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    Summary
    EudraCT Number:2006-003579-11
    Sponsor's Protocol Code Number:TRX4_DM_004_EU_06
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2006-08-01
    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 ConcernedGermany - PEI
    A.2EudraCT number2006-003579-11
    A.3Full title of the trial
    Tolerability and Safety of Multiple Dose Regimens of TRX4 Anti-CD3 Monoclonal Antibody in Type 1 Diabetes Mellitus
    A.4.1Sponsor's protocol code numberTRX4_DM_004_EU_06
    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 SponsorTolerRx, 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 nameTRX4 (Monoclonal anti-CD3 Antibody)
    D.3.4Pharmaceutical form Concentrate for 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.3.9.2Current sponsor codeTRX4 (monoclonal anti-CD3 antibody)
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5.1
    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) Yes
    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 Information not present in EudraCT
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Type I Diabetes Mellitus
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    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
    1) Define a maximum dose level at which there is negligible cytokine release, especially for the first dose of each multiple dose regimen.

    2) Evalute the effect of TRX4 on standard safety parameters (CBC, WBC differential, hepatic function tests and other serum chemistries, ECG, etc. ) and on EBV reactivation.
    E.2.2Secondary objectives of the trial
    1) Confirm that there is progressively less cytokine release with each dose of the four-dose regimens.
    2) Determine the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of TRX4 in Type 1 Diabetes Mellitus (T1 DM).
    3) Compare safety, PK/PD, and cytokine release data with similar data collected in previous studies in psoriasis and new onset Type 1 Diabetes Mellitus (NOT1DM).
    4) Characterize whether TRX4 is immunogenic.
    5) Evaluate the effect of TRX4 on long-term safety (months 6-48) after the Core Study (3 months) is completed.
    6) Identify an appropriate prophylaxis regimen to minimize cytokine release-related symptoms.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Subjects able to give informed consent
    2) Men or women of any race, between 18 and 60 years old (inclusive), in good general health
    3) Confirmed diagnosis of Type 1 Diabetes Mellitus, insulin-requiring, on a relatively stable insulin regimen for one month prior to initiating TRX4 dosing, with good metabolic control (HbA1c less than 8.5 %)
    4) Less than 10 % weight loss due to Diabetes in the past six months
    5) Positive for at least one Type 1 Diabetes Mellitus autoantibody, i.e. anti-GAD (glutamic acid decarboxylase), IA-2, or insulin autoantibody
    6) Willingness to remain in the clinic for the inpatient portion of the study
    7) Prescription medications must be stable for at least four weeks before the first dose of study drug
    8) Female subjects must not be pregnant or lactating and either be surgically sterile, postmenopausal for at least one year, or using an acceptable method of contraception defined as oral, implanted, or transdermal contraceptive, plus one of the following barrier methods: diaphragm with spermicidal cream/jelly or use of a condom by sexual partner
    9) Screen body-mass-index of less than 34
    10) Negative PPD skin test at screen (may be reactive, but not positive)
    11) No clinically significant abnormal laboratory values within one week of the first TRX4-dose
    12) Negative Hepatitis-C antibody, Hepatitis-B surface antigen, Hepatitis-B core antibody
    13) Negative HIV antibody and no risk factors for HIV infection
    14) Seropositive for Epstein-Barr-Virus (EBV) with quantitative polymerase chain reaction of less than 10000 copies of EBV DNA / 1000000 lymphocytes
    15) CD4+ lymphocyte counts must be within normal limit within 35 days prior to the first dose of TRX4.
    16) Negative syphilis test.
    17) Negative qualtitative urine drug or alcohol test at screen.
    18) Other than T1DM, all organ systems must be free of significant disease and the subject cannot have undergone recent clinically significant surgery.
    20) The investigator must judge all pre-admission vital signs, physical examination, laboratory, or any safety variables to be within normal limits or clinically insignificant.
    21) Negative / below detectable limit serum rheumatoid factor (RF).
    E.4Principal exclusion criteria
    1) Subjects with a current or prior malignancy, other than non-melanoma skin cancer (subjects with more than 5 occurrences of non-melanoma skin cancer and the last occurrence within 3 months of study entry).
    2) Subjects that have received a vaccine within 30 days before TRX4 dosing, OR anticipate requiring a vaccine within 14 days after the last dose of TRX4.
    3) Subjects considering or have scheduled any surgeries during the Core Study.
    4) Subject with any significant mental or physical illness within a one year period prior to the first dose, including a history of alcohol and/or drug abuse.
    5) Subjects having donated plasma or blood within 30 days prior to the first dose of TRX4.
    6) Subjects having used any investigational drugs within three months prior to the first dose of TRX4 or within the core study period.
    7) Subjects with a history of anaphylactic reactions.
    8) Subjects having experienced a significant systemic infection within three months before the first dose of TRX4.
    9) Subjects who may, based on medical history, require treatment with systemic corticosteroids during the study.
    10) Subjects thought to have an allergy or sensitivity to TRX4 or excipients based upon known allergies to compounds of a similar class, or which, in the opinion of the principal investigator, suggests an increased potential for an adverse hypersensitivity to TRX4.
    11) Subjects having received any other anti-CD3 Mab at any time in the past (e.g., OKT3; ChAglyCD3; OKT3 ala-ala).
    12) Subjects having undergone splenectomy.
    E.5 End points
    E.5.1Primary end point(s)
    1) Pharmacokinetics:
    Blood samples will be collected prior to, during, and at specified times following dosing of study medication for determination of free TRX4 concentrations in serum. Using noncompartmental analyses, single dose parameters including Cinf, Cmax, tmax, AUC(0-z), AUC(0-∞), AUC(0-24h), CL, lambda-z, t1/2, and Vd will be calculated. In addition, pharmacokinetic linearity will be examined.

    2) Pharmacodynamics:
    Saturation and modulation of CD3 on the surface of circulating T cells, utilizing mean channel fluorescence as determined by flow cytometry, will be presented graphically by dose and time. Individual lymphocyte subset values will be presented graphically by dose and time based on two types of cell quantification, percent of baseline for each subset (as a percent) and percent of baseline for absolute cell count. Exploratory endpoints and other pharmacodynamic assessments will include: 1) C-reactive protein, 2) C-peptide levels, 3) exogenous insulin requirements, 4) HbA1c, 5) glycemic excursions, 6) hypoglycemic occurrences, and 7) tolerance induction mechanisms and/or markers. These data will be presented graphically by dose and time.

    3) Safety:
    Safety assessments will include: medical history; physical examination; monitoring for AE; concomitant medications; vital signs; 12-lead ECG; tests to measure orthostatic blood pressure; laboratory tests; cytokine levels; viral serology; viral load using quantitative polymerase chain reaction (qPCR); flow cytometric assessment of T cell and lymphocyte subsets (including B cell kappa/lambda ratio); serum and urine immunoelectrophoresis (IEP) and immunofixation (IF); and antiglobulin response to TRX4 (immunogenicity).
    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 No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    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
    Tolerability
    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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 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 No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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
    Last visit in month 12 of the long-term follow-up study component by last patient recruited for the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days4
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    E.8.9.2In all countries concerned by the trial days4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 Information not present in EudraCT
    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 30
    F.4.2.2In the whole clinical trial 30
    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 the last visit in month 12 post-dose, subjects will be asked to participate in an Extension Study under a separate protocol and ICF. They will be contacted yearly up to 48 months post dose and asked about their basic medical condition and specifically about the development of any immune deficiencies, opportunistic infections, new autoimmune disorders, or cancer.

    For full information refer to Protocol, section 5.2 (Study schematic)
    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 Decision2007-02-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-03-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2007-11-28
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