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    Summary
    EudraCT Number:2017-000639-15
    Sponsor's Protocol Code Number:TG1101-RMS302
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-04-13
    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 ConcernedCroatia - MIZ
    A.2EudraCT number2017-000639-15
    A.3Full title of the trial
    Phase III: UbLiTuximab In Multiple Sclerosis Treatment Effects (ULTIMATE II STUDY)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    UbLiTuximab In Multiple Sclerosis Treatment Effects
    A.3.2Name or abbreviated title of the trial where available
    ULTIMATE II STUDY
    A.4.1Sponsor's protocol code numberTG1101-RMS302
    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 SponsorTG Therapeutics
    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 supportTG Therapeutics
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPSI CRO Hungary LLC
    B.5.2Functional name of contact pointGyorgy Andor
    B.5.3 Address:
    B.5.3.1Street AddressSzabadsag ter 7
    B.5.3.2Town/ cityBudapest
    B.5.3.3Post code1054
    B.5.3.4CountryHungary
    B.5.4Telephone number+361 555 6755 6417
    B.5.5Fax number+361555 6570
    B.5.6E-mailgyorgy.andor@psi-cro.com
    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 nameUblituximab
    D.3.2Product code TG-1101
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNUBLITUXIMAB
    D.3.9.2Current sponsor codeTGTX 1101
    D.3.9.3Other descriptive nameLFB-R603
    D.3.9.4EV Substance CodeSUB182428
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    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 No
    D.IMP: 2
    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 nameTeriflunomide
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTERIFLUNOMIDE
    D.3.9.1CAS number 108605-62-5
    D.3.9.4EV Substance CodeSUB25218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number14
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) 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 injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Sclerosis
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10029202
    E.1.2Term Nervous system disorder
    E.1.2System Organ Class 10029205 - Nervous system 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 determine the Annualized Relapse Rate (ARR) in subjects with RMS
    after 96 weeks (approximately 2 years) treatment with IV infusion of
    ublituximab/oral placebo compared to 14 mg oral teriflunomide/IV
    placebo.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to examine the effects of ublituximab/oral
    placebo as compared to teriflunomide/IV placebo as follows:
    •On MRI parameters,
    •Confirmed Disability Progression (CDP),
    •No Evidence of Disease Activity (NEDA),
    •Symbol Digit Modality Test (SDMT),
    •To evaluate the safety of ublituximab/oral placebo, as determined by
    adverse events (AEs) and serious adverse event (SAEs), including MS
    worsening.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 18-55 age
    2. Diagnosis of RMS (McDonald criteria 2010)
    3. ≥ 2 relapses in prior 2 years or 1 relapse in the year prior to screening and/or ≥1 Gd enhancing lesion
    4. Documented MRI of brain with abnormalities consistent with MS
    5. Active disease
    6. EDSS 0-5.5 (inclusive) at screening
    7. B cell counts ≥5% of total lymphocytes
    8. Neurologic stability ≥ 30 days prior to screening and baseline
    9. Female subjects who are not of child-bearing potential, have documented surgical sterilization ,and female subjects of child-bearing potential who have a negative serum pregnancy test at baseline. Female subjects of child-bearing potential, and all male partners must consent to use a medically/clinically acceptable method of contraception throughout the treatment period and for 20 weeks after the cessation of active treatment. Female subjects of child-bearing potential must agree to undertake urine pregnancy tests every 4 weeks during active treatment and the follow up period.
    10. Fertile male subjects participating in the study who are sexually active with women of child bearing potential, must agree to use a condom during the treatment period and for an additional 20 weeks after cessation of active treatment. Agree to use an accelerated elimination procedure after the last dose of study medications or early termination from the study
    11. Willingness and ability to comply with trial and follow-up procedures, give written consent
    E.4Principal exclusion criteria
    1.Treatment with Anti-CD20 or other B cell directed treatment
    2.Treatment with the following therapies at any time prior to randomization:
    a.Alemtuzumab
    b.Natalizumab,
    c.Teriflunomide,
    d.Leflunomide
    e.Stem cell transplantation
    3.Contraindications to teriflunomide or incompatibility with it's use
    4.Therapies that are disallowed (min. of 4 weeks prior to randomization): phenytoin, warfarin, tolbutamide, St John’s Wort or cholestyramine
    5.Prior DMT exposure within months of screening:
    a.24 months with cladribine
    b.6 months with daclizumab, azathioprine, methotrexate, or cyclophosphamide
    c.90 days with fingolimod, or experimental S1P modulators,, IV immunoglobulin, and plasmapheresis
    d.30 days with glatiramer acetate, interferons, dimethyl fumarate, laquinimod or glucocorticoids
    6.Diagnosed with Primary Progressive MS (PPMS)
    7.Pregnant or nursing
    8.≥ 10 years disease duration from onset with subjects EDSS ≤ 2.0
    9.Contraindication for MRI and/or gadolinium
    10.Known presence of other neurologic disorders that may mimic MS
    11.Current evidence or known history of clinically significant infection including:
    a.Chronic or ongoing active viral, bacterial, or fungal infectious disease requiring long term systemic treatment such as, but not limited to: PML, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C
    b.Previous serious opportunistic or atypical infections
    c.History of positive serology for hepatitis B or hepatitis C or HIV
    12. History of clinically significant CNS trauma (e.g., traumatic brain injury, cerebral contusion, spinal cord compression)
    13.History of liver disease, including but not limited to:
    a.Known history of active hepatitis B or C any time prior to randomization or known history of active hepatitis A within 3 years prior to randomization
    b.Presence of clinically significant chronic liver or biliary disease
    c.Moderate or severe hepatic impairment defined as Child Pugh Score B or C, respectively, based on measurement of total bilirubin, serum albumin, International Normalized Ratio (INR) and as well as on presence /absence and severity of ascites and hepatic encephalopathy
    d.Any of the following abnormal laboratory values at screening or first infusion:
    •ALT/SGPT>2X the Upper Limit of Normal (ULN)
    •AST/SGOT>2X ULN
    14.Previous diagnosis with a congenital or acquired immunodeficiency (AIDS)
    15.History of renal impairment, including, but not limited to:
    a.Hypoproteinemia (e.g., in case of severe renal disease or nephrotic syndrome) with serum albumin <3.0 g/dL
    b.Severe renal insufficiency requiring renal dialysis
    16.Past or current history of medically significant adverse effects (including allergic reactions) from:
    a.Corticosteroids
    b.Diphenhydramine
    c.Murine or mouse/human chimeric antibodies
    17.Subjects with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia
    a.Hematocrit <24% and/or
    b.Absolute white blood cell count <4,000 cells/mm3 and/or
    c.Platelet count <150,000 cells/mm3 and/or
    d.Absolute neutrophil ≤ 1,500 cells/mm3
    18.Absolute lymphocyte counts less than 1000/microliter
    19.Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
    a.Symptomatic, or history of documented congestive heart failure (New York Heart Association functional classification III-IV [see Appendix B]
    b.QTcF: Female >450 msec; male > 430 msec Angina not well-controlled by medication
    c.Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting in the past 6 months prior to screening
    20.Other significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which could affect the subject’s safety, impair the subject’s reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol, as determined by the PI of the trial
    21.Current participation in any other interventional clinical trial. Participation in non-interventional trial requires approval by the Sponsor
    22.Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol
    23.Lack of immunity to varicella as determined by screening based on
    the level of VZV IgG. Subject may receive vaccine and be rescreened
    24.Vaccination with live virus within 2 months of randomization
    25.History or presence of malignancy (except for surgically excised basal or squamous cell skin lesions), lymphoproliferative disease, or history of total lymphoid irradiation or bone marrow transplantation
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is ARR defined as the number of IRAPconfirmed
    relapses per-subject year. The estimate of ARR for a
    treatment group will be the total number of relapses for subjects in the
    respective treatment group divided by the sum of treatment duration for
    subjects in that specific
    treatment group.
    E.5.1.1Timepoint(s) of evaluation of this end point
    96 weeks
    E.5.2Secondary end point(s)
    1. Total number of gadolinium enhancing (Gd-enhancing) T1-lesions per
    MRI scan by Week 96.
    2. Total number of new and enlarging T2 hyperintense lesions (NELs) per
    MRI scan by Week 96.
    3. Time to Confirmed Disability Progression (CDP) for at least 12 weeks
    occurring during the 96-week double-blind treatment period. *
    4. Proportion of subjects with No Evidence of Disease Activity (NEDA)
    from Week 24 to Week 96.
    5. Proportion of subjects reaching impaired SDMT (Symbol Digit
    Modalities Test) from baseline to Week 96.
    6. Percentage change in Brain Volume from baseline to Week 96
    * Confirmed Disability Progression for at least 12 weeks during the 96-
    week treatment period will be analyzed using pooled data
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 12, 24, 48, 72, 96
    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 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 Yes
    E.8.1.7.1Other trial design description
    double-dummy
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Belarus
    Croatia
    Georgia
    Romania
    Russian Federation
    Serbia
    Spain
    Ukraine
    United Kingdom
    United States
    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
    LVLS
    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 days0
    E.8.9.2In all countries concerned by the trial years3
    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 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: 440
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 440
    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)
    Treatment per Standard of Care and therapy for acelerated elimination of teriflunomide.
    In addition, at the end of the study, patients may be eligible to enroll in the open label study.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-11-12
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