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    Summary
    EudraCT Number:2012-003608-11
    Sponsor's Protocol Code Number:RG_12-125
    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:2013-12-04
    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 number2012-003608-11
    A.3Full title of the trial
    IciCLLe: Assessment of the Mechanism of Action of Ibrutinib (PCI-32765) in B-cell Receptor Pathway Inhibition in CLL.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Assessing how the drug ibrutinib works in Chronic Lymphocytic Leukaeamia.
    A.3.2Name or abbreviated title of the trial where available
    IciCLLe -Assessment of the Mechanism of Action of Ibrutinib
    A.4.1Sponsor's protocol code numberRG_12-125
    A.5.4Other Identifiers
    Name:CAS number Number:HM2048
    Name:LLR refNumber:12028
    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 of Birmingham
    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 supportLLR
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportPharmacyclics
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Birmingham
    B.5.2Functional name of contact pointKathryn Paterson
    B.5.3 Address:
    B.5.3.1Street AddressCRCTU, School of Cancer Sciences
    B.5.3.2Town/ cityUniversity of Birmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214158782
    B.5.5Fax number01214146061
    B.5.6E-mailIciclle@trials.bham.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 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 nameIbrutinib
    D.3.2Product code PCI-32765
    D.3.4Pharmaceutical form Capsule, hard
    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 INNIbrutinib
    D.3.9.1CAS number 936563-96-1
    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 number140
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Lymphocytic leukaemia
    E.1.1.1Medical condition in easily understood language
    A form of leukaemia in which there are an excess of mature but poorly functioning lymphocyte cells in the blood.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10009310
    E.1.2Term CLL
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this clinical study is to investigate how the drug, called ibrutinib (previously PCI32765), affects the rate of growth, and the lifespan, of leukaemia cells in patients with Chronic Lymphocytic Leukaemia (CLL). The purpose of the trial is to gain a better understanding of how the drug works in order to use it in logical combinations with other drugs that treat CLL which will be tested in future clinical studies. We hope to achieve this by taking frequent blood samples from patient being treated with the drug and analysing them using methods called flow-cytometery and histology.
    E.2.2Secondary objectives of the trial
    The amount of patients should a Complete Remission (CR) Complete Remission with incomplete marrow recovery (Cri) or Partial Remission (PR), to ibrutinib at 6 months, assessed according to the IWCLL Response Criteria
    The changes in CLL cell protein expression levels.
    At 6 and 12 months we will also be looking at where and how the drug is acting within the body by measuring the biological response in both the circulating CLL cells blood and in the CLL cells in the bone marrow. We will also study the CLL cells that are responsible for increasing the number of cancer cells.
    To determine the amount of patients for who their disease has not worsened at 1 and 2 years.
    To determine the amount of patients alive 1 and 5 years after the start of treatment.
    To assess the toxicity of the drug over 6 months of treatment.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Kinetic Substudy
    To assess the tumour proliferation rate by measuring the in-vivo incorporation of denueterated glucose in the CLL cells.
    UK CLL biobank
    Blood, and salivia collected as part of the ethically approved UK CLL biobank project. A separate consent form will be used for consent to this study.
    E.3Principal inclusion criteria
    Cohort A (Treatment naive)
    • Progressive Stage A, Stage B or Stage C CLL
    • CLL requiring therapy by the IWCLL criteria
    • ECOG performance status (PS) of 0, 1, or 2
    • Life expectancy of at least 6 months
    • Age ≥16
    • Age <65 years or ≥65 years with deletion 17p
    • Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations)
    • Able to give informed consent

    Cohort B (Relapsed/Refractory)
    • CLL requiring therapy
    • Refractory CLL defined as any of the following:
    • Failure to achieve a response (CR or PR by IWCLL Criteria) to a purine analogue alone or in combination with chemotherapy, or:
    • Relapse within 6 months of responding to a purine analogue alone or in combination with chemotherapy, or:
    • Relapse within 24 months of responding to a fludarabine, cyclophosphamide and rituximab (FCR), or:
    • Patients with CLL with deletion of chromosome 17p who have failed at least one previous therapy.
    • ECOG performance status (PS) of 0, 1, or 2 (see appendix 6)
    • Life expectancy of at least 6 months
    • Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations)
    • Age ≥ 16
    • Able to give informed consent
    E.4Principal exclusion criteria
    Both cohorts A and B
    • Unwilling to undergo the protocol assessments including the bone marrow assessments
    • Active infection
    • Other severe, concurrent (particularly cardiac or pulmonary) diseases or mental disorders that could interfere with their ability to participate in the study
    • Use of prior investigational agents within 6 weeks
    • Pregnancy or lactation
    • Unwilling to use appropriate contraception during and for 12 months following treatment
    • CNS involvement with CLL
    • Mantle cell lymphoma
    • Known HIV positive
    • Active or prior Hepatitis B or C
    • Active secondary malignancy excluding basal cell carcinoma
    • Persisting severe panocytopenia (nNeutrophils <0.5 x109/L) or transfusion dependent anaemia unless due to direct marrow infiltration by CLL (to be confirmed via bone marrow biopsy)
    • Active haemolysis (not controlled with Prednisolone at 10 mg or less)
    • Patients requiring or who have received anticoagulation treatment with warfarin or vitamin K antagonists within 1 week of the first dose of ibrutinib
    • Patients requiring concomitant use of strong CYP3A4/5 inhibitors
    • Patients with evidence or history of transformation and/or PLL
    Cohort A (Treatment naive)
    • Previous treatment for CLL. This does not include steroids.

    Cohort B (Relapsed/Refractory)
    • Previous treatment with ibrutinib or an alternative inhibitor of B-Cell receptor pathway
    E.5 End points
    E.5.1Primary end point(s)
    • Assessment of the proliferating cells in the peripheral blood and bone marrow by flow cytometry and histology
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, day 1, day 2, week 1, Week 2, 1 month, 2 month, 6 month, 9 months and 12 months.
    E.5.2Secondary end point(s)
    • Disease response, whether complete, CRi or partial, to ibrutinib at 6 months, according to the 2008 IWCLL Criteria
    • Changes in CLL cell levels and proliferating compartment
    • Biological response (complete, partial or nodal) at 6 and 12 months, according to the modified IWCLL Criteria.
    • 1 and 2 year progression free survival for relapsed/refractory and treatment naïve patients
    • 1 and 5 year overall survival for relapsed/refractory and treatment naïve patients
    • Toxicity of ibrutinib within 6 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Disease response IWCLL, at 6 months
    • Changes in CLL cell levels and proliferating compartment at 6 and 12 months
    • Biological response, modified IWCLL Criteria, at 6 and 12 months
    • Progression free survival at 1 and 2 years
    • Overall survival at 1 and 5 years
    • Toxicity of ibrutinib within 6 months
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) 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 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 concerned10
    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 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
    For the purposes of the MHRA the end of trial will be 6 months after the last patient has completed protocol defined interventional treatment. For the purposes of main REC approval, the trial end date is deemed to be 6 months after last data capture following either death of all of the trial patients or 5 years of follow up from day 1 of trial treatment, whichever occurs latest. The trial office will notify the MHRA and REC when the trial has ended and provide a summary report within 12 months.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months5
    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 Yes
    F.1.1Number of subjects for this age range: 1
    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: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    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)
    All patients will remain on study for at least 12 months and will remain on treatment, at the cost of the collaborating Pharmaceutical company, until disease progression. After 12 months of treatment patients will be given the option to leave the trial to move on to either an industry expanded access or registration protocol or an academic extension study. Follow-up information will still be collected for all trial outcomes.
    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 Decision2013-11-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-02-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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