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    Summary
    EudraCT Number:2017-001117-86
    Sponsor's Protocol Code Number:16/0340
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-05-18
    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 ConcernedUK - MHRA
    A.2EudraCT number2017-001117-86
    A.3Full title of the trial
    A phase IV, prospective, randomised single-blind UK multicentre non-inferiority trial of low-dose versus standard dose rituximab for prevention of relapses in acquired TTP
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Elective rituximab in TTP
    A.3.2Name or abbreviated title of the trial where available
    Elective rituximab in TTP
    A.4.1Sponsor's protocol code number16/0340
    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 College London
    B.1.3.4CountryUnited Kingdom
    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 supportAnswering TTP Foundation
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London Joint
    B.5.2Functional name of contact pointSponsor Regulatory Advisor
    B.5.3 Address:
    B.5.3.1Street AddressUCL, Gower Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1E 6BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02076796469
    B.5.5Fax number02031082312
    B.5.6E-maila.akinyemi@ucl.ac.uk
    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 Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMabthera
    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.3.9.4EV Substance CodeAS1
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acquired thrombotic thrombocytopenic purpura
    E.1.1.1Medical condition in easily understood language
    TTP
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    We know that a fall in ADAMTS13 activity in remission can be a sign of upcoming TTP relapse. We plan to see if low dose rituximab is as effective as the standard dose in preventing TTP relapse by looking at the length of time until patients need to be treated again with ritiuximab or other immunosuppression
    E.2.2Secondary objectives of the trial
    We will also look to see if low-dose rituximab is as effective as standard dose rituximab in:
    • the time it takes for ADAMTS13 activity to normalise after rituximab
    • how long ADAMTS13 stays normal after rituximab
    • subsequent relapse rates of patients with a clinical TTP episode
    • subsequent re-treatment rates of patients using rituximab or other immunosuppression

    and also whether there is a difference in side effects between the 2 doses, either related to the infusion itself or other rituximab-related adverse effects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, age>18
    2. Antibody-mediated TTP with at least one previous acute TTP episode
    3. ADAMTS13 activity dropping to ≤15% documented on 2 separate occasions on different days, , with platelets>150 and no evidence of microangiopathic haemolytic anaemia and LDH <1.5 x upper limit normal
    4. Females of childbearing potential and males agree to use an effective method of contraception from the time consent is signed for 12 months after treatment completion. Effective methods of contraception acceptable for this trial are oral, implanted or injected hormonal methods of contraception, IUD or IUS, and barrier methods of contraception
    5. Females of childbearing potential have a negative pregnancy test within 7 days prior to being randomised. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal
    6. Willing and able to provide written informed consent.
    7. Willing and able to comply with the trial protocol
    E.4Principal exclusion criteria
    1. Females who are pregnant, planning pregnancy or breastfeeding
    2. Concurrent and/or recent involvement in other research that is likely to interfere with the intervention within 3 months of study enrolment
    3. Known allergies to rituximab
    4. Patients currently undergoing plasma infusion/exchange
    5. Patients on therapy with other immunosuppressive medication (except steroids)
    6. Patients with a current acute severe infection or a history of recurring or chronic infections or underlying conditions which may further predispose patient to serious infection.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome will be time to re-treatment with rituximab/other immunosuppression measured in days from day of first rituximab infusion (D1)until D1 of any subsequent course of elective rituximab, or introduction of other immunosuppression initiated with the aim of preventing clinical relapse of TTP.

    This will be analysed as a time-to-event variable.
    E.5.2Secondary end point(s)
    Time to normalisation of ADAMTS13 activity–number of days from D1 of first rituximab infusion until ADAMTS13 activity returns to normal range; this is a time-to-event outcome.

    Duration of ADAMTS13 response – number of days from normalisation of ADAMTS13 activity to ADAMTS13 activity dropping outside of remains in normal range; this is a time-to-event outcome.

    Subsequent relapse rate with clinical TTP episode (%) – the proportion of patients who experience a clinical relapse of TTP during trial follow-up compared to patients who do not; this is a binary outcome.

    Subsequent re-treatment rate with rituximab/other immunosuppression (%) – the proportion of patients who are retreated with rituximab or other immunosuppression, for the prevention of clinical relapse of TTP, during trial follow-up compared to patients who are not; this is a binary outcome.

    Time to B cell depletion – number of days from D1 to CD19 count <0.005x109/L0.5% ; this is a time-to-event outcome .

    Time to B cell return – number of days from D1 to CD19 count returning to normal range; this is a time-to-event outcome.

    Infusion-related adverse effects

    Delayed rituximab-related adverse effects eg serum sickness, abnormal LFTs, cytopenias, infections- not occurring during rituximab infusion
    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 Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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) 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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Low dose rituximab
    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 concerned8
    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 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 end of trial is will be a database lock 2 months after the date of the last visit of the last participant to allow time to enter data, clean/check data.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years5
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 55
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    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 state52
    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)
    The standard of care will continue to be available, including routine clinic visits, blood tests and further rituximab treatment if needed
    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 Decision2017-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-19
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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