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    Summary
    EudraCT Number:2008-002205-40
    Sponsor's Protocol Code Number:TRX4_DM_007_EU_08
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-01-22
    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 number2008-002205-40
    A.3Full title of the trial
    DEFEND-1: Durable Response Therapy Evaluation For Early Or New Onset Type 1 Diabetes
    A.3.2Name or abbreviated title of the trial where available
    DEFEND-1
    A.4.1Sponsor's protocol code numberTRX4_DM_007_EU_08
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTOLERX,INC.
    B.1.3.4CountryUnited States
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameOtelixizumab
    D.3.2Product code TRX4
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 881191-44-2
    D.3.9.2Current sponsor codeTRX4
    D.3.10 Strength
    D.3.10.1Concentration unit ml millilitre(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    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) Information not present in EudraCT
    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 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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 typeanticorpo monoclonale
    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
    Early or New Onset Type 1 Diabetes
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10045228
    E.1.2Term Type I diabetes mellitus
    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 demonstrate that subjects who receive an 8-day series of otelixizumab infusions have greater improvement that subjects who receive placebo in endogenous insulin secretion,as assessed by area under the concentration-time curve (AUC) for mixed meal stimulated C-peptide,at 12 months after study drug administration.
    E.2.2Secondary objectives of the trial
    1. To assesss endogenous insulin secretion,as measured by mixed meal-stimulated C-peptide AUC,at Months 6, 18 and 24 for the otelixizumab and placebo groups and selected subpopulations 2.To assess exogenous insulin use for the otelixizumab and placebo groups and for selected subpopulations 3.To assess glycemic control,as measured by HbA1c,for the otelixizumab and placebo groups and for selected subpopulations 4.To assess the safety of an 8-day series of otelixizumab infusions,especially with regards to adverse events (AEs),hypoglycemic and hyperglicemic excursions,and Epstein-Barr virus monitoring 5.To assess the pharamcodynamic effects of an 8-day series of otelixizumab infusions,especially with regards to absolute counts and percentages of lymphocyte subsets,CD3/T cell receptor (TCR) and modulation,and serum levels of cytokines and cellular mediators,in an intensive analysis subset (IAS) of subjects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. No condition that,in the investigator`s judgement,is likely to cause the subject to be unable to understand the information in the Informed Consent Document (ICD) or provide informed consent. Such conditions would include,but are not limited to,psychoses or mental retardation with IQ below 65 2.Informed Consent Document signed by the subject 3.Male or female, aged 18 to 35 years,inclusive,at the time of anticipated first dose of study drug 4.Diagnosis of diabetes mellitus according to ADA and WHO criteria (Appendix 2) and consistent with type 1a (autoimmune) DM,with interval of 90 days or less between the initial diagnosis and first dose of study drug.Written documentation of the diagnosis of DM,including the date of diagnosis,must be obtained from the diagnosing physician 5. Currently requires insulin treatment for T1DM.The subject may use long-acting,intermediate-acting,regular,and/or very short-acting insulin.Use of an insulin pump is permitted but not required;use of inhaled insulin is prohibited 6. Willing to undergo intensive insulin therapy and to self-monitor blood glucose level at least 4 times daily from screening through Month 24 and 7 times daily over 7 consecutive days during the 2 weeks before each study visit 7. Willing to record home insulin use,blood glucose levels,and signs and symptoms of hypoglycemic excursions using an electronic personal device assistant,complying with all data transmission requirements,for the planned duration of study participation (2 years after the last dose of study drug) 8.Willing to remain at the study center for at least 6 hours on each day of dosing,i.e.,on 8 consecutive days,and to undergo the mixed meal tolerance test (MMTT) at intervals of 3-12 months 9.positive for one or both of the following autoantibodies typically associated with T1DM:antibody to glutamic acid dexarboxylase (anti-GAD) or antibody to protein tyrosine phosphatase-like protein (anti-IA-2) 10. Evidence of residual functioning beta cells as measured by a stimulated C-peptide level >0,20 nmol/L during the Screening or Predose MMTT when glucose blood level is >70 mg/dL and equal or less to 200 mg/dL 11. Maximum stimulated C-peptide level equal or less then 3.50 nmol/L 12 Body Mass Index (BMI)< 32.
    E.4Principal exclusion criteria
    1. Pregnant, breastfeeding,or planning to become pregnant during the 60 days after the last dose of study drug 2.If of childbearing potential (defined as woman who are premenopausal -have had at least 1 menstrual period during the last past year-and have not had a hysterectomy or tubal ligation),not using adequate contraception if sexually active 3.Significant systemic infection during the 6 weeks before the first dose of study drug 4. Current or prior malignancy,other than non-melanoma skin cancer (subject must have fewer than 5 occurrences of non-melanoma skin cancer,and the last occurrence must not be within 3 months of study entry) 5.A positive intradermal skin test for tuberculosis using purified protein derivative (PPD) 6.Significant and/or active disease in any body system likely to increase the risk to the subject or interfere with the subject`s participation in or completion of the study 7.Clinically significant abnormal laboratory values during the screening period,other than those due to T1DM 8.Positive results for Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, and Hepatitis C 9.Positive results for antibodies to HIV I and II,and considered by the investigator to be at high risk for HIV infection 10. EBV viral load of >10,000 copies per 106 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR) 11. A positive result on the Rapid Plasma Reagin (RPR test) for syphilis;or,if result of RPR test is positive, a negative confirmatory test (for example,fluorescent treponemal antibody absorbed test-FTA-ABS) 12. Have used any investigational drug within the 3 months before signing the ICD,and planning to take any investigational drug for the planned duration of the study participation (2 years after the last dose of study drug) 13.Have used any potent immunosuppressive agent (e.g. systemic high-dose corticosteroids on a chronic basis,methothrexate,cyclosporine,or anti-TNF agents)within the 30 days before signing the ICD,and expected to require such a treatment within 3 months after the last dose of study drug ( intranasal,inhaled,and topical corticosteroid medications are permitted if used at reccomended dosages) 14.Have received a vaccine within the 30 days before signing the ICD,and expected to require a vaccine during the dosing period of the 14 days after the last dose of the study drug 15. Have previously received otelixizumab or any other anti-CD3 monoclonal antibody,e.g. OKT3 (muromonab or Orthoclone),ChAglyCD3,or hOKT3gama1 (ala-ala),and not willing to refrain from using any such antibody for the planned duration of study participation (2 years after the last dose of study drug) 16.Have previously received any anti-lymphocyte monoclonal antibody,such as anti-CD20,anti-thymocite globulin(ATG),rituximab (Rituxan),or alemtuzumab (Campath), and not planning to use any such antibody for the planned duration of study partecipation (2 years after the last dose of study drug) 17. Prior allergic reaction,including anaphylaxis,to any human,humanized,chimeric,or rodent antibody 18. Condition or situation that, in investigator`s judgement,is likely to cause the subject to be unable or unwilling to participate in study procedures or to complete all scheduled assessments
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is change from baseline in 2-hour mixed meal stimulated peptide AUC at month 12.
    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 No
    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) 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.8.3 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 concerned10
    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 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
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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.1.3Elderly (>=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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 240
    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 Decision2008-06-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-10-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-01-31
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