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    EudraCT Number:2019-001573-89
    Sponsor's Protocol Code Number:D8220C00008
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-23
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-001573-89
    A.3Full title of the trial
    A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects with Chronic Lymphocytic Leukemia
    Étude de Phase 3b, multicentrique, en ouvert, à un bras, évaluant l’acalabrutinib (ACP-196) chez des patients présentant une leucémie lymphoïde chronique
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with Acalabrutinib in patients with chronic lymphocytic leukemia
    Traitement avec Acalabrutinib chez des patients présentant une leucémie lymphoïde chronique
    A.4.1Sponsor's protocol code numberD8220C00008
    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 SponsorAstraZeneca AB
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Address1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post code19850-5437
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018002369933
    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 nameAcalabrutinib
    D.3.2Product code ACP-196
    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 INNAcalabrutinib
    D.3.9.1CAS number 1420477-60-6
    D.3.9.2Current sponsor codeACP-196
    D.3.9.3Other descriptive nameACP-196
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic lymphocytic leukemia
    E.1.1.1Medical condition in easily understood language
    Patients with chronic lymphocytic leukemia 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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    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
    To evaluate the safety and tolerability of acalabrutinib monotherapy in subjects with treatment-naive or relapsed/refractory chronic lymphocytic leukemia
    Évaluer la sécurité et la tolérance de l’acalabrutinib en monothérapie chez des patients présentant une leucémie lymphoïde chronique naïve de traitement ou en récidive/réfractaire
    E.2.2Secondary objectives of the trial
    To evaluate the investigator-assessed overall response rate, duration of response, and progression-free survival in subjects receiving acalabrutinib monotherapy;
    Évaluer le taux de réponse global estimé par l’investigateur, la durée de la réponse et la survie sans progression chez les patients recevant l’acalabrutinib en monothérapie
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women ≥18 years of age;
    2. Diagnosis of CLL that meets published diagnostic criteria:
    a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥1 B-cell marker (CD19, CD20, and CD23) and CD5;
    b. Prolymphocytes may comprise <55% of blood lymphocytes;
    c. Presence of ≥5 × 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis);
    3. Active disease per IWCLL 2018 criteria that requires treatment:
    a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/μL).
    b. Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
    c. Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
    d. Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of <30x109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
    e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
    f. B-symptoms documented in the participants chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs (please refer to protocol for related symptoms);
    4. Must meet 1 of the following criteria:
    a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria:
    i. A score of >6 on the Cumulative Illness Rating Scale (CIRS).
    ii. Creatinine clearance of 30 to 69 ml/min using the Cockcroft-Gault equation.
    b. Have previously received therapy for CLL and have either refractory or relapsed CLL.
    c. Have received prior BTKi therapy (i.e., defined as a participant who discontinued a BTKi for any reason except disease progression) for CLL.
    d. Have either TN or R/R CLL and are receiving concomitant vitamin K antagonists (e.g., coumadin).
    5. ECOG performance status of ≤2;
    6. Female subjects of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilized male partner must use ≥1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study treatment. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide during the study.
    7. Fluorescence in situ hybridization (FISH) results within 60 days before screening reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Participants must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
    8. Participants must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.
    1. Hommes et femmes âgés de ≥18 ans.
    2. Diagnostic de LLC répondant aux critères diagnostiques publiés (Hallek et al. 2018) :
    a. Lymphocytes B monoclonaux (chaîne légère kappa ou lambda uniquement) coexprimant clonalement ≥ 1 marqueur des lymphocytes B (CD19, CD20 et CD23) et CD5
    b. Les prolymphocytes peuvent constituer <55 % des lymphocytes sanguins
    c. Présence de ≥5 × 109lymphocytes B/L (5 000/µL) dans le sang périphérique (à tout moment depuis le diagnostic initial)
    3. Maladie active selon les critères 2018 de l’IWCLL, nécessitant un traitement
    a. Signes d’insuffisance médullaire évolutive, se manifestant par le développement ou l’aggravation d’une anémie (hémoglobine <10 g/dL) et/ou d'une thrombocytopénie (plaquettes <100 000/μL)
    b. Splénomégalie massive (c’est-à-dire ≥6 cm sous le rebord costal gauche), évolutive ou symptomatique
    c. Lymphadénopathie à ganglions massifs (c’est-à-dire ≥10 cm dans le diamètre le plus long), évolutive ou symptomatique
    d. Lymphocytose évolutive avec augmentation >50 % sur une période de 2 mois ou temps de doublement lymphocytaire (TDL) < 6 mois. Le TDL peut être obtenu par extrapolation par régression linéaire de la numération absolue des lymphocytes obtenue à intervalles de 2 semaines sur une période d'observation de 2 à 3 mois. Chez les patients présentant une numération lymphocytaire initiale <30x109/L (30 000/μL), le TDL ne doit pas être utilisé comme unique paramètre pour définir l’indication du traitement. En outre, les facteurs contribuant à la lymphocytose ou à la lymphadénopathie autres que la LLC (par exemple, infections) doivent être exclus.
    e. Anémie et/ou thrombocytopénie autoimmune répondant mal au traitement standard
    f. Symptômes B documentés dans le dossier du patient avec des mesures objectives les corroborant de manière appropriée, définies comme ≥1 des symptômes ou signes (Veuillez vous référer au protocole pour connaître les symptômes associés )
    4. Doivent satisfaire à l’1 des critères suivants :
    a. Pas de précédent traitement de la LLC et satisfaction de l’un des critères suivants :
    i. Score of >6 sur l'échelle CIRS (Cumulative Illness Rating Scale) (Annexe G du protocole)
    ii. Clairance de la créatinine de 30 à 69 ml/min en utilisant l’équation de Cockcroft-Gault
    b. Précédent traitement de la LLC et LLC soit réfractaire, soit en récidive
    c. Précédent traitement par BTKi (c’est-à-dire, patient ayant arrêté un BTKi pour une quelconque raison autre qu’une progression de la maladie) pour la LLC
    d. LLC NT ou R/R et traitement concomitant par antagonistes de la vitamine K (par exemple, coumadine)
    5. Indice de performance ECOG ≤2
    6. Les femmes en âge de procréer (c’est-à-dire n'ayant pas subi de stérilisation chirurgicale ou ménopausée) sexuellement actives dont le partenaire est un homme non stérilisé doivent utiliser ≥1 méthode hautement efficace de contraception à partir de la sélection et accepter de maintenir de telles précautions pendant 2 jours après la dernière dose de traitement à l’étude. Les hommes non stérilisés ayant des rapports sexuels avec une femme en âge de procréer doivent utiliser un préservatif masculin plus un spermicide pendant l'étude. Se reporter à l’Annexe F du protocole pour connaître les recommandations et les définitions concernant la reproduction et la contraception.
    7. Résultats de hybridation in situ en fluorescence (FISH) dans les 60 jours précédant la sélection reflétant la présence ou l’absence de del(17p), 13q del, 11q del, et trisomie du chromosome 12 avec le pourcentage de cellules présentant une délétion, ainsi que séquençage du TP53. Les patients doivent également faire l’objet d’une analyse moléculaire pour détecter le statut mutationnel de l’IGHV à tout moment depuis le diagnostic.
    8. Les patients doivent avoir la volonté de respecter le calendrier des visites de l'étude et en être capables, comprendre et se conformer aux autres exigences du protocole et fournir leur consentement éclairé écrit et l'autorisation d’utiliser les informations de santé protégées.
    E.4Principal exclusion criteria
    1. Participants who have had disease progression while on a BTKi for any malignant or nonmalignant condition.
    2. Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the participant has been disease-free for ≥2 years.
    3. History of confirmed progressive multifocal leukoencephalopathy.
    4. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia’s formula (QTcF) >480 msec at screening. Note: participants with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
    5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
    6. Evidence of active Richter's transformation. If Richter’s transformation is suspected (i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomographycomputed tomography (PET-CT) and/or biopsy according to guidelines.
    7. Central nervous system (CNS) involvement by CLL.
    8. Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with participants who are on ongoing anti-infective treatment and participants who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
    a. Participants who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.
    b. Participants who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded.
    9. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks).
    10. History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment.
    11. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
    12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before Screening.
    13. Major surgical procedure within 4 weeks before first dose of study treatment. Note: Participants who have had major surgery, must have recovered adequately from any
    toxicity and/or complications from the intervention before the first dose of study treatment.
    14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
    15. All participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment except those participants who will be enrolled into the vitamin K antagonist cohort.
    16. Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion.
    17. Total bilirubin >1.5 x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0 x ULN. Exception will be for Gilbert syndrome; if an
    investigator feels that a participants total bilirubin is elevated secondary to Gilbert’s, the participant must have a documented unconjugated bilirubin being >80% of the total bilirubin number. The investigator must also document that hemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin.
    18. Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement).
    19. Breastfeeding or pregnant.
    1. Patients ayant présenté une progression de la maladie pendant un traitement par BTKi pour toute affection maligne ou non maligne
    2. Précédent cancer (autre que la LLC), sauf un carcinome basocellulaire ou épidermoïde de la peau, un cancer in situ, un cancer de la prostate de stade précoce ou un autre cancer correctement traités dont le patient ne présente aucun signe ou symptôme depuis ≥2 ans
    3. Antécédents de leucoencéphalopathie multifocale progressive confirmée
    4. Maladie cardiovasculaire significative telle qu’une arythmie symptomatique, une insuffisance cardiaque congestive ou un infarctus du myocarde au cours des 6 mois précédant la sélection, ou toute maladie cardiaque de classe 3 ou 4 selon la classification fonctionnelle de la New York Heart Association, ou intervalle QT corrigé selon la formule de Fridericia (QTcF) > 480 msec lors de la sélection. Remarque : les patients présentant une fibrillation auriculaire asymptomatique à rythme contrôlé sont autorisés à participer à l'étude.
    5. Syndrome de malabsorption, maladie affectant significativement la fonction gastro-intestinale, résection de l’estomac, résection importante de l’intestin grêle susceptible d’avoir une incidence sur l'absorption, maladie inflammatoire de l’intestin symptomatique, obstruction intestinale partielle ou complète, ou restrictions gastriques et chirurgie bariatrique, comme un bypass gastrique
    6. Signes de transformation de Richter active. Si une transformation de Richter est suspectée (c’est-à-dire, augmentation de la lactate déshydrogénase [LDH], croissance asymétrique et rapide des ganglions lymphatiques ou suspicion clinique), elle doit être écartée par tomographie par émission de positons-tomodensitométrie (TEP-TDM) et/ou biopsie conformément aux lignes directrices
    7. Envahissement du système nerveux central (SNC) par la LLC
    8. Antécédents connus de virus de l’immunodéficience humaine, statut sérologique reflétant une infection active à virus de l’hépatite B ou à virus de l’hépatite C, toute infection systémique active non contrôlée, patients recevant un traitement antiinfectieux en cours et patients ayant reçu un vaccin atténué vivant dans les 4 semaines précédant la première dose de traitement à l'étude
    a. Les patients positifs pour les anticorps dirigés contre la nucléocapside du virus de l’hépatite B (anti-HBc) et négatifs pour les antigènes de surface du virus de l'hépatite B (HBsAg) devront fournir un résultat de PCR négatif pour le virus de l’hépatite B avant le recrutement. Les patients positifs pour les antigènes de surface du virus de l’hépatite B (HbsAg) ou positifs par PCR pour le virus de l’hépatite B ne pourront pas participer à l'étude.
    b. Les patients positifs pour les anticorps dirigés contre le virus de l'hépatite C devront fournir un résultat de PCR négatif pour le virus de l'hépatite C avant le recrutement. Les patients positifs par PCR pour le virus de l’hépatite C ne pourront pas participer à l'étude.
    9. Anémie hémolytique autoimmune non contrôlée ou purpura thrombocytopénique idiopathique, défini comme une baisse du taux d’hémoglobine ou de plaquettes secondaire à une destruction autoimmune au cours de la période de sélection ou la nécessité de doses élevées de stéroïdes (>20 mg par jour de prednisone ou l'équivalent pendant plus de 2 semaines)
    10. Antécédents d’AVC ou d’hémorragie intracrânienne dans les 6 mois précédant la première dose de traitement à l'étude
    11. Antécédents de diathèse hémorragique (par exemple, hémophilie ou maladie de von Willebrand)
    12. Présence d'un ulcère gastro-intestinal diagnostiqué par endoscopie dans les 3 mois précédant la sélection
    13. Intervention chirurgicale majeure dans les 4 semaines précédant la première dose de traitement à l'étude. Remarque : Si un patient subit une chirurgie majeure, il doit avoir correctement récupéré de toute toxicité et/ou complication de l’intervention avant l’administration de la première dose de traitement à l’étude.
    14. Traitement requis par inhibiteurs de la pompe à protons (par exemple, oméprazole, ésoméprazole, lansoprazole, dexlansoprazole, rabéprazole ou pantoprazole). Les patients recevant des inhibiteurs de la pompe à protons qui passent sous antagonistes des récepteurs H2 ou antiacides sont éligibles à la participation à cette étude.
    15. Tous les patients nécessitant ou recevant une anticoagulation par warfarine ou antagonistes de la vitamine K équivalents (par exemple, phenprocoumon) au cours des 7 jours précédant la première dose de traitement à l'étude, sauf ceux qui seront recrutés dans la cohorte sous antagoniste de la vitamine K
    16. Taux absolu de neutrophiles (TAN) <0,50 x 109/L ou taux de plaquettes <30 x 109/L, sauf s'il est démontré que ce taux est dû à la LLC ou a augmenté au-dessus des limites par traitement par facteur de stimulation des colonies de granulocytes (G-CSF) et/ou transfusion plaquettaire

    Note: Veuillez vous référer au protocole pour connaître les autres critères de non-inclusion.

    E.5 End points
    E.5.1Primary end point(s)
    Frequency and relatedness of all AEs, which will also include:
    - Grade ≥3 AEs
    - SAEs
    - AEs that lead to discontinuation of treatment
    - ECIs defined as cardiac rhythm disorders, opportunistic infections,interstitial lung disease, major hemorrhage, and cytopenias
    Fréquence et lien de causalité de tous les événements indésirables, incluant également :
    • Événements indésirables de Grade ≥ 3
    • Événements indésirables graves
    • Événements indésirables conduisant à l’arrêt du traitement
    • Événements d'intérêt clinique, définis comme les troubles du rythme cardiaque, les infections opportunistes, les pneumopathies interstitielles, les hémorragies majeures et les cytopénie
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analyses at the study end
    E.5.2Secondary end point(s)
    - ORR (objective response rate)
    - DOR (duration of response)
    - PFS (progression-free survival)
    -Taux de réponse objective
    -Durée de réponse
    -Survie sans progression
    E.5.2.1Timepoint(s) of evaluation of this end point
    - ORR will be defined as a subject achieving CR, CRi, or PR, according to the IWCLL 2018 criteria as assessed by the investigator.
    - Duration of response (DOR) will be defined as the time from the first objective response of CR, CRi, or PR to the time of documented disease progression or death due to any cause, whichever occurs first.
    - PFS will be defined as the interval from the start of study treatment with study treatment to completion of 48 cycles or the earlier of the first documentation of disease progression or death from any cause.
    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 No
    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. 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Korea, Republic of
    Russian Federation
    United Kingdom
    United States
    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
    The duration of the study will be approximately 72 months from the first subject enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per cycle); additional study time will be accrued during the follow-up period for those subjects remaining on study treatment after completion of 48 cycles (the amount of time will vary by subject).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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 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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 350
    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 Yes
    F. of subjects incapable of giving consent
    Subjects incapable of giving consent for physical or physiological reasons, or reasons linked to their medical condition (e.g. coma, mental disability and in accordance with national requirements)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state41
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 297
    F.4.2.2In the whole clinical trial 600
    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 subjects will have a Safety Follow-Up (SFU) visit approximately 30 days after the last dose of study treatment. If a subject continues to derive benefit from treatment at the end of 48 cycles, they will continue to be provided with study treatment (for more details please refer to protocol section 4.3)
    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 Decision2019-08-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-16
    P. End of Trial
    P.End of Trial StatusOngoing
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