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    Summary
    EudraCT Number:2019-003854-99
    Sponsor's Protocol Code Number:CLL17
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-22
    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 ConcernedIreland - HPRA
    A.2EudraCT number2019-003854-99
    A.3Full title of the trial
    A phase 3 multicentre, randomized, prospective, open-label trial of Ibrutinib monotherapy versus fixed-duration Venetoclax plus Obinutuzumab versus fixed-duration Venetoclax plus Ibrutinib in patients with previously untreated chronic lymphocytic leukaemia (CLL)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Untreated patients with blood cancer (chronic lymphocytic leukemia) are randomized into three treatment arms. In one treatment arm an inhibitor is continuously taken. The other treatment arms are fixed in time, combining an inhibitor with another inhibitor or a monoclonal antibody.
    A.4.1Sponsor's protocol code numberCLL17
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04608318
    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.1.3.4CountryGermany
    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 supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportJanssen Pharmaceutica NV
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportAbbVie Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGerman CLL Study Group
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressGleueler Str. 176-178
    B.5.3.2Town/ cityCologne
    B.5.3.3Post code50935
    B.5.3.4CountryGermany
    B.5.4Telephone number004902214788820
    B.5.5Fax number0049022147886886
    B.5.6E-mailcll-17@uk-koeln.de
    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 Gazyvaro®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche/Genentech
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameObinutuzumab / GA101
    D.3.2Product code RO5072759
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNOBINUTUZUMAB
    D.3.9.1CAS number 949142-50-1
    D.3.9.3Other descriptive nameOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 No
    D.IMP: 2
    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 nameABT-199 (GDC-0199), Venetoclax
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.3Other descriptive nameABT-199
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    D.IMP: 3
    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 nameABT-199 (GDC-0199), Venetoclax
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.3Other descriptive nameABT-199
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 No
    D.IMP: 4
    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 nameABT-199 (GDC-0199), Venetoclax
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.3Other descriptive nameABT-199
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 No
    D.IMP: 5
    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 Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.9.1CAS number 936563-96-1
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with previously untreated CLL requiring treatment
    E.1.1.1Medical condition in easily understood language
    Patients with previously untreated chronic lymphocytic leukaemia (blood cancer) in need of treatment
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10008958
    E.1.2Term Chronic lymphocytic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL.
    E.2.2Secondary objectives of the trial
    Secondary objectives are efficacy parameters, including rates of
    undetectable MRD negativity (for VG vs VI). Comparison of MRD levels
    measured in PB by flow cytometry at different time points for all three
    treatment arms will be performed. Additionally, BM MRD at final
    restaging and 12 months after final restaging in comparison between all
    three treatment arms will be done.
    Moreover, comparisons of overall survival will be made between all three
    treatment arms. Other secondary endpoints are overall response rate
    and complete response ratewith regard to best response achieved,
    duration of response as well as event-free survival, time to next CLL
    treatment, duration of uMRD, and PFS after second-line treatment. The
    incidence of safety parameters is another important endpoint with
    regards to type, frequency, and severity of adverse events and adverse
    events of special and particular interest and their relationship to study
    treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Documented CLL/ SLL requiring treatment according to iwCLL criteria.
    2. Age at least 18 years.
    3. Life expectancy ≥ 6 months.
    4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
    5. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as fol-lows, unless cytopenia is due to CLL:
    a. Absolute neutrophil count ≥ 1.0 × 109/L
    b. Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L
    c. Total haemoglobin ≥ 8 g/dL (without transfusion support, unless anaemia is due to CLL)
    6. GFR >30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.
    a. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated pa-tients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hy-dration is > 30 ml/min.
    7. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
    8. Negative serological testing for hepatitis B (HbsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), and for hepatitis C (anti-HCV-ab
    negative; in case of positive HCV anti-body test, negative HCV-PCR is required).

    9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
    E.4Principal exclusion criteria
    1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
    2. Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.
    3. Patients with a history of PML.
    4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients’ safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract).
    5. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treat-ing physician or showing signs of progression after curative treatment.
    6. Uncontrolled or active infection.
    7. Patients with known infection with human immunodeficiency virus (HIV).
    8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start).
    9. Anticoagulant therapy with warfarin or phenprocoumon,
    (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
    10. History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.
    11. Known bleeding disorders
    12. Child B / C liver cirrhosis
    13. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
    14. Vaccination with live vaccines 28 days prior to registration for study screening.
    15. Major surgery less than 30 days before start of study treatment.
    16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
    17. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
    18. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
    19. Fertile men or women of childbearing potential unless:
    a. surgically sterile or ≥ 2 years after the onset of menopause
    b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
    20. Legal incapacity.
    21. Prisoners or subjects who are institutionalized by regulatory or court order.
    22. Persons who are in dependence to the sponsor or an investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Investigator-assessed PFS, defined as the time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines), or death from any cause, whichever occurs first.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The first analysis will be the interim PFS analysis and will take place after 65% of the total 213 events have been observed, i.e. 138 PFS events and a follow-up of at least 24 months after last patient enrolled will trigger the interim analysis.
    The final PFS analysis will be conducted as soon as 213 events have occurred. This will trigger the time point of the analysis of secondary endpoints. With an accrual duration of 36 months, the interim and final PFS analysis will be reached 60 months and 80 months after the first patient has been randomized respectively. Safety analyses are independent from primary and secondary efficacy analyses.
    E.5.2Secondary end point(s)
    • Rates of undetectable MRD (uMRD, i.e. <10-4) in peripheral blood (PB) and bone marrow (BM) at final restaging (RE), which will be at cycle 18 after start of treatment, and additional BM assessment approx. 12 months after RE
    • MRD levels in PB at different time points (cycle 1 before start of ther-apy, start of cycle 7, start of cycle 13 [ end of VG treatment], start of cycle 16 [ end of VI treatment], final restaging [cycle 18], after-wards every 6 months to end of study)
    • Duration of undetectable MRD (uMRD)
    • Overall response rate (ORR; defined as rate of a response of CR, CRi, or PR) as per iwCLL guidelines at final restaging
    • Complete response rate (CRR; defined as rate of a response of CR or CRi) at final restaging as per iwCLL guidelines
    • Overall survival (OS)
    • Event-free survival (EFS) (I vs VG and I vs VI)
    • Time to next treatment (TTNT)
    • PFS2 (i.e. PFS after second-line treatment)
    Safety parameters:
    • Type, frequency, and severity of
    o adverse events (AEs) and
    o adverse events of special interest (AESI)
    o adverse events of particular interest (AEPI)
    and their relationship to study treatment
    • Tumour lysis syndrome (TLS) risk category after G or I lead-in (before venetoclax ramp up)
    Exploratory analyses:
    • Evaluation of relationship between various baseline markers and clini-cal outcome parameters (e.g. PFS, OS, ORR relative to del17p/TP53, IGHV, fitness, etc)
    • MRD by methods other than flow cytometry
    • Correlation between MRD in BM and PB
    • Correlation between MRD in BM and PFS/ EFS/ OS
    Correlation between MRD in PB and PFS/ EFS/ OS
    • Health-related quality of life by EORTC QLQC30 and QLQ-CLL17 questionnaires
    • Medical Resource Utilization
    • SARS-CoV-2-antibody levels before and 30 days, 6 months and 12 months after vaccination
    E.5.2.1Timepoint(s) of evaluation of this end point
    Analyses of secondary efficacy endpoints will not be tested formally and there is no control of type I error of any study endpoint. Every endpoint will be descriptively analyzed and reported. Analyses will be based on the ITT population.
    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) 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 Yes
    E.8.1.3Single blind No
    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) Yes
    E.8.2.2Placebo No
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA146
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Belgium
    Denmark
    Finland
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    Norway
    Spain
    Sweden
    Switzerland
    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 the clinical trial is defined as the time point 213 PFS events have been reached. This will take place approximately 80 months after first patient has been randomized (FPI).
    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 months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months8
    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: 897
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 897
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 747
    F.4.2.2In the whole clinical trial 897
    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)
    For patients randomized to the I arm: In countries where local legislation and regulations permit, patients who remain on treatment with ibrutinib at closure of study, but who cannot access ibrutinib in routine clinical practice, may access ibrutinib via the manufacturer.
    For patients randomized to the VG and VI arm, treatment is administered over a fixed-duration (see treatment schedules) and therefore no continuation of treatment is required post study.
    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 Decision2020-10-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-20
    P. End of Trial
    P.End of Trial StatusOngoing
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