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    EudraCT Number:2014-000925-19
    Sponsor's Protocol Code Number:BAY80-6946/17322
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-09-28
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-000925-19
    A.3Full title of the trial
    A randomized, double-blind Phase III study of copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (iNHL) - CHRONOS-2
    Studio randomizzato, in doppio cieco, di Fase III, su copanlisib rispetto al placebo in pazienti affetti da linfoma non-Hodgkin indolente (iNHL) refrattario a rituximab – CHRONOS-2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the efficacy and safety of copanlisib versus placebo inpatients with rituximab-refratory indolent non-Hodgkin's lymphoma.
    Copanlisib nell’iNHL di Fase III refrattario a rituximab
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberBAY80-6946/17322
    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 SponsorBAYER HEALTHCARE AG
    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 supportBayer HealthCare AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clin. Trials Contact CTP Team
    B.5.3 Address:
    B.5.3.1Street AddressBayer Pharma AG, S102, Level 2, Room 156
    B.5.3.2Town/ cityBERLIN
    B.5.3.3Post code13342
    B.5.4Telephone numberNA
    B.5.5Fax numberNA
    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 nameCopanlisib
    D.3.2Product code BAY 84-1236
    D.3.4Pharmaceutical form Powder for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rituximab-refractory indolent non-Hodgkin's lymphoma
    Linfoma non-Hodgkin indolente a B-cellule recidivato
    E.1.1.1Medical condition in easily understood language
    Patients with rituximab-refractory indolent non-Hodgkin's lymphoma
    Linfoma non-Hodgkin indolente a B-cellule recidivato
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10029600
    E.1.2Term Non-Hodgkin's lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    to investigate whether copanlisib as monotherapy is superior to placebo in prolonging progression-free survival (PFS) in patients with rituximab-refractory iNHL who have received two or more prior lines of treatment, have been exposed to rituximab and alkylating agent(s), and have progressed within six months of the end of the last previous rituximab-containing regimen
    Valutare se copanlisib in monoterapia sia superiore al placebo nel prolungare la sopravvivenza libera da progressione (PFS) in pazienti affetti da iNHL refrattario a rituximab che hanno ricevuto due o più linee precedenti di trattamento, sono stati esposti a rituximab ed ad agenti alchilanti e sono progrediti entro sei mesi dalla conclusione dell’ultimo regime precedente contenente rituximab (modificato secondo emendamento 1)
    E.2.2Secondary objectives of the trial
    the secondary objectives of this study are to evaluate:- Efficacy including tumor response, time to progression and overall survival.- The following characteristics of disease-related symptoms: time to deterioration and time to improvement.- Safety.The other objectives of this study are to evaluate:- PFS2 in placebo-treated patients who switched to open-label copanlisibtreatment.- Pharmacokinetics.- Biomarkers.- Quality of life.
    sopravvivenza (modificato secondo emendamento 1).
    • Le seguenti caratteristiche dei sintomi correlati alla malattia: tempo al peggioramento e al miglioramento (modificato secondo emendamento 1).
    • La sicurezza del farmaco.
    Ulteriori obiettivi:
    obiettivi di questo studio sono quelli di valutare:
    • PFS2 in pazienti trattati con placebo che sono passati alla terapia in aperto con copanlisib (modificato secondo emendamento 1).
    • La farmcocinetica.I biomarcatori.
    • La qualità di vita

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure.
    2. Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype limited to the following: o Follicular lymphoma (FL) grade 1-2-3a. o Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 109/L at the time of diagnosis and at study entry. o Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). o Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal).3. Patients must have received two or more prior lines of treatment. A previous regimen is defined as one of the following: at least two months of single-agent therapy, at least two consecutive cycles ofpolychemotherapy, autologous transplant, radioimmunotherapy.4. Prior therapy must include rituximab and alkylating agent(s). Prior exposure to idelalisib or other PI3K inhibitors is acceptable provided thatthere is no resistance.5. Patients must be refractory to the last rituximab-based treatment (no response or response lasting < 6 months).6. Patients must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.
    7. Patients affected by WM, who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment, must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 xupper limit of normal (ULN).8. Male or female patients ≥ 18 years of age.9. ECOG performance status ≤ 1.10. Life expectancy of at least 3 months.11. Availability of fresh (preferred) and/or archival tumor tissue at Screening.12. Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies since signing of the ICF until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequatecontraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.13. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before start of study treatment: o Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for patients with Gilbert-Meulengracht syndrome or for patients with cholestasis due to compressive adenopathies of the hepatic hilum). o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their lymphoma). o Amylase and lipase ≤ 1.5 x the ULN
    o Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to theModification of Diet in Renal Disease (MDRD) abbreviated formula. o International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN.Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring is recommended according to the local standard of care. o Platelet count ≥ 75,000/mm3. o Hemoglobin (Hb) ≥ 10 g/dL. o Absolute neutrophil count (ANC) ≥ 1500/mm3.14. Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal (LLN) for the Institution.

    Diagnosi confermata istologicamente di NHL a B-cellule, indolente, con sottotipo istologico limitato a:
    • Linfoma follicolare (LF) di grado 1-2-3a.
    • Linfoma linfocitico (SLL) con conta linfocitaria assoluta < 5 x 109/L alla diagnosi ed all’ingresso in studio.
    • Linfoma linfoplasmocitoide/macroglobulinemia di Waldenström (LPL/WM).
    • Linfoma marginale (MZL) (splenico, linfonodale od extra-nodale).
    I pazienti devono aver ricevuto due o più precedenti linee di trattamento (modificato secondo emendamento 1). Un regime precedente è definito come uno dei seguenti: almeno due mesi consecutivi di monoterapia, almeno due cicli consecutivi di polichemioterapia, trapianto autologo, radioimmunoterapia.
    La terapia precedente deve includere rituximab e agenti alchilanti. Una precedente esposizione all’idelalisib o ad altri inibitori della PI3K è accettabile, se c’è evidenza che non è stata sviluppata resistenza (modificato secondo emendamento 1).
    I pazienti devono essere refrattari all’ultimo trattamento a base di rituximab (nessuna risposta o risposta che duri < 6 mesi).
    I pazienti devono aver almeno una lesione misurabile bi-dimensionalmente (che non sia stata irradiata precedentemente) secondo le raccomandazioni dei “Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification (modificato secondo emendamento 1).
    I pazienti affetti da LPL/WM, che non presentano almeno una lesione misurabile bi-dimensionalmente alla valutazione basale, devono avere una malattia misurabile definita come la presenza di una componente monocolonale M (IgM) con un livello massimo di IgM ≥ 2 volte oltre il limite superiore della norma (ULN) (modificato secondo emendamento 1).
    Pazienti di sesso maschile o femminile ≥ 18 anni d’età.

    E.4Principal exclusion criteria

    1. Previous assignment to treatment during this study. 2. Close affiliation with investigational site.3. Histologically confirmed diagnosis of FL grade 3b.4. Chronic lymphocytic leukemia.5. Transformed disease: o histological confirmation of transformation, or o clinical and laboratory signs: rapid disease progression, high standardized uptake value (>12) by positron emission tomography at baseline if PET scans are performed.6. Previous/concurrent cancer that is distinct in primary site/histology from indolent B-cell NHL within 5 yrs before start of study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta, Tis and T1].8. Bulky disease o Lymph nodes/tumor mass (except spleen) ≥7cm LDi (longest diameter).11. Known lymphomatous involvement of the central nervous system.12. Congestive heart failure > NYHA class 2.
    13. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 mths). Myocardial infarction less than 6 mths before start of study treatment.14. Uncontrolled arterial hypertension (systolic blood pressure >150mmHg or diastolic blood pressure >90mmHg despite optimal medical management).15. Type I/II diabetes mellitus with HbA1c >8.5% or fasting plasma glucose >160mg/dL at Screening.16. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 mths before start of study treatment.17. Non-healing wound, ulcer, or bone fracture.18. Active clinically serious infections > CTCAE Grade 2.19. Known history of HIV infection.20. Hepatitis B or C. All patients must be screened for HBV and HCV up to28 days before start of study treatment using the routine hepatitis virus laboratory panel. Patients positive for HBsAg or HBcAb will be eligible if negative for HBV-DNA. Patients positive for HCV IgG will be eligible if negative for HCV-RNA.21. Patients with seizure disorder requiring medication.22. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 wks before start of study treatment.23. Renal failure requiring hemo- or peritoneal dialysis.24. Proteinuria as measured by urine protein/creatinine ratio >3.5 on a
    random urine sample.25. History/concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function.26. Concurrent diagnosis of phaeochromocytoma.27. Pregnant/breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a max. of 7 days before start of study treatment, and a negative result must be documented before start of study treatment.28. Unresolved toxicity > CTCAE Grade 1 attributed to any prior therapy/procedure excluding alopecia and ≤ CTCAE Grade 2 peripheral neuropathy.29. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.30. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.31. Any illness/medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.33. Treatment with investigational drugs within 28 days before start of study treatment.34. Ongoing immunosuppressive therapy.35. Radiotherapy or immuno/chemotherapy within 4 wks before start of study treatment.36. Radioimmunotherapy/autologous transplant within 3 mths before start of study treatment.
    37. Myeloid growth factors within 14 days before start of study treatment.38. Blood/platelet transfusion within 14 days before start of study treatment.39. Ongoing systemic corticosteroid therapy at a daily dose higher than 15mg prednisone or equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed dose 7 days before performing the screening CT/MRI and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the Screening.40. History of having received an allogeneic bone marrow/organ transplant.41. Major surgical procedure/significant traumatic injury within 28 days before start of study treatment; open biopsy within 7 days before start of study treatment.42. Anti-arrhythmic therapy.43. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until SFU visit.44. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until SFU visit.45. Documented evidence of resistance to a prior treatment with idelalisib or other PI3K inhibitors defined as: o No response (defined as PR or CR) at any time during therapy, or o Progression (PD) after any response (PR/CR) or after stable disease (SD) within 6 mths from the end of the therapy with a PI3K inhibitor.
    E.5 End point(s)
    Diagnosi confermata istologicamente di LF di grado 3b.
    Leucemia linfatica cronica (CLL).
    Malattia trasformata (valutata da uno sperimentatore):
    • Conferma istologica di trasformazione, oppure
    • Segni clinici e di laboratorio: rapida progressione della malattia, SUV (standardized uptake value) elevata (>12) mediante tomografia ad emissione di positroni (PET) al basale se viene effettuata la PET (opzionale).
    Malattia Bulky (modificato secondo emendamento 1):
    Linfonodi o massa tumorale (tranne la milza) ≥ 7 cm LDi (diametro più lungo).
    Noto interessamento linfomatoso del sistema nervoso centrale.
    Diabete mellito di tipo 1 o 2 con valore di HbA1c > 8.5% oppure glicemia a digiuno > 160 mg/dL allo screening.
    Nota infezione da parte del virus dell’immunodeficienza umana (HIV).
    Epatite B (HBV) o epatite C (HCV). I pazienti positivi per l’HBsAg o l’HBcAb saranno eleggibili se sono negativi per il DNA dell’HBV. I pazienti positivi per l’immunoglobulina G dell’HCV (IgG) saranno eleggibili se sono negativi per l’RNA dell’HCV.
    Storia o diagnosi concomitante di pneumopatia interstiziale di qualsiasi severità e/o funzionalità polmonare gravemente alterata (modificato secondo emendamento 1).
    Documentata resistenza a terapie precedenti con idelalisib o altri inibitori PI3K definita come (modificato secondo emendamento 1):

    • Nessuna risposta (risposta definita come risposta parziale (PR) o completa (CR) in qualsiasi momento durante il trattamento, o
    • Progressione (PD) dopo qualsiasi risposta (PR/CR) o dopo stabilità di malattia (SD) entro 6 mesi dalla fine della terapia con l’inibiltore del PI3K
    I pazienti che discontinuano dal trattamento per motivi diversi dalla progressione di malattia, e che non hanno segni di PD, potranno essere arruolati in questo studio dopo discussione con lo sponsor.

    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS), defined as the time (in days) from randomization to disease progression or death from any cause (if no progression is documented).
    La variabile primaria è la PFS, definita come il tempo (in giorni) intercorso fra la randomizzazione e la PD valutata in base alla revisione centralizzata o la morte per qualsiasi causa (se non è documentata alcuna progressione).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tihe time (in days) from randomization to disease progression or death from any cause (if no progression is documented). The actual date of tumor assessments will be used for this calculation. PFS for patients without PD or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS for patients who have neither tumor assessments nor death after baseline will becensored at Day 1.
    Tempo (in giorni) dalla randomizzazione alla progressione di malattia o alla morte per qualsiasi causa (se non vi è progressione documentata). La data della rivalutazione del tumore verrà usata per questo calcolo. la PFS per i Pazienti senza progressione o morte verrà calcolata alla data dell’ultima rivalutazione del tumore. PFS per i Pazienti che non hanno avuto rivalutazioni del tumore o morte dopo il basale verrà valutata al Giorno 1.
    E.5.2Secondary end point(s)
    - Objective tumor response rate (ORR) assessed in all patients up to the time of analysis of PFS.- Duration of response (DOR)-Complete response rate (CRR), assessed in all patients up to the time ofanalysis of PFS.- Time to progression (TTP)- Overall survival (OS)- Time to deterioration in disease-related symptoms – physical (DRS-P) of at least 3 points.-Time to improvement in DRS-P of at least 3 points
    - ORR fino all'analisi PFS - DOR-CRR fino all'analisi PFS Risposta obbiettiva del tumore (ORR) valutata in tutti pazienti al momento dell’analisi della PFS- Durata della risposta (DOR)- tasso di risposta completa (CRR) valutata in tutti pazienti al momento dell’analisi della PFS- , il tempo alla progressione (TTP)- la sopravvivenza (OS)- tempo al peggioramento e al miglioramento dei sintomi correlati alla malattia
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR: proportion of patients who have a best response rating over the duration of the study - DOR: the time (in days) from first observed tumor response (CR, VGPR,PR or MR) until PD or death from any cause.- CRR: assessed in all patients up to the time of analysis of PFS.- TTP: the time (in days) from randomization to PD or death related to PD.- OS: time (in days) from randomization until death from any cause. -Time to deterioration in DRS-P of at least 3 points: measured by the FLymSI-18 questionnaire. -Time to improvement in DRS-P of at least 3 point: measured by the FLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less.
    - ORR: proporzione di pazienti che abbiano la migliore risposta - DOR: tempo in giorni dall prima risposta al tumore (CR, VGPR,PR o MR) fino a PD o morte per qualsiasi causa - CRR: valutato in tutti i pazienti fino all'analisi di PFS. - TTP: tempo in giorni dalla randomizzazione a PD o morte correlata a PD. - OS: tempo in giorni dalla randomizzazione fino a morte per qualsiasi causa. - Tempo al peggioramento e al miglioramento dei sintomi correlati alla malattia di almeno 3 punti: misurati secondo questionario FLymSI-18. -Tempo al miglioramento DRS-P di almeno 3 punti: misurato tramite questionario FLymSI-18 in pazienti con un punteggio basale DRS-P di 30 punti o meno.
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Progression free survival, biomarkers and Quality of Life
    PFS (sopravvivenza libera da progressione), Biomarcatori, Qualità della Vita
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    Hong Kong
    Russian Federation
    South Africa
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    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: 85
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 104
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 94
    F.4.2.2In the whole clinical trial 189
    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)
    After the end of study treatment, further therapy is at the discretion of the investigator
    Alla fine del trattamento la continuazione della terapia sarà a discrezione dello Sperimentatore
    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 Decision2015-04-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-10
    P. End of Trial
    P.End of Trial StatusOngoing
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