evitare la gravidanza in ogni partner per almeno un anno dalla
    randomizzazione.
    10. Disposto e accettabile dal punto di vista clinico a rimandare le vaccinazioni con vaccino vivo per un anno dopo il trattamento.
    11. Disposto a rinunciare ad altre forme di trattamento sperimentale durante lo studio.
    E.4Principal exclusion criteria
    1. If =18yo: Diabetes, or have a screening OGTT with:
    a. Fasting plasma glucose =126 mg/dL, or
    b. 2 hour plasma glucose = 200mg/dL
    2. If <18yo: Diabetes, or have a screening random glucose =200mg/dL
    3. Lymphopenia (< 1000 lymphocytes/µL).
    4. Neutropenia (< 1500 PMN/µL ).
    5. Thrombocytopenia (< 150,000 platelets/µL).
    6. Anemia (Hgb < 10 grams/deciliter [g/dL]).
    7. AST or ALT >1.5 x ULN.
    8. Total bilirubin >1.5 x upper limit of normal (ULN) with the exception of subjects with the
    diagnosis of Gilbert's syndrome who may be eligible provided they have no other causes leading to
    hyperbilirubinemia.
    9. INR > 0.1 above the upper limit of normal at the participating center's laboratory.
    10. Chronic active infection other than localized skin infections.
    11. A positive PPD test.
    12. Vaccination with a live virus within 8 weeks of randomization
    13. Vaccination with a killed virus within 4 weeks of randomization.
    14. A history of infectious mononucleosis within the 3 months prior to enrollment.
    15. Laboratory or clinical evidence of acute infection with EBV or CMV.
    16. Serological evidence of current or past HIV, Hepatitis B or Hepatitis C infection.
    17. Be currently pregnant or lactating, or anticipate getting pregnant.
    18. Chronic use of steroids or other immunosuppressive agents.
    19. A history of asthma or atopic disease requiring chronic treatment.
    20. Untreated hypothyroidism or active Graves' disease at randomization.
    21. Current use of non-insulin pharmaceuticals that affect glycemic control.
    22. Prior OKT®3 or other anti-CD3 treatment.
    23. Administration of a monoclonal antibody within the year before randomization.
    24. Participation in any type of therapeutic drug or vaccine clinical trial within the 12 weeks
    before randomization.
    25. Any condition that, in the opinion of the investigator, would interfere
    with the study conduct or the safety of the subject.
    1. Se =18yo: diabete, o di una proiezione OGTT con:
    a. Glicemia a digiuno =126 mg / dL, o
    b. 2 ore = glicemia 200 mg / dL
    2. Se <18anni: diabete, o avere un di screening di glucosio casuale =200mg / dL
    3. linfopenia (<1000 linfociti / mL).
    4. neutropenia (<1.500 PMN / mL).
    5. Trombocitopenia (<150.000 piastrine / mL).
    6. L'anemia (Hb <10 g / dl [g / dl]).
    7. AST o ALT> 1,5 x ULN.
    8. bilirubina totale> 1,5 volte il limite superiore della norma (ULN) con l'eccezione di soggetti con diagnosi di sindrome di Gilbert,
    che possono essere ammissibili purché non abbiano altre cause che portano a iperbilirubinemia.
    9. INR> 0,1 oltre il limite superiore del normale al laboratorio del centro partecipante.
    10. Infezione cronica attiva diversa da infezioni cutanee localizzate.
    11. Un test PPD positivo.
    12. La vaccinazione con un virus vivo entro 8 settimane dalla randomizzazione
    13. La vaccinazione con un virus ucciso entro 4 settimane dalla randomizzazione.
    14. Una storia di mononucleosi infettiva entro i 3 mesi precedenti all’arruolamento.
    15. Laboratorio o evidenza clinica di un'infezione acuta da EBV o CMV.
    16. evidenza sierologica di attuale o passato infezione da HIV, epatite B o epatite C.
    17. essere attualmente in stato di gravidanza o in allattamento, o anticipare di rimanere incinta.
    18. L'uso cronico di steroidi o di altri agenti immunosoppressivi.
    19. Una storia di asma o di malattia atopica che richiedono un trattamento cronico.
    20. ipotiroidismo non trattato o attiva malattia di Graves al momento della randomizzazione.
    21. L'uso corrente di farmaci non-insulina che influiscono il controllo glicemico.
    22. Precedenti OKT®3 o altri trattamenti anti-CD3.
    23. La somministrazione di un anticorpo monoclonale entro l'anno prima della randomizzazione.
    24. La partecipazione a sperimentazione clinica con qualsiasi tipo di farmaco terapeutico o vaccino entro le 12 settimane
    precedenti la randomizzazione.
    25. Qualsiasi condizione che, a giudizio dello sperimentatore, potrebbero interferire con la condotta dello studio o la sicurezza del
    soggetto.
    E.5 End points
    E.5.1Primary end point(s)
    The time from random assignment of
    treatment to the development of diabetes.
    Il tempo trascorso dalla randomizzazione del trattamento allo sviluppo del diabete.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 years
    6 anni
    E.5.2Secondary end point(s)
    Secondary end point (up to 4000 characters) (End point secondario in inglese): Subgroup analyzes will be conducted
    comparing the effects of teplizumab than the control on the risk of diabetes within subsets of the study cohort. Subgroups of the
    population will be classified by age (layer), sex, race / ethnicity, baseline antibody status, and the presence or absence of HLA
    DQB1 * 0602. will test the effectiveness of the treatment differences between subgroups using a covariate in interaction term
    between treatment groups in a pattern PH.
    Le analisi dei sottogruppi sar¿ condotta confrontando gli effetti di teplizumab rispetto al controllo
    sul rischio di diabete all¿interno di sottoinsiemi di studio di coorte. Sottogruppi della popolazione saranno classificati per et¿
    (strato), sesso, razza / etnia, stato di anticorpo specifico al basale, e la presenza o assenza di HLA DQB1 * 0602. Verranno testate
    le differenze di efficacia del trattamento tra i sottogruppi usando una covariata in termine di interazione tra i gruppi di trattamento
    in un modello PH.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 years
    6 anni
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    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 Yes
    E.7.1.3.1Other trial type description
    phase II for efficacy
    fase II per l'efficacia
    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 No
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    Germany
    Italy
    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
    The total sample size and study duration can only be approximated.
    The study plans to enroll approximately 71 subjects over
    approximately 2-3 years, and is projected to last between 4 and 6
    years. As the study progresses, projections of the study end will be
    computed and updated based on the rate of enrollment, the observed
    hazard rate and the rate of loss-to-follow-up.
    La dimensione del campione e lo studio durata totale pu¿ essere approssimata.
    Lo studio prevede di arruolare circa 71 soggetti over
    circa 2-3 anni, e si prevede che una durata compresa tra 4 e 6
    anni. Come lo studio progredisce, le proiezioni di fine studio saranno
    calcolato e aggiornato sulla base del tasso di iscrizione, l'osservato
    tasso di rischio e il tasso di perdita-to-follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 28
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 28
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    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 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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 71
    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)
    Although subjects who develop diabetes will have reached the study endpoint, these individuals will be offered annual follow up for a minimum of two years Those individuals who have not developed diabetes by study end will continued to be followed as part of the TrialNet Natural History/Pathway to Prevention study protocol.
    Anche se i soggetti che sviluppano il diabete avranno raggiunto gli endpoint dello studio, a questi soggetti sar¿ offerto un follow-up annuale per un minimo di due anni. Quei soggetti che non hanno sviluppato diabete entro la fine dello studio continueranno ad essere seguiti come parte del protocollo di studio TrialNet Natural History/
    Pathway to Prevention.
    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 Decision2015-12-11
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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