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    The EU Clinical Trials Register currently displays   38573   clinical trials with a EudraCT protocol, of which   6335   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2013-003211-22
    Sponsor's Protocol Code Number:CLL12
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-02-04
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2013-003211-22
    A.3Full title of the trial
    A Placebo-Controlled, Double-Blind, Randomized, Multicenter, Three Arm Phase III Trial to Compare the Efficacy and Safety of Ibrutinib vs. Placebo in Previously Untreated Binet Stage A CLL Patients with Risk of Early Disease Progression
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to compare the effect of Ibrutinib or placebo on prolongation of event free survival in patients with early stage Binet A CLL with a high risk for disease progression defined by various clincial and laboratory risk factors.
    A.4.1Sponsor's protocol code numberCLL12
    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 Cologne
    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 supportJanssen Cilag
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital of Cologne
    B.5.2Functional name of contact pointGerman CLL Study Group
    B.5.3 Address:
    B.5.3.1Street AddressGleueler Strasse 176-178
    B.5.3.2Town/ cityCologne
    B.5.3.3Post code50935
    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. name Imbruvica
    D. of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical 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.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB88115
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboCapsule, hard
    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
    Patients with Chronic Lymphocytic Leukemia Binet A stage.
    E.1.1.1Medical condition in easily understood language
    Confirmed previously untreated, asymptomatic stage Binet A chronic lymphocytic leukemia (CLL) according to the updated iwCLL guidelines
    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
    The primary objective of the study is to demonstrate superiority of ibrutinib over placebo in prolonging EFS for subjects with treatment-naïve CLL stage A and intermediate or (very) high risk of disease progression. All subjects with intermediate, (very) high risk randomized to the experimental treatment arm will be treated up to active progressive disease with treatment indication according to iwCLL-Guidelines with the objective to demonstrate prolongation of EFS for the ibrutinib arm. EFS is defined as the time between randomization until active progressive disease with treatment indication according to the iwCLL-Guidelines with subsequent treatment for CLL or death.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    • To demonstrate superiority of ibrutinib over placebo in prolonging overall survival (OS) for subjects with treatment-naïve CLL stage A and intermediate or (very) high risk of disease Progression
    • To evaluate the safety of ibrutinib versus placebo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Confirmed diagnosis of previously untreated CLL according to the updated iwCLL guidelines
    • Stage Binet A without need for treatment
    • Age ≥ 18 years
    • Life expectancy ≥ 6 months
    • ECOG performance status 0 – 2
    • Absolute neutrophil count (ANC ≥ 1 x 109 / L)
    • Signed written informed consent of patient and treating physician

    Females of childbearing potential (FCBP)† in the experimental treatment arm (placebo / ibrutinib) must:
    • Have one negative medically supervised pregnancy test prior to starting the study therapy.
    • Either commit to continued abstinence from heterosexual intercourse or agree to use, and be able to comply with, two reliable forms of effective contraception simultaneously to achieve a PEARL-Index <1 without interruption (Highly effective methods: Intrauterine device (IUD), Hormonal (birth control pills, injections, implants), Tubal ligation, Partner’s vasectomy, Additional effective methods: Male condom, Diaphragm, Cervical Cap), 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 30 days after discontinuation of study therapy

    Male subjects in the experimental treatment arm (placebo / ibrutinib) must:
    • Agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy.
    • Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
    • For males these restrictions apply for 3 months after the last dose of study medication.

    All subjects in the experimental treatment arm (placebo / ibrutinib) must:
    • Have an understanding that the study drug could have a potential teratogenic risk.
    • Agree not to share study medication with another person.
    • Be counseled about pregnancy precautions and risks of fetal exposure.
    • Willingness to inform the general practicioner
    E.4Principal exclusion criteria
    • Any prior CLL specific therapy
    • Recent therapeutic interventions including:
    - All other chemotherapy, radiation therapy within 3 weeks prior to randomization
    - Any surgery within 4 weeks prior to randomization
    • Prior treatment with Ibrutinib or BTK inhibitors
    • Chronic use of steroids in excess of prednisone 20mg/day or its equivalent
    • Active infections requiring systemic antibiotics
    • An life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion could compromise the subject’s safety, interfere with the absorption or metabolism of Ibrutinib capsules, or put the study outcomes at undue risk
    • Pregnant or lactating females
    • Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of leukemic meningitis must have a lumbar puncture procedure performed within two weeks prior to randomization
    • Known second malignancy that limits survival to less than two years
    • Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) and/or active Hepatitis C Virus (HCV) infection.
    • Any of the following laboratory abnormalities:
    a. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 2.5 x upper limit of normal (ULN)
    b. Serum total bilirubin > 1.5 ULN (with the exception of Gilbert’s Syndrome)
    c. Creatinine clearance < 30ml/min
    • Requires anticoagulant with warfarin or phenoprocoumon
    • Requires anticoagulant with oral direct Xa inhibitors (rivaroxaban, apixaban, edoxaban)
    • History of stroke or intracranial hemorrhage within 6 months prior to randomization
    • Requires treatment with strong CYP3A4/5 inhibitors (see section 8.6.3)
    • Participation in any clinical study for CLL or having taken any investigational therapy which would interfere with the study drug for a disease other than CLL within 28 days prior to initiating treatment.
    • Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator
    • Patients with uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia
    E.5 End points
    E.5.1Primary end point(s)
    Primary study endpoint:
    • EFS based on an internal medical review according to iwCLL guidelines
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint analysis for EFS will be conducted as soon as 71 EFS events have been documented for patients from the study arms II and III. Based on the current recruitment and observed event pattern this time point will likely be reached at the end of recruitment or closely thereafter (month 52 after FPI or later). Nonetheless, recruitment must be finished at the time of analysis. If the event number will be reached before, the analysis will be shifted to the end of recruitment.
    E.5.2Secondary end point(s)
    Secondary endpoints for treatment arms:
    - OS defined by the time between randomization and death due to any cause
    - Progression-free survival (PFS)
    - Treatment-free survival (TFS)
    - Type, response and duration of response to subsequent treatment for CLL
    - Safety (excluding second primary malignancies)
    - Assessment of medication-taking behavior (compliance to study mediacation)

    Secondary endpoints for all study arms
    - Overall survival (OS)
    - Other toxicities
    - Health quality and health outcome
    - exploratory endpoints

    Secondary endpoints for study arm I (watch&wait cohort)
    - OS defined by the time between completed registration and death due to any cause
    - Event-free survival
    - Time to first CLL treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoint OS will be analyzed two years after the end of recruitment (approximately month 76) for the first time within one formal interim analysis for assessing both efficacy and futility (including non-binding boundaries).
    The final OS analysis will be conducted either as soon as 46 OS events have been observed or at the end of the study (90 months after randomization of the first subject).
    At this time-point, other secondary endpoints will be fully analyzed based on all patients from study arms I, II and III.
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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. 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 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 trial3
    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 concerned86
    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
    Recruitment duration is approximately 52 months. After the recruitment period a clinical phase including follow-up until month 90 continues. 90 month after randomization of the first patient treatment will be stopped for all patients. End of the trial is 28 days after end of treatment of the last patient. The total study duration will be approximately 90 months.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days
    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: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 324
    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 state540
    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)
    Since Ibrutinib is a non-registered medical product at this timepoint it is not clear wether Ibrutinib will be available for Binet A CLL at termination of the trial.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-03-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-31
    P. End of Trial
    P.End of Trial StatusOngoing
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