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    Summary
    EudraCT Number:2016-004340-11
    Sponsor's Protocol Code Number:17403
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-02-09
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2016-004340-11
    A.3Full title of the trial
    A randomized, open label, multicenter Phase 2/3 study to evaluate the efficacy and safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy
    Ensaio aleatorizado, aberto e multicêntrico de Fase 2/3 para avaliar a eficácia e a segurança de rogaratinib (BAY 1163877) em comparação com quimioterapia em doentes com carcinoma urotelial localmente avançado ou metastático positivo para FGFR e que receberam tratamento anterior com quimioterapia contendo platina
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2/3 study of rogaratinib (pan FGFR inhibitor) vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma with a high amount of specific cell growth factor receptors 1 and 3 (FGFR1 and 3) in the tumor cells
    Ensaio de Fase 2/3 de rogaratinib (BAY 1163877) vs. quimioterapia em doentes com carcinoma urotelial localmente avançado ou metastático positivo para FGFR
    A.4.1Sponsor's protocol code number17403
    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 AG, D-51368 Leverkusen, Germany
    B.1.3.4CountryGermany
    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 AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCPT Team / Ref: "EU CTR"/ Bayer AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayer.com
    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 nameBAY 1163877 hydrochloride coated tablet 200 mg
    D.3.2Product code BAY 1163877 hydrochloride coated tablet 200 mg
    D.3.4Pharmaceutical form 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 INNROGARATINIB
    D.3.9.2Current sponsor codeBAY 1213802 hydrate
    D.3.9.3Other descriptive nameBAY 1163877 hydrochloride hydrate
    D.3.9.4EV Substance CodeSUB188629
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Docetaxel cell pharm
    D.2.1.1.2Name of the Marketing Authorisation holdercell pharm GmbH
    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 nameDocetaxel cell pharm
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNDOCETAXEL
    D.3.9.1CAS number 114977-28-5
    D.3.9.4EV Substance CodeSUB12492MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Paclitaxel Aurobindo
    D.2.1.1.2Name of the Marketing Authorisation holderPUREN Pharma GmbH & Co. KG
    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 namePaclitaxel Aurobindo
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Javlor
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    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 nameJavlor
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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 INNVINFLUNINE
    D.3.9.1CAS number 162652-95-1
    D.3.9.4EV Substance CodeSUB00063MIG
    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 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
    mRNA FGF receptor 1 and 3 positive locally advanced or metastatic
    urothelial carcinoma progressed after prior platinum-containing
    chemotherapy
    Carcinoma urotelial (mRNA FGF receptor 1 e 3 positivo) localmente avançado ou metastático com progressão após o uso anterior de quimioterapia com platina.
    E.1.1.1Medical condition in easily understood language
    Locally advanced or metastatic bladder cancer with a high amount
    of specific cell growth factor receptors 1 and 3 (FGFR1 and 3) in the
    tumor
    cells
    Cancro de bexiga localmente avançado ou metastático com elevado número de receptores específicos do fator de crescimento celular 1 e 3 (FGFR1 e 3) nas células do tumor.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064467
    E.1.2Term Urothelial carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective of this trial is to demonstrate the superiority of rogaratinib over chemotherapy in
    terms of prolonging overall survival of urothelial carcinoma patients with
    FGFR positive tumors.

    The objective for the Phase 2 part of the study is to demonstrate the efficacy of rogaratinib over chemotherapy in terms of objective response rate of urothelial carcinoma patients with FGFR positive tumors.
    Objetivo primário:
    · Demonstrar a superioridade de rogaratinib sobre a quimioterapia em termos de prolongamento da sobrevivência global de doentes com carcinoma urotelial com tumores positivos para FGFR.
    O objetivo para a parte de Fase 2 do ensaio é demonstrar a eficácia de rogaratinib sobre a quimioterapia em termos da taxa de resposta objetiva de doentes com carcinoma urotelial com tumores positivos ao FGFR.
    E.2.2Secondary objectives of the trial
    Secondary objective of this trial is to evaluate additional efficacy including the following variables:
    Progression-free survival (PFS)
    Objective response rate (ORR)
    Disease control rate (DCR)
    Duration of response (DOR)
    and to evaluate the safety of rogaratinib (adverse events)
    Tertiary objectives are:
    Patient-reported outcome (PRO)
    Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related)
    Pharmacokinetics
    effect and/or safety) and/or the pathomechanism of the disease.
    Pharmacokinetics
    Objetivos secundários:
    · Avaliar a eficácia adicional, incluindo as seguintes variáveis:
    o sobrevivência livre de progressão (SLP)
    o taxa de resposta objetiva (TRO)
    o taxa de controlo da doença (TCD)
    o duração da resposta (DR)
    · Avaliar a segurança de rogaratinib (eventos adversos)
    Objetivos terciários:
    · Resultados referidos pelo doente (RRD)
    · Analisar biomarcadores para investigar o medicamento (ou seja, o efeito e/ou segurança relacionados com o modo de ação) e/ou o mecanismo patológico da doença
    · Farmacocinética
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Existence of archival or fresh biopsy for FGFR testing.
    FGFR testing of patients will be performed at the investigators’ discretion up to a max. of 90 days prior to start of screening (signing of informed consent for study treatment eligibility). Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment within this timeframe. If the patient is positive for FGFR 1 and/or 3 and is unable start screening by 90 days after FGFR testing, the patient may still be considered for screening after discussion with the sponsor’s designated medical representative and approval by the sponsor
    Male or female patients ≥ 18 years of age (at least age of legal
    maturity).
    Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria:
    Histologically or cytologically confirmed. Patients with mixed histologies are required to have a dominant transitional cell pattern.
    Locally advanced (T4b, any N; or any T, N 2−3) or metastatic disease (any T, any N and M1).
    Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3).
    ECOG Performance Status of 0 or 1.
    Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment.
    High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+; measurement is part of this protocol) in archival or fresh tumor biopsy specimen.
    At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI.
    Adequate laboratory and organ function:
    Absolute neutrophil count (ANC) ≥ 1,500/mm3
    Platelet count ≥ 100,000/mm3
    Hemoglobin ≥ 9.0 g/dL (without transfusion or erythropoietin within 4 weeks before randomization).
    Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Known Gilbert syndrome is allowed if total bilirubin is ≤ 3 x ULN.
    Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer).
    Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver and bone involvement of their cancer).
    Lipase < 2 x ULN
    Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to Modification of Diet in Renal Disease (MDRD) abbreviated formula.
    International normalized ratio (INR) ≤ 1.5  ULN, and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5  ULN. Patients being treated with anticoagulant, e.g. warfarin or heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a pre-dose measurement as defined by the local standard of care.
    Women of childbearing potential (WOCBP) and fertile men must agree to use adequate contraception when sexually active from signing of the ICF for study treatment eligibility until at least 12 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) contraception methods include:
    Combined (estrogen and progesterone containing: oral, intravaginal, transdermal) and progesterone-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation.
    Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
    Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole sexual partner and has received medical assessment of the surgical success).
    Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient).
    Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
    Male patients with a female partner of childbearing potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 12 weeks after last study drug administration.
    Negative serum pregnancy test in women of childbearing potential (performed within 7 days before randomization). Negative results must be available prior to study drug administration.
    Principais critérios de inclusão:
    • Existência de biopsia de tecido fresco ou em arquivo, para análise do FGFR
    • A análise do FGFR dos doentes será realizada segundo critério dos investigadores até um máximo de 90 dias antes do início da triagem.
    Os investigadores devem garantir que todos os doentes serão elegíveis em termos de estado da doença e linhas de tratamento neste intervalo temporal.
    • Doentes do sexo masculino ou feminino ≥ 18 anos de idade
    • Carcinoma urotelial documentado (carcinoma das células de transição) que compreenda a bexiga, pélvis renal, ureteres, uretra, cumprindo todos os critérios seguintes:
    o Confirmado por histologia ou citologia
     Os doentes com histologias mistas devem apresentar um padrão de células de transição dominante.
    o Doença localmente avançada (T4b, qualquer N; ou qualquer T, N2-3) ou metastática (qualquer T, qualquer N e M1).
    O cancro da bexiga localmente avançado deve ser irressecável, ou seja, invadindo a parede pélvica ou abdominal (estadio T4b) ou apresenta uma doença ganglionar volumosa (N2-3).
    • Capacidade funcional ECOG de grau 0 ou 1.
    • Progressão da doença durante ou após tratamento com pelo menos um regime contendo platina (os doentes devem ter sido tratados durante pelo menos 2 ciclos). Nos doentes que receberam previamente quimioterapia adjuvante/neoadjuvante contendo platina, a progressão deverá ter ocorrido no período de 12 meses após o tratamento.
    • Níveis elevados de expressão do RNAm de FGFR1 ou 3 (score de 3+ ou 4+ na RNAescopia; a medida faz parte deste protocolo) na amostra de biópsia tumoral fresca ou de arquivo.
    • Pelo menos 1 lesão mensurável de acordo com os Critérios de Avaliação de Resposta em Tumores Sólidos (Response Evaluation Criteria in Solid Tumor - RECIST v.1.1) por TC ou por RM com contraste (a menos que contraindicado).
    • Valores laboratoriais e funcionais adequados:
    o Contagem absoluta de neutrófilos (CAN) >= 1500/mm3
    o Contagem de Plaquetas >=100/mm3
    o Hemoglobina >=8.0 g/dL (sem transfusão ou eritropoietina nas quatro semanas antes da aleatorização)
    o Bilirrubina total <= 1.5 vezes o valor de referência máximo (VRM). Doentes com Sindrome de Gilbert são permitidos desde que a bilirrubina total seja <=3 x VRM
    o Alanina Aminotransferase (ALT) e Aspartato Aminotransferase (AST) <= 2.5 x VRM (<=5 x VRM para doentes com doença oncológica no fígado)
    o Limite da Fosfatase Alcalina <=2.5 x VRM (<=5 x VRM para doentes com doença oncológica no fígado e nos ossos)
    o Lipase <2 x VRM
    o Taxa de Filtração Glomerular (GFR) >=30 mL/min/1.73 m2 de acordo com a fórmula abreviada para a Modificação da Dieta na Doença Renal (MDRD)
    o Rácio Internacional Normalizado (INR) <= 1.5 e Tempo de Tromboplastina Parcial (PTT) ou a PTT ativada (aPTT) <=1.5 x VRM. Será permitido que doentes que estejam a ser tratados com anticoagulantes, por. Ex. varfarina ou heparina, desde que não haja evidência anterior de qualquer condição relacionada com estes parâmetros. De acordo com a prática clínica, será efetuada uma monitorização apertada, pelo menos semanalmente, até o valor de INR estabilizar, com medições em pré-dose.
    • Mulheres e Homens férteis, se sexualmente ativos, devem concordar em utilizar contraceção adequada desde que assinam o ICF para a elegibilidade para o tratamento em estudo, até 12 semanas depois da última dose do medicamento em estudo . O Investigador deverá instruir o doente em como fazer uma contraceção efetiva. Uma contraceção efetiva (taxa de falha de menos de 1%) inclui:
    o Contraceção hormonal associada à ovulação combinada (oral, intravaginal, transdermica contendo estrogénio e progesterona) e apenas com progesterona (oral, injetável, implantável).
    o Dispositivo intra-Uterino (DIO) ou Sistema Intra-Uterino (SIU).
    o Oclusão bilateral ou vasectomia do parceiro (desde que o parceiro seja o único parceiro sexual e o sucesso da cirurgia tenha tido confirmação médica)
    o Abstinência sexual (a confiança será avaliada de acordo com a duração do ensaio e com o estilo de vida do doente)
    • Abstinência Peródica (por exemplo, métodos de calendário, ovulação, sintotérmica ou pos-ovulação) e retirada não são métodos contracetivos aceitáveis.
    • Doentes homens com parceiras férteis devem usar um preservativo e assegurar uma forma adicional de contraceção, até às 12 semanas após a última dose do medicamento em estudo.
    • Teste de gravidez negativo, em soro, em todas as mulheres férteis (realizado até 7 dias antes da aleatorização). O resultado negativo deve estar disponível antes da administração da primeira dose do medicamento em estudo.

    E.4Principal exclusion criteria
    Previous or concurrent cancer except:
    cervical carcinoma in situ
    treated basal-cell or squamous cell skin carcinoma
    any cancer curatively treated > 3 years before randomization
    ocuratively treated incidental prostate cancer (T1/T2a)
    Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has no radiological evidence of tumor growth and is clinically stable with respect to the tumor at randomization. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies).
    Known human immunodeficiency virus (HIV) infection.
    Renal dialysis.
    Any malabsorption condition.
    Breast-feeding.
    Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine.
    More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma.
    Ongoing or previous anti-cancer treatment within 4 weeks before randomization:
    Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided at least 5 half-lives (approximately 75 days) have elapsed before randomization.
    Prior cancer vaccines and cellular immunotherapy are permitted.
    Previous radiotherapy is acceptable under the following conditions:
    Therapeutic radiotherapy ≥ 3 weeks before the baseline tumor scan.
    Palliative radiotherapy for bone metastases or soft tissue lesions is allowed and should be completed >7 days prior to baseline tumor scan.
    Lesions at the site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.
    Anti-cancer therapy is defined as any agent or combination of agents with clinically proven anti-tumor activity administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints.
    Use of strong inhibitors and inducers of CYP3A4 (see Appendix 16.1) should have been stopped 2 weeks before randomization.
    Concomitant therapies that are known to increase serum calcium or phosphate levels and cannot be discontinued or switched to a different medication before randomization.
    Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
    Major surgery, or significant trauma within 4 weeks before randomization (central line surgery is not considered major surgery).
    Unresolved toxicity higher than National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/procedure excluding alopecia, anemia and/or hypothyroidism.
    History or current condition of an uncontrolled cardiovascular disease including any of the following conditions:
    Congestive heart failure (CHF) NYHA > Class 2.
    Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization).
    Myocardial infarction (MI) within past 6 months before randomization.
    Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible.
    Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before randomization.
    Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia).
    Current diagnosis of any retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion.
    Active infection with hepatitis B or C, requiring treatment
    Active infections (≥ CTCAE v.4.03 Grade 3)
    Evidence or history of bleeding diathesis or coagulopathy
    Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 weeks before randomization.
    Seizure disorder requiring therapy
    Serious, non-healing wound, ulcer or bone fracture
    Any condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study.
    Inability to swallow oral medications.
    Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
    Previous assignment to study treatment during this study.
    Investigational drug treatment outside of this study during or within 4 weeks before randomization.
    Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site).




    Principais critérios de exclusão:
    • Cancro concomitante ou anterior, exceto
    o carcinoma cervical in situ
    o carcinoma basocelular ou espinocelular tratado
    o qualquer cancro clinicamente tratado > 3 anos antes da aleatorização
    o Carcinoma da próstata incidental clinicamente tratado (T1/T2a)
    • Tumores cerebrais ou meningeais metastáticos e sintomáticos, a menos que tenham passado mais de 6 meses da terapêutica definitiva, não haja evidencia de crescimento tumoral e esteja clinicamente estável na aleatorização relativamente a esse tumor. Também o doente não deverá estar a fazer terapêutica gradual ou aguda com esteroides (terapêutica crónica com esteroides é aceitável desde que a dose seja estável no mês anterior e depois dos estudos radiográficos da triagem).
    • Infeção conhecida por Virus da Imunodeficiência Humana (VIH)
    • Dialise renal
    • Qualquer condição clínica de má absorção.
    • Amamentação
    • Tratamento em curso ou anterior com terapêuticas anti-FGFR (p. ex., inibidores do recetor da tirosina quinase que incluam rogaratinib ou anticorpos específicos do FGFR) ou com taxanos ou vinflunina.
    • Mais de duas linhas prévias de terapêutica anticancerígena sistémica para tratamento do carcinoma urotelial
    • Tratamento anticancerígeno em curso ou anterior nas 4 semanas antes da aleatorização.
    o Doentes que receberam tratamento anterior com anti-CTLA-4 poderão participar desde que pelo menos 5 semividas (aproximandamente 75 dias) tenham ocorrido antes da aleatorização
    o Vacinas oncológicas anteriores anteriores e imunoterapia são permitidas
    o Radioterapia anterior é aceitável nas seguintes condições:
    • Radioterapia terapêutica >= 3 semanas antes da TAC de baseline.
    • Radioterapia paliativa para metástases ósseas ou lesões em tecidos moles é permitida e deve ter terminado >7 dias antes da TAC de baseline.
    • A lesão no local da radioterapia anterior, se for o único local da doença, deverá ter evidência de progressão de doença.
    • A terapêutica anti cancerígena é definida como qualquer medicamento ou combinação de medicamentos que tenham atividade anti tumoral clinicamente comprovada, administrados por qualquer via e com o objetivo de afetar a doença maligna, incluindo enpoints terapêuticos e paliativos.
    • Utilização de inibidores e indutores CYP3A4 deverão ter sido interrompidos2 semanas antes da aleatorização.
    • Terapêutica concomitante conhecida por aumentar os níveis séricos de cálcio ou fosfato e que não possa ser interrompida ou alterada para uma medicação diferente antes da aleatorização.
    • Abuso de substâncias, condições médicas, psicológicas ou sociais que possam interferir na participação do doente no ensaio ou na avaliação dos resultados do ensaio.
    • Cirurgia major ou trauma significativo nas 4 semanas antes da aleatorização (cirurgia de linha central não é considerada major).
    • História
    • Toxicidade não resolvida superior ao Grau 1 dos Critérios de Terminologia Comuns para Eventos Adversos do National Cancer Institute, versão 4.03 (CTCAE v.4.03) atribuída a qualquer terapêutica/procedimento anterior, excluindo alopecia, anemia e/ou hipotiroidismo
    • Antecedentes ou condição atual de uma doença cardiovascular não controlada, incluindo qualquer uma das seguintes:
    o Insuficiência cardíaca congestiva (ICC) > Classe 2 da NYHA
    o Angina instável (sintomas de angina em repouso) ou angina de novo (nos 3 meses anteriores à aleatorização)
    o Enfarte do miocárdio (EM) nos 6 meses anteriores à aleatorização
    o Arritmias cardíacas instáveis que exijam terapêutica antiarrítmica. Os doentes com arritmia controlada com terapêutica antiarrítmica, como os bloqueadores beta ou a digoxina, são elegíveis.
    • Acontecimento de trombose venosa ou arterial ou embolias, tais como acidente vascular cerebral (incluindo ataques isquémicos transitórios), trombose venosa profunda ou embolia pulmonar nos 3 meses anteriores à aleatorização
    • Evidência atual de alteração endócrina da homeostase do cálcio-fosfato (p. ex., doenças das paratiroides, historial de paratiroidectomia, síndrome de lise tumoral, calcinose tumoral, hipercalcemia paraneoplásica)
    • Diagnóstico atual de qualquer descolamento da retina, descolamento do epitélio pigmentar da retina (DEPR), retinopatia serosa ou oclusão da veia da retina
    • Infeção ativa de hepatite B ou C, com necessidade de tratamento
    • Infeções ativas (≥ CTCAE v.4.03 grau 3)
    • Evidência ou antecedentes de diátese hemorrágica ou coagulopatia
    • Qualquer evento de hemorragia/sangramento ≥ Grau 3 CTCAE v.4.03 nas 4 semanas antes da aleatorização
    • Doença convulsiva que necessite tratamento.
    • Ferida grave, úlcera ou fratura óssea não-saráveis
    • Alguma condição instável ou que possa pôr em causa a segurança do doente e a adesão ao estudo
    • Incapacidade de engolir medicamentos orais
    • Hipersensibilidade conhecida aos medicamentos do estudo, à classe de medicamentos do estudo ou a excipientes utilizados na formulação
    • ....
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival is the primary efficacy variable.
    The primary efficacy variable is overall survival (OS). OS data will be considered mature and the final OS analysis (i.e. primary completion) will be performed when approximately a total of 232 PIK3CA and RAS WT patients have died, in accordance with the power calculations specified for the full analysis set (FAS). For the primary efficacy variable of overall survival, a hierarchical fixed-sequence procedure based on stratified log-rank test controlling type I error at a level of 0.025 (one-sided) will be conducted for the WT population first (step 1). A full alpha of 0.025 (one-sided) will be passed on to OS in all study population and some selected secondary endpoints (step 2), if and only if the null hypothesis of OS for WT population is rejected.in the following sequence: step 1) WT population; step 2) all study population. Step 2 will be tested if and only if the null hypothesis of step 1) is rejected. Details on controlling family-wise type I error within step 2 for OS in all study population and selected secondary endpoints will be specified in the Statistical Analysis Plan (SAP).
    In addition, the hazard ratio (rogaratinib / chemotherapy) for OS and its 95% confidence interval will be calculated using the Cox model, stratified by the same factors used for randomization, for both PIK3CA and/or RAS WT and all study population (referred as “both populations” below). Kaplan-Meier (KM) estimates for OS and KM survival curves will also be presented for each treatment arm and both populations. The KM estimates at time points such as 3 months, 6 months etc. together with corresponding 95% confidence intervals as well as the differences of these estimates will also be calculated between the rogaratinib arm and the chemotherapy arm for both populations.


    This study follows a Phase 2/3 design with interim analysis, meaning the patients recruited to the Phase 2 part of the study will automatically continue to the Phase 3 part without interruption if futility is not demonstrated at the 1st interim ORR analysis. The Phase 2 part will end at the time of the cut-off for the 1st interim ORR analysis. To help structure the protocol flow, we present this Phase 2/3 study as one study protocol with two interim analyses, while the first interim indicates the end of the Phase 2 part, and the second and final analyses are considered as the Phase 3 part including Phase 2 patients in the analyses.
    A variável primária é Sobrevivência global (SG; definida como o tempo desde a aleatorização até à morte por qualquer causa).
    A variável de eficácia primária é a sobrevivência global (SG). Considera-se que os dados de SG atingiram a maturidade e será realizada a análise final da SG (ou seja, a conclusão primária) quando aproximadamente um total de 232 doentes com PIK3CA e RAS WT morreram, de acordo com os cálculos de potência especificados para o conjunto de análise completo (CAC). Para a variável de eficácia primária de sobrevivência global, será realizado primeiro um teste de log-rank estratificado que controla o erro de tipo I a um nível de 0,025 (unilateral) para a população WT (passo 1). Um erro alfa completo de 0,025 (unilateral) será transferido para a SG em toda a população em estudo e alguns parâmetros de avaliação final secundários selecionados (passo 2) se, e apenas se, a hipótese zero de SG para a população WT for rejeitada. Os detalhes sobre o controlo do erro de tipo I a nível familiar no passo 2 para a SG em toda a população em estudo e os parâmetros de avaliação final secundários selecionados serão especificados no Plano de Análise Estatística (PAE).
    Além disso, a razão de risco (rogaratinib / quimioterapia) para a SG e o seu intervalo de confiança de 95% serão calculados utilizando o modelo de Cox, estratificado pelos mesmos fatores utilizados para a aleatorização, tanto para a população PIK3CA e RAS WT como para toda a população em estudo (referidas abaixo como “ambas as populações”). Serão também apresentadas estimativas de Kaplan-Meier (KM) para a SG e curvas de sobrevivência de KM para cada braço de tratamento, e para ambas as populações. As estimativas de KM em pontos temporais, tais como 3 meses, 6 meses, etc., juntamente com os intervalos de confiança de 95% correspondentes, bem como as diferenças dessas estimativas serão também calculados entre o braço rogaratinib e o braço quimioterapia, para ambas as populações.
    Este ensaio segue um desenho de Fase 2/3 com análise interina, o que significa que se a futilidade não for demonstrada na 1ª análise interina da TRO, os doentes recrutados na Fase 2 do ensaio passarão automaticamente para a Fase 3, sem interrupções. A Fase 2 terminará no momento do cut-off para a 1ª análise interina da TRO. Para ajudar a estruturar o fluxo do protocolo, apresentamos este ensaio de Fase 2/3 como um protocolo de ensaio com duas análises interinas, no qual a primeira análise interina indica o fim da Fase 2 e a segunda análise e final é considerada a Fase 3, incluindo os doentes da Fase 2 nas análises.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Final OS analysis: at approx. 232 deaths in WT population (approx. 44.9 months after the start of randomization).
    In addition, two interim analyses are planned:
    1st interim ORR analysis (Phase 2 part):
    At approx. the first 116 PIK3CA and RAS WT patients complete 4.5 months of Treatment.
    2nd interim OS analysis (Phase 3 part):
    At approx. 116 deaths in PIK3CA and RAS WT patients (50% of 232 total death events in WT population, approx. 28.7 months after start of randomization).
    Análise final da SG: em aproximadamente 232 mortes na população WT (aprox. 44,9 meses após o início da aleatorização).
    Além disso, estão planeadas duas análises interinas:
    · 1ª Análise interina da TRO (parte de fase 2): em aprox. os primeiros 116 doentes com PIK3CA e RAS WT que completam 4,5 meses de tratamento
    2ª Análise interina da SG (parte de fase 3): em aprox. 116 mortes em doentes com PIK3CA e RAS WT (50% de um total de 232 eventos de morte na população WT, aprox. 28,7 meses após o início da aleatorização)
    E.5.2Secondary end point(s)
    Secondary efficacy variables include PFS, ORR, DCR and DOR based on independent central review assessments.
    Secondary efficacy variables including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) (see Section 9.4 for definitions) will be analyzed based on final database when approximately a total of 232 PIK3CA and RAS WT patients have died.
    The formal testing procedure controlling family-wise type I error of 0.025 as one-sided for PFS and ORR in WT and all study population will be specified in a separate Statistical Analysis Plan (SAP) document. Further analysis details with respect to PFS, ORR, DCR and DOR are summarized below.
    For analyses of PFS, in both populations, the two treatment arms will be compared using a log-rank test stratified by the same stratification factors as used in the analyses of the primary variable, based on independent central review assessments. The hazard ratio (rogaratinib / chemotherapy) and 95% confidence interval will be provided. KM estimates and KM curves will also be presented for each treatment arm. The KM estimates at time points such as 2 months, 4 months etc. together with corresponding 95% confidence intervals as well as the differences of these estimates between the rogaratinib arm and the chemotherapy arm will also be calculated.
    ORR as well as DCR will be compared between treatment arms using the Cochran-Mantel-Haenszel (CMH) test adjusting for the same stratification factors as used in the analyses of the primary variable, based on independent central review assessments for both populations. Estimates and 95% confidence intervals will be computed for each treatment arm. The differences in ORR and DCR between the rogaratinib and chemotherapy arms and the corresponding 95% confidence intervals will also be calculated.
    For both populations, summary statistics will be displayed for all best response categories: CR, PR, SD, Non CR/Non PD, PD by central radiographic imaging, and PD by clinical judgment. Frequency counts and percentages with exact 95% confidence intervals will be displayed.
    Since the responders are not a randomized group, no statistical testing will be performed for DOR. Analysis of DOR will be descriptive in nature for both populations based on central review assessments. KM estimates and KM curves will be displayed for each treatment arm.
    Analyses based on investigator’s review assessments will also be performed for PFS, ORR, DCR and DOR as sensitivity analyses.

    Summary of adverse events (AEs) is considered as a secondary variable objective for the study. Descriptive tables will be presented by treatment arm for both populations. AEs will be summarized by the Medical Dictionary for Regulatory Activities (MedDRA) terms (v.20.0 or later) and worst grade based on the National Cancer Institute (NCI) Common Terminology Criteria Adverse Event (CTCAE), version 4.03. For all events, the relationship to treatment and the severity of the event will be determined by the investigator and summarized by treatment for both populations.

    PRO data as measured by the EORTC QLQ-C30 and EQ-5D will be analyzed to assess differences in health-related Quality of Life (HRQoL) and health utility values between treatment arms based on time-adjusted Area Under the Curve (AUC) using all available data.

    Patients’ biomarker status at baseline will be correlated with treatment effect in OS, PFS and response to explore which biological targets may be particularly important in defining the appropriate therapeutic population for the agent. Biomarker analyses and results will be provided in a separate report.

    Pharmacokinetic variables
    The samples collected on Day 1 of Cycles 1 through 5 at pre-dose and between 0.5 and 1.5 hours post-dose will document a longitudinal exposure under steady state condition. The longitudinal exposure data will be used in exposure-response modelling of adverse events and clinical responses. Evaluation of the data described above will be presented in a separate report. In the clinical study report, only plasma concentration data for all analytes will be listed.
    As variáveis de eficácia secundárias incluem a SLP, TRO, TCD e DR com base nas avaliações da revisão central. As variáveis de eficácia secundárias incluindo a sobrevivência livre de progressão (SLP), a taxa de resposta objetiva (TRO), a taxa de controlo da doença (TCD) e a duração da resposta (DR) serão analizadas na base de dados final quando aproximadamente um total de 232 doentes com PIK3CA e RAS WT tiverem morrido.
    Os detalhes sobre o controlo do erro de tipo I a nível familiar no passo 2 para a SG em toda a população em estudo e os parâmetros de avaliação final secundários selecionados serão especificados no Plano de Análise Estatística (PAE).
    São sumarizados em baixo mais detalhes da análise no que diz respeito a SLP, TRO, TCD e DR.
    Para as análises de SLP, em ambas as populações, os dois braços de tratamento serão comparados usando um teste de log-rank estratificado da mesma forma que que os fatores usados nas análises da variável primária, com base nas avaliações da revisão central. A razão de risco (rogaratinib / quimioterapia) e o intervalo de confiança de 95% serão calculados. Estimativas e curvas de KM serão também apresentadas para cada braço de tratamento. As estimativas de KM aos 2 meses, aos 4meses, etc. em conjunto com o intervalo de confiança correspondente de 95%, assim como as diferenças entre as estimativas entre o braço de rogaratinib e a quimiotrapia serão também calculadas.
    A TRO assim como a TCD serão comparadas entre os braços de tratamento usando um teste Cochran-Mantel-Haenszel (CMH) ajustado aos mesmos fatores de estratificação usados nas análises da variável primária, com base nas avaliações da revisão central para as duas populações. As estimativas e intervalos de 95% de confiança serão calculados para cada braço de tratamento. As diferenças em TRO e TCD entre os braços de rogaratinib e da quimioterapia e os correspondentes intervalos de confiança de 95% serão calculados.
    Para ambas as populações, serão apresentadas estatísticas sumário para as melhores categorias de resposta: CR, PR, SD, Não CR/ Não PD, PD por avaliação centrao das imagens e PD por decisão clínica. Contagem de frequência e percentagens com intervalos de confiança de 95% exatos serão apresentados. Uma vez que os respondedores não são um grupo aleatorizado, não será realizado nenhum teste estatístico para a DR. A análise da DR será de natureza descritiva para as duas populações, com base nas avaliações centrais. As estimativas e curvas KM serão apresentadas para cada braço de tratamento.
    Serão feitas análises de SLP, TRO, TCD e DR baseadas nas avaliações feitas pelos Investigadores, como análises de sensibilidade.

    O resumo dos eventos adversos (EA) é considerado um objetivo secundário do ensaio. Serão apresentadas tabelas descritivas por braço de tratamento para ambas as populações. Os EA serão resumidos de acordo com os termos do Dicionário Médico para Atividades Regulamentares (MedDRA; v.20.0 ou posterior) e o pior grau com base na versão 4.03 dos Critérios de Terminologia Comuns para Eventos Adversos (CTCAE) do National Cancer Institute (NCI). Para todos os eventos, a relação com o tratamento e a gravidade do evento serão determinadas pelo investigador e resumidas por tratamento, para ambas as populações.
    Os resultados referidos pelo doente serão medidos utilizando os questionários QLQ-C30 e EQ-5D-3L da EORTC serão analizadospara avaliar as diferenças na Qualidade de Vida relacionada com a saúde (HRQoL) e os valores de utilidade de saúde entre os braços de tratamento baseados na Area Under The Curve (AUC) ajustada ao tempo usando todos os dados disponíveis.
    O estado dos biomarcadores na baseline será correlacionado com o efeito do tratamento na SG, SLP e resposta para explorar quais os alvos biológicos poderão ser particularmente importantes na definição da população apropriada ao tratamento com o agente. As análises de biomarcadores e e os resultados serão fornecidos num relatório separado.

    Variáveis de Farmacocinética
    As amostras colhidas no Dia 1 dos Ciclos 1 a 5 em pré-dose e entre 0.5 e 1.5 horas pós dose vão documentar a exposição longitudinal numa condição estacionária. Os dados da exposição longitudinalvão ser usados em modelos de resposta-exposição dos eventos adversos e das respostas clínicas. A avaliação dos dados acima descritos será apresentada num relatório separado. No relatório do ensaio clínico serão apresentados apenas os dados de concentração no plasma para todos os parametros serão listados.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy variables will be analyzed based on final database when approximately a total of 232 PIK3CA and RAS WT patients have died (approx. 44.9 months after the start of randomization).
    As variáveis secundárias de eficácia serão analisadas com base no banco de dados final quando aproximadamente um total de 232 pacientes PIK3CA e RAS WT tiverem falecido (aproximadamente 44,9 meses após o início da randomização).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    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 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 EEA107
    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
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hong Kong
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Democratic People's Republic of
    Netherlands
    Poland
    Portugal
    Russian Federation
    Singapore
    Slovakia
    Spain
    Sweden
    Switzerland
    Taiwan
    United Kingdom
    United States
    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
    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
    The end of the study as a whole will be reached when the last visit of the last patient has been achieved in all participating centers (EU and non-EU), or the primary completion event has been reached, whichever comes later.
    Para cada país da UE participante, o final do estudo de acordo com a directiva da avaliação clínica da UE será alcançada quando a última visita do último paciente para todos os centros no país respectivo.
    O final do estudo como um todo será alcançado quando a última visita do último paciente foi alcançado em todos os centros participantes (UE e não-UE), ou quando for alcançado o endpoint primário, o que acontecer primeiro.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days11
    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: 976
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 651
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 925
    F.4.2.2In the whole clinical trial 1627
    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)
    None
    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 Decision2018-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-02
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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