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    Summary
    EudraCT Number:2012-000145-12
    Sponsor's Protocol Code Number:5997
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-07-04
    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 number2012-000145-12
    A.3Full title of the trial
    Rituximab for the Treatment of Fatigue in Primary Biliary Cirrhosis (PBC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pilot study of Rituximab for the treatment of fatigue in PBC
    A.3.2Name or abbreviated title of the trial where available
    RITPBC Study
    A.4.1Sponsor's protocol code number5997
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN03978701
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02376335
    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 SponsorThe Newcastle 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 supportThe MRC and NIHR - Efficacy and Mechanism Evaluation Programme
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportDepartment of Health - Subvention Grand
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNewcastle Clincial Trials Unit, Newcastle University
    B.5.2Functional name of contact pointDr Alison Steel
    B.5.3 Address:
    B.5.3.1Street AddressNewcastle University, 1-4 Claremont Terrace
    B.5.3.2Town/ cityNewcastle upon Tyne
    B.5.3.3Post codeNE2 4AE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01912087249
    B.5.6E-mailalison.steel@newcastle.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.3.8INN - Proposed INNRituximab
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameN/A
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    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
    Severe fatigue in Primary Biliary Cirrhosis
    E.1.1.1Medical condition in easily understood language
    Severe fatigue in Primary Biliary Cirrhosis
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10004661
    E.1.2Term Biliary cirrhosis primary
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Does Rituximab therapy significantly improve the fatigue experienced by patients with PBC?
    2. Does any improvement in fatigue result from a reduction in the PDH-directed antibody response in PBC and the effects that these antibodies have on muscle cell energy generation?
    3. What is the safety profile of Rituximab therapy in patients with PBC?
    4. How sustained is any effect of Rituximab on fatigue?
    E.2.2Secondary objectives of the trial
    1. To undertake a proof of efficacy clinical intervention study of B-cell depleting therapy in PBC patients with anti-PDH antibody (>95% of patients) who experience significant fatigue. The primary endpoint is reduction of fatigue severity assessed using a disease specific quality of life measure.
    2. To explore the extent to which any such improvement in fatigue is related to reduction in the level of anti-PDH antibody in PBC patients and any associated effect on biomarkers of bioenergetic function assessed using unique MRS protocols developed by the CI and co-investigators.
    3. To further explore the safety of Rituximab in PBC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age 18 years or over
    • Patient has capacity and provided written informed consent for participation in the study prior to any study specific procedures
    • Moderate or severe fatigue as assessed using previously designated cut-offs of the PBC-40 fatigue domain (i.e. fatigue domain score >33)
    • Presence of AMA (anti-PDH antibody) at a titre of >1:40
    • Adequate haematological function Hb >9g/L, absolute neutrophil count >1.5x109/L, platelet count > 50x109/L
    • Bilirubin ≤ 50 μmol
    • INR ≤ 1.5
    • Child-Pugh score < 7
    • ECOG performance status < 2
    • Adequate renal function Cockroft and Gault estimation > 40ml/min
    • Women of childbearing potential should have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued for 12 months after completion of treatment
    E.4Principal exclusion criteria
    • Advanced or decompensated disease (variceal bleed, hepatic encephalopathy or ascites)
    • History or presence of other concomitant liver diseases (including hepatitis due to hepatitis B (surface antigen positive or core antibody positive) or C or evidence of chronic viraemia on baseline screening), primary sclerosing cholangitis or biopsy proven non-alcoholic steatohepatitis)
    • Average alcohol ingestion >21 units/week (male) or >14 units / week (female)
    • Chronic sepsis or intercurrent condition likely to predispose to chronic sepsis during the study
    • Previous treatment with B-cell depleting therapy
    • Previous history of aberrant response or intolerance to immunological agents
    • Presence of significant untreated intercurrent medical condition itself associated with fatigue
    • Presence of significant risk of depressive illness (HADS score indicating caseness)
    • Current statin therapy or statin use within 3 months of enrolment
    • Ongoing participation in other clinical trials or exposure to any investigational agent 4 weeks prior to baseline or within <5 half lives of the investigational drug
    • Major surgery within 4 weeks of trial entry
    • Vaccination within 4 weeks of trial entry, patients requiring seasonal flu or travel vaccines will be required to wait a minimum of 4 weeks post vaccination to enroll in the trial
    • Pregnant or lactating women
    • Psychiatric or other disorder likely to impact on informed consent
    • Patient is unable and/or unwilling to comply with treatment and study instructions
    • Any other medical condition that, in the opinion of the investigator would interfere with safe completion of the trial
    • Hypersensitivity to the active substance (Rituximab) or to any of the excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water (for infusion)) or to murine proteins
    • Active, severe infections (e.g. tuberculosis, sepsis or opportunistic infections)
    • Known HIV infection
    • Clinical history of Latent TB infection unless the patient has completed adequate antibiotic prophylaxis
    • AST/ALT 4 x Upper Limit of Normal
    • Severe immune-compromised state
    • Severe heart failure (NYHA Class IV) or severe uncontrolled cardiac disease
    • Malignancy (other than basal cell carcinoma) within the last 10 years
    • Demyelinating disease
    • Previous participation in this trial
    • Any contraindication to Rituximab therapy not covered by other exclusions
    E.5 End points
    E.5.1Primary end point(s)
    Change in PBC-40 fatigue domain score between baseline and 12 week assessment in patients with severe fatigue (PBC-40 fatigue domain score >33 at study outset: a value validated against a control population in a now validated normal population version of the PBC-40. Change in the other domains of the PBC-40 will be assessed on the same basis as secondary outcome measures.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is severity of fatigue as assessed using PBC-40, a disease-specific quality of life measure and will be evaluated at baseline, 12 weeks, and three monthly thereafter up to 12 months.
    E.5.2Secondary end point(s)
    The breadth of the clinical effect of Rituximab in PBC, exploring impact on other symptoms, functional status and mood, as well as the nature and severity of underlying liver injury.

    The mechanism of action of Rituximab in terms of its effects on anti-PDH antibody of all isotypes and the B-cells producing it and the associated impact on muscle bioenergetic and cardiorespiratory function.

    The acceptability of Rituxmab therapy for patients in terms of tolerability and safety.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation of the secondary endpoints will be at baseline and 12 weeks.
    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 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 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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    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 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 months11
    E.8.9.2In all countries concerned by the trial days30
    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: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 29
    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 state58
    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)
    This is a trial to explore the efficacy and mechanisms of fatigue. If we confirm efficacy, funding will be sought for a randomised multicentre study of effectiveness.
    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 Decision2012-08-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-09-12
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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