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    Summary
    EudraCT Number:2016-000209-35
    Sponsor's Protocol Code Number:7805
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-04-18
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-000209-35
    A.3Full title of the trial
    Adjuvant rituximab – a potential treatment for the young patient with Graves’
    hyperthyroidism
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Will a single dose of Rituximab treatment, when taken with anti thyroid drugs for 1 year, stop the over-activity of the thyroid gland from returning once you stop ATD treatment?
    A.3.2Name or abbreviated title of the trial where available
    Rituximab in Graves' Disease (RIGD)
    A.4.1Sponsor's protocol code number7805
    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 SponsorNewcastle upon Tyne Hospitals NHS Foundation Trust
    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 supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle University Clinical Trial Unit
    B.5.2Functional name of contact pointAnn Marie Hynes
    B.5.3 Address:
    B.5.3.1Street Address1-4 Claremont Terrace
    B.5.3.2Town/ cityNewcastle-upon-Tyne
    B.5.3.3Post codeNE2 4AE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01912082519
    B.5.6E-mailann.hynes@ncl.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 Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products ltd
    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 Infusion
    D.3.2Product code Rituximab
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    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) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Graves' hyperthyroidism
    E.1.1.1Medical condition in easily understood language
    An overactive thyroid gland that produces too much thyroid hormone
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    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
    The principal question is to establish whether a single 500mg dose of RTX, when administered together with a short 12 month course of 'conventional' anti-thyroid drug (ATD), is likely to result in a meaningful improvement in the proportion of young people with Graves' hyperthyroidism entering disease remission.
    E.2.2Secondary objectives of the trial
    • To examine whether there is a relationship between thyrotropin receptor antibody (TRAb) titre in recruited subjects and thyroid hormone status (TSH, FT4 and FT3) at the beginning and end of the trial. This will help to establish whether there is a biologically compelling relationship between disease severity, as assessed by autoantibody status, and biochemical outcome following the proposed treatment regimen.

    • To examine whether the immune cellular response is related to disease outcome by examining the relationship between time to recovery of immune cell numbers (CD 19+ cells) to within the local normal reference range and thyroid hormone status at the end of the trial.

    • To examine whether the total dose of ATD is related to disease outcome by examining the nature of the relationship between the cumulative dose of ATD (mg/kg) in relation to thyroid hormone status at the end of the trail.

    • To examine the time taken for TSH concentrations to normalise post Rituximab and to
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Excess thyroid hormone concentrations at diagnosis: elevated free tri-iodothyronine (FT3) and / or free thyroxine (based on local assay).
    • Suppressed (un-recordable) TSH (based on local assay).
    • Patients between the ages of 12-20 years inclusive that are less than 6 weeks from first diagnosis of Graves’ hyperthyroidism
    • Elevated thyroid binding inhibitory immunoglobulin or thyroid receptor antibodies (TRAb including TBII) based on local assay. Patients may or may not have a raised TPO antibody titre.
    • Willingness to travel to the regional centres in Birmingham, Doncaster, Edinburgh, Leeds, Newcastle-upon-Tyne or Sheffield.
    • If females are of childbearing potential, must have a negative serum pregnancy test at screening.
    • Willingness to use 2 forms of contraception for 12 months post-treatment with rituximab (all females of childbearing potential).
    • Able and willing to adhere to a 2 year study period.
    E.4Principal exclusion criteria
    • Previous episodes of autoimmune thyroid disease
    • Other concurrent immunomodulatory treatment apart from inhaled steroids for asthma (such as beclomethasone) or topical steroids for skin disorders such as eczema.
    • Pregnancy, planned pregnancy during the study period or current breast-feeding
    • Absence of informed consent from parent/legal guardian for participants age <16 years.
    • Participants with previous use of immunosuppressive or cytotoxic drugs (including rituximab and methylprednisolone but excluding inhaled glucocorticoid and oral glucocorticoid for asthma or topical glucocorticoid for eczema).
    • Participants with active viral illness including HIV, Hepatitis B or C, shingles/Zoster.
    • Participants with significant chronic cardiac, respiratory or renal disorder or non-autoimmune liver disease.
    • Participants with known allergy or contraindication to rituximab or methylprednisolone.
    • Participants with evidence of Hepatitis B/C infection, assessed by determining hepatitis ‘B’ surface antigen (HBsAg) status, hepatitis ‘B’ Core antibody (HB Core antibody) status and hepatitis ‘C’ virus antibody (HCV antibody) status.
    • Participants in families who know they will be moving out of the catchment areas during the 2 years following RTX treatment.
    • Participants currently involved in any other clinical trial of an IMP or who have taken an IMP within 30 days prior to trial entry.
    E.5 End points
    E.5.1Primary end point(s)
    The number of patients in remission at 24 months will be compared to the critical number. Formal justification to proceed to a larger randomised trial is based upon observing a minimum number achieving remission, referred to as the critical number (35). The critical number depends upon the desired and unacceptable remission rates, set at 40% and 20%, respectively, and the error levels set at 10% alpha (type I) and 20% beta (type II). The remission rate corresponding to the critical number will lie between 40% and 20% and will be specified in the Statistical Analysis Plan. If the true remission rate is 40% there is an 80% chance (power) of proceeding to a further trial; if the true remission rate is 20%, there is a small 10% (alpha) chance of proceeding to a further trial. With these parameters the target recruitment is 27 patients who will receive rituximab. This is the smallest number of patients which satisfies the design criteria, assuming a 10% loss to follow-up.

    This is equivalent to a formal comparison of the hypotheses that the remission rate is greater than or equal to 40% as opposed to less than or equal to 20%. The primary outcome measure, remission rate, will be presented with a one sided 90% lower bound.
    E.5.1.1Timepoint(s) of evaluation of this end point
    2 years after treatment with Rituximab
    E.5.2Secondary end point(s)
    1). The distribution of TRAb titres will be compared between patients in and out of remission by graphical summary, numerical summary statistics (median and interquartile range) and a Mann-Whitney test.

    2). Time to recovery of B cell lymphocyte numbers (CD 19+ cells) to the normal range in relation to thyroid hormone status. This will be compared between patients in and out of remission by graphical summary, numerical summary statistics (median and interquartile range) and a Mann-Whitney test.

    3). Cumulative dose of ATD (Carbimazole) in mg/kg in relation to thyroid hormone status. This will be compared between patients in and out of remission by graphical summary, numerical summary statistics (median and interquartile range) and a Mann-Whitney test.

    4). We will assess the time taken for TSH concentrations to normalise (increase above 0.1mU/l) post Rituximab and describe biochemical thyroid status, as assessed by TSH, FT4 and FT3 concentration, in the period between cessation of ATD therapy and the end of the trial in each patient. Specifically we will plot the time taken for TSH to normalise in individual patients and determine the proportion of time that TSH, FT4 and FT3 concentrations are within the normal reference range in the period between ATD stopping (end of year 1) and trial end (end of year 2).

    5). The frequency and nature of adverse events.
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 years after treatment with Rituximab
    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 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 No
    E.7.1.3.1Other trial type description
    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 No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    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 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
    Last visit of the last patient which will be up to 1st March 2020
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 12
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    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.1.3.1Number of subjects for this age range: 0
    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 state27
    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)
    Not applicable - rituximab is being administered once and once only.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation North East and North Cumbria Clinical Research Network
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-08-27
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