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    Summary
    EudraCT Number:2017-004293-33
    Sponsor's Protocol Code Number:RPC01-3202
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-27
    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 number2017-004293-33
    A.3Full title of the trial
    Induction Study #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Oral Ozanimod as Induction Therapy for Moderately to Severely Active Crohn¿s Disease
    Estudo de Indução n.º 2 - Estudo de fase 3, multicêntrico, aleatorizado, com dupla ocultação e controlado com placebo de ozanimod oral como terapêutica de indução para a doença de Crohn ativa moderada a grave
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Multicenter Study of Oral Ozanimod as Induction Therapy in patients with Moderately to Severely Active Crohn¿s Disease
    Estudo multicêntrico de Ozanimod oral como terapêutica de indução em doentes com doença de Crohn ativa moderada a grave.
    A.4.1Sponsor's protocol code numberRPC01-3202
    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 SponsorCelgene International II Sàrl
    B.1.3.4CountrySwitzerland
    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 supportCelgene International II Sàrl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationReceptos Services, LLC
    B.5.2Functional name of contact pointKeath Usiskin
    B.5.3 Address:
    B.5.3.1Street AddressRue du Pré-Jorat 14
    B.5.3.2Town/ cityCouvet
    B.5.3.3Post code2108
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+1908 897 6550
    B.5.6E-mailkusiskin@celgene.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 nameozanimod
    D.3.2Product code RPC1063 (equivalent to ozanimod HCl)
    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 INNOzanimod
    D.3.9.3Other descriptive nameOZANIMOD
    D.3.9.4EV Substance CodeSUB181335
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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 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 nameozanimod
    D.3.2Product code RPC1063 (equivalent to ozanimod HCl)
    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 INNOzanimod
    D.3.9.3Other descriptive nameOZANIMOD
    D.3.9.4EV Substance CodeSUB181335
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderately to Severely Active Crohn¿s Disease
    Doença de Crohn ativa moderada a grave
    E.1.1.1Medical condition in easily understood language
    Crohn¿s Disease
    Doença de Crohn
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10011401
    E.1.2Term Crohn's disease
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Demonstrate the efficacy of ozanimod compared to placebo on the induction of clinical remission
    Demonstrar a eficácia de ozanimod em comparação com o placebo na indução da remissão clínica.
    E.2.2Secondary objectives of the trial
    - Demonstrate the efficacy of ozanimod compared to placebo on induction of clinical response, endoscopic response, endoscopic remission, and histologic improvement
    - Evaluate the efficacy of ozanimod compared to placebo, in subjects who had previously received biologic therapy (eg, anti-IL-12, anti-IL-23, anti-TNF, or anti-integrin therapy)
    - Demonstrate the efficacy of ozanimod compared to placebo on the induction of clinical remission and clinical response in adolescent subjects (aged 12 to 17 years, inclusive)
    - Characterize the population pharmacokinetics (PK) and PK/pharmacodynamics (PD) relationship of ozanimod
    - Demonstrate the safety and tolerability of ozanimod as induction therapy
    ¿ Demonstrar a eficácia de ozanimod em comparação com o placebo na indução da
    resposta clínica, da remissão clínica, da resposta endoscópica, da remissão endoscópica e da melhoria histológica
    ¿ Demonstrar a eficácia de ozanimod em comparação com o placebo, em indivíduos que receberam terapêutica biológica prévia (por ex., terapêutica anti-IL-12, anti-IL-23, anti-TNF ou anti-integrina)
    ¿ Caracterizar a farmacocinética (PK) da população e a relação PK/farmacodinâmica (PD) de ozanimod
    ¿ Demonstrar a segurança e a tolerabilidade de ozanimod como terapêutica de indução
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A twenty-four (24)-hour ambulatory blood pressure monitoring substudy will be conducted on a total of approximately 75 adult subjects (~50 active and ~25 placebo subjects) at selected sites, with assessments at 24 hours pre-baseline (i.e. between Screening and before Day 1) and 24 hours post-dose on Day 8. At these participating sites, monitoring will be hourly during the day and every two hours at night. Heart rate will also be assessed throughout the 24 hour period at both time points (i.e. prebaseline and day 8). Paper diary will be used to collect information on all subjects during the 24 hour period for symptoms associated with changes in blood pressure.
    E.3Principal inclusion criteria
    1. Male or female subjects aged 12 to 75 years (at Screening), inclusive with adolescents (12 to 17) with a body weight ≥ 45 kg
    2. Note: Countries or sites with local restrictions that prohibit enrollment of adolescents (aged 12 to 17 years) will only enroll subjects who are 18 years of age or older. Enrollment of adolescent subjects will begin only after the applicable regulatory requirements for enrolling subjects in that age group have been satisfied and the necessary health authority agreements have been granted. Where national or regional guidelines for the definition of adolescence differ from the definition stated above, the national or regional guidelines may be used to determine eligibility. Subjects should not have any constraints under local regulations and must provide written informed consent prior to any study-related procedures, and have the ability to comply with the Table of Events. For adolescents, a parent/legal guardian of the adolescent must sign the informed consent form. In addition, adolescent subjects must also agree to participate in the study by signing an assent form. A parent or guardian must be willing to supervise adherence to the protocol requirements. Adolescent subjects who reach the legal age of consent while participating in the study will be asked to sign an ICF themselves to acknowledge their willingness to continue in the study.
    3. Subject has signs and symptoms consistent with a diagnosis of CD for at least 3 months (prior to first IP administration). The diagnosis should be confirmed by clinical and endoscopic evidence and corroborated by a histology report. (Note: endoscopy and histopathology confirmation may be obtained during Screening if no prior report is readily available).
    4. Subject has met each of the following 2 criteria:
    ¿ a CDAI score ¿ 220 and ¿ 450
    ¿ an average daily stool frequency ¿ 4 points and/or an abdominal pain of ¿ 2 points
    5. Subject has a SES-CD score of ¿ 6 (or SES-CD ¿ 4 in subjects with isolated ileal disease).
    6. Subject has an inadequate response or loss of response to or is intolerant of at least 1 of
    the following CD treatments: corticosteroids, immunomodulators, biologic therapy (eg, ustekinumab, TNF¿ antagonists, or vedolizumab)
    7. If the subject is taking the following background therapies for CD, a stable dose must be maintained as indicated below:
    ¿ oral aminosalicylates (eg, mesalamine, sulfasalazine, olsalazine, balsalazide) with a stable dose for at least 3 weeks prior to Screening endoscopy
    ¿ prednisone (doses ¿ 20 mg per day) or equivalent with a stable dose for at least 2 weeks prior to Screening endoscopy
    ¿ budesonide therapy (doses ¿ 9 mg per day) or beclomethasone doses ¿ 5 mg/day at a stable dose for at least 2 weeks prior to the Screening endoscopy
    8. Subject at high risk (ie, family history, CD duration) for colonic malignancy has documented evidence of having had a surveillance colonoscopy within the last 2 years or according to local and national medical guidelines to evaluate for polyps, dysplasia, or malignancy. If there is no recent history of surveillance colonoscopy, this can be done as part of the colonoscopy performed during Screening. Any visualized adenomatous polyps must be removed and any suspicious lesion confirmed free of cancer and/or dysplasia prior to randomization.
    9. Female subjects of childbearing potential (FCPB):
    Note: For the purposes of this study, a female patient is considered to be of childbearing potential if she is ≥ 12 years of age or has reached menarche, whichever occurred first, and 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been postmenopausal for at least 24 consecutive months (that is, has had menses at any time during the preceding 24 consecutive months). Must agree to practice a highly effective method of contraception throughout the study until completion of the 90-day Safety Follow-Up Visit. Examples of effective methods of contraception are those that alone or in combination result in a failure rate of a Pearl Index of less than 1% per year when used consistently and correctly. Periodic abstinence (calendar, symptothermal, post-ovulation methods),
    withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted for FCBP. The Investigator will educate all FCBP about the different options of contraceptive methods or abstinence at Screening and Day 1, as appropriate. The FCBP's chosen form of contraception must be
    effective by the time she is randomized into the study.
    10. Subjects must have documentation of positive varicella zoster virus (VZV) immunoglobulin G (IgG) antibody status or complete VZV vaccination at least 30 days prior to randomization.
    1. Indivíduos do sexo masculino ou do sexo feminino com idades entre 18 e 75 anos (na selecção), inclusive
    2. O indivíduo tem de dar consentimento informado por escrito antes de quaisquer procedimentos relacionados com o estudo e tem de ter capacidade para cumprir a Tabela de Procedimentos.
    3. O indivíduo tem sinais e sintomas compatíveis com um diagnóstico de DC durante pelo menos 3 meses (antes da primeira administração do ME). O diagnóstico deve ser confirmado por evidência clínica e endoscópica e confirmado por um relatório histológico. (Nota: a confirmação por endoscopia e histopatologia pode ser obtida durante a selecção, caso não esteja imediatamente disponível um relatório anterior).
    4. O indivíduo cumpra cada um dos 2 critérios seguintes:
    ¿ uma pontuação do CDAI ¿ 220 e ¿ 450
    ¿ uma frequência de fezes diária média ¿ 4 pontos e/ou uma dor abdominal ¿ 2 pontos
    5. O indivíduo tem uma pontuação da SES-CD ¿ 6 (ou SES-CD ¿ 4 em indivíduos com doença ileal isolada).
    6. O indivíduo apresente uma resposta inadequada ou perda de resposta ou seja intolerante a pelo menos 1 dos seguintes tratamentos para a DC:
    ¿ corticosteróides
    ¿ imunomoduladores
    ¿ terapêutica biológica (por ex., ustecinumab, antagonistas do TNF¿ ou vedolizumab)
    7. Se o indivíduo estiver a fazer as seguintes terapêuticas de basepara a DC, tem de se encontrar a fazer uma dose estável, como indicado abaixo:
    ¿ aminosalicilatos orais (por ex., mesalamina, sulfasalazina, olsalazina, balsalazida) com uma dose estável durante pelo menos 3 semanas antes da endoscopia da selecção
    ¿ prednisona (doses ¿ 20 mg por dia) ou equivalente com uma dose estável durante pelo menos 2 semanas antes da endoscopia da selecção
    ¿ terapêutica com budesonida (doses ¿ 9 mg por dia) ou doses de beclometasona ¿
    5 mg/dia com uma dose estável durante pelo menos 2 semanas antes da endoscopia da selecção
    8. Indivíduo com risco elevado (ou seja, história familiar, duração da DC) de neoplasia no cólon com evidência documentada de ter realizado uma colonoscopia de vigilância nos últimos 2 anos ou de acordo com as orientações médicas locais e nacionais para avaliar a existência de pólipos, displasia ou neoplasia. Caso não exista história recente de colonoscopia de vigilância, esta pode ser realizada como parte da colonoscopia efetuada durante a selecção. Quaisquer pólipos adenomatosos visualizados têm de ser removidos e qualquer lesão suspeita tem de ser confirmada como estando isenta de cancro e/ou displasia antes da aleatorização.
    9. Indivíduos do sexo feminino em idade fértil:
    Têm de aceitar utilizar um método de contracepção altamente eficaz durante todo o estudo até à conclusão da consulta de acompanhamento de segurança. Os métodos de contracepção altamente eficazes são os que, isolados ou em combinação, resultam numa taxa de insucesso do Índice de Pearl inferior a 1% ao ano quando utilizados de forma consistente e correta. Os métodos aceitáveis de controle de natalidade no estudo são os seguintes:
    ¿ contracepção hormonal combinada (com estrogénio e progestagénio), que poderá ser oral, intravaginal ou transdérmica
    ¿ contracepção hormonal apenas com progestagénio associada a inibição da ovulação, que poderá ser oral, injetável ou implantável
    ¿ colocação de um dispositivo intrauterino (DIU)
    ¿ colocação de um sistema intrauterino libertador de hormonas (SIU)
    ¿ laqueação bilateral das trompas
    ¿ parceiro vasectomizado
    ¿ abstinência sexual
    Indivíduos do sexo masculino:
    Têm de aceitar utilizar um preservativo de látex durante o contacto sexual com mulheres em idade fértil enquanto participarem no estudo até à conclusão da consulta de acompanhamento de segurança.
    Todos os indivíduos:
    10. A abstinência periódica (os métodos do calendário, sintotérmicos e pós-ovulação), o coito
    interrompido, apenas espermicidas e o método da amenorréia lactacional não são métodos de contracepção aceitáveis. Os preservativos femininos e masculinos não devem ser utilizados em conjunto.Os indivíduos têm de dispor de documentação sobre o estado do anticorpo da imunoglobulina G (IgG) do vírus da varicela zoster (VZV) positivo ou vacinação completa anti-VZV pelo menos 30 dias antes da aleatorização.
    E.4Principal exclusion criteria
    1. Subject has any clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric, or other major systemic disease making implementation of the protocol or interpretation of the study difficult or that would put the subject at risk by participating in the study. 2. Subject is likely to require, in the physician's judgment, bowel resection within 12 weeks of entry into the study. 3. Subject has a diagnosis of UC, indeterminate colitis, radiation colitis, or ischemic colitis, or has strictures with prestenotic dilatation. 4. Subject has current stoma, ileal-anal pouch anastomosis, fistula that is likely to require surgical or medical intervention within 12 weeks of entry into the study or need for ileostomy or colostomy. 5. Subject has extensive small bowel resection (> 100 cm) or known diagnosis of short bowel syndrome, or subject requires total parenteral nutrition. 6. Subject has suspected or diagnosed intra-abdominal or perianal abscess that has not been appropriately treated. 7. Documentation of a positive test for toxin producing C. difficile, or PCR examination of the stool on their most recent test, which must have been done in the past 60 days. 8. Documentation of positive examination for pathogens 9. Subject is pregnant, lactating, or has a positive serum ß-hCG measured during Screening. 10. Any condition that would make implementation of the protocol or interpretation of the study difficult 11. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c (HbA1c) > 9%, or is a diabetic subject with significant comorbid conditions such as retinopathy or nephropathy. 12. History of uveitis or clinically confirmed diagnosis of macular edema. 13. Known active bacterial, viral, fungal, mycobacterial infection (including tuberculosis or atypical mycobacterial disease), or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of Screening or oral antibiotics within 14 days of Screening. 14. History or known presence of recurrent or chronic infection (eg, hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV]); recurrent urinary tract infections are allowed. 15. Subject has a history of active cancer within 5 years, including solid tumors and hematological malignancies or colonic dysplasia that has not been completely removed 16. Subject has a history of alcohol or drug abuse within 1 year prior to initiation of Screening 17. Hypersensitivity to active ingredients or excipients of ozanimod or placebo. 18. Prior participation in an ozanimod clinical study 19. Subject has a history of primary nonresponse to 2 or more approved biologic agents or has been treated with 4 or more biologics for CD 20. Subject has been treated with a biologic agent within 8 weeks or 5 elimination half-lives (whichever is shorter) prior to the first dose of IP 21. Subject has a history of treatment with an investigational agent within 5 elimination half-lives of that agent prior to the first dose of IP 22. Subject has received a live or live attenuated vaccine within 4 weeks prior to the first dose of IP 23. Subject has received previous treatment with lymphocyte-depleting therapies 24. Subject has received previous treatment with D-penicillamine, leflunomide, orthalidomide 25. Subject has received previous treatment with natalizumab or fingolimod or other S1P receptor modulators 26. Subject has received previous treatment with oral cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 16 weeks of initiation of Screening 27. Subject has a history of treatment with IVIg, or plasmapheresis within 3 months prior to first dose of IP 28. Subject has discontinued oral 5-ASA or corticosteroids within 2 weeks prior to the screening endoscopy. 29.Subject has received rectal therapy within 2 weeks of screening endoscopy or has planned concurrent use of any per rectum therapy. 30. Subject has planned concurrent treatment with immunomodulatory agents after randomization. Subjects receiving azathioprine, 6-MP, or methotrexate at screening must discontinue treatment with these agents prior to first dose of IP 31. Subject has chronic nonsteroidal anti-inflammatory drug (NSAID) use 32. Subject is receiving treatment with Class Ia or Class III anti-arrhythmic drugs or with 2 or more agents in combination known to prolong PR interval. 33. Subject receiving treatment with breast cancer resistance protein (BCRP) inhibitors (eg, cyclosporine, eltrombopag). 34. Subject has received cholestyramine or other drugs interfering with enterohepatic circulation within 3 weeks of screening 35. Subject is receiving treatment with any of the following drugs or interventions within the corresponding timeframe:
    - At randomization o CYP2C8 inhibitors and inducers
    - Two weeks prior to randomization o Monoamine oxidase inhibitor
    Exclusions Related to Laboratory Results: Please see the protocol
    1. O indivíduo apresenta uma qualquer doença hepática, neurológica, pulmonar, oftalmológica, endócrina, psiquiátrica clinicamente relevante ou outra doença sistémica significativa que dificulte a implementação do protocolo ou a interpretação do estudo ou que coloque o indivíduo em risco por participar no estudo. 2. É provável que o indivíduo necessite, na opinião do médico, de ressecção intestinal no prazo de 12 semanas após a inclusão no estudo. 3. O indivíduo apresenta um diagnóstico de colite ulcerosa, colite indeterminada, colite devido a radiação ou colite isquémica ou apresenta estrituras ou estenoses conhecidas que possam conduzir a sintomas de obstrução. 4. O indivíduo apresenta estoma atual, anastomose ileo-anal com bolsa, fístula sintomática com drenagem de pus com probabilidade de vir a necessitar, na opinião do médico, de intervenção cirúrgica ou médica no prazo de 12 semanas após a inclusão no estudo ou necessidade de ileostomia ou colostomia. 5. O indivíduo apresenta uma extensa ressecção do intestino delgado (> 100 cm) ou diagnóstico conhecido de síndrome do intestino curto ou o indivíduo necessita de nutrição parentérica total.
    6. O indivíduo apresenta suspeita ou diagnóstico de abcesso intra-abdominal ou perianal que não foi tratado adequadamente. 7. O indivíduo dispõe de documentação de um teste positivo para Clostridium difficile (C. difficile) produtor de toxinas ou exame da reacção em cadeia da polimerase (PCR) das fezes no teste mais recente, que deve ter sido realizado nos últimos 60 dias. Caso seja positivo, os indivíduos podem ser tratados e novamente testados não antes de 7 dias após a conclusão do tratamento. 8. O indivíduo apresenta documentação de um exame positivo para agentes patogénicos (ovos, parasitas e bactérias), o que deve ter sido efetuado nos últimos 60 dias. Caso seja positivo, os indivíduos podem ser tratados e testados novamente. 9. A pessoa em questão está grávida, em lactação ou apresenta soro positivo para beta-gonadotrofina coriónica humana (ß-hCG) medida durante a selecção. 10. O indivíduo apresenta doenças cardiovasculares clinicamente relevantes, dificultando a implementação do protocolo ou a interpretação do estudo ou que coloque o indivíduo em risco ao participar no estudo, incluindo história ou presença do seguinte:
    ¿ Ocorrência recente (nos últimos 6 meses) de enfarte do miocárdio, angina instável, AVC, acidente isquémico transitório, insuficiência cardíaca descompensada com necessidade de hospitalização, insuficiência cardíaca de Classe III/IV, disfunção do nó sinusal ou apneia do sono grave não tratada
    ¿ Bloqueio atrioventricular (AV) de segundo grau ou bloqueio cardíaco de terceiro grau, excepto doentes com pacemaker
    ¿ QT prolongado corrigido para frequência cardíaca utilizando o intervalo da fórmula de Fridericia (QTcF), (QTcF > 450 ms nos indivíduos do sexo masculino, > 470 ms nos indivíduos do sexo feminino)
    ¿ Frequência cardíaca (FC) em repouso <55 bpm na medição dos sinais vitais como parte do exame físico na selecção.
    11. O indivíduo apresenta história de diabetes mellitus tipo 1 ou diabetes mellitus tipo 2 descontrolada com hemoglobina A1c (HbA1c) > 9% ou é diabético com comorbidadess significativas, tais como retinopatia ou nefropatia. 12. O indivíduo tem uma história de uveíte (no último ano antes da selecção) ou diagnóstico clinicamente confirmado de edema macular. 13. O indivíduo apresenta uma infeção bacteriana, viral, fúngica, micobacteriana ativa conhecida ou outra infeção (incluindo tuberculose ou doença micobacteriana atípica [excluindo infeção fúngica dos leitos ungueais, infeções menores do trato respiratório superior e infeções cutâneas menores]) ou qualquer episódio significativo de infeção que tenha necessitado de hospitalização ou tratamento com antibióticos intravenosos (IV) até 30 dias antes da selecção ou de antibióticos orais até 14 dias antes da selecção.
    14. História ou presença conhecida de infeção recorrente ou crónica (por ex., vírus da hepatite B [HBV], vírus da hepatite C [HCV], vírus da imunodeficiência humana [VIH]); são permitidas infeções recorrentes do trato urinário. 15. O indivíduo tem uma história de cancro ativo nos últimos 5 anos, incluindo tumores sólidos e neoplasias hematológicas (excepto carcinomas das células basais e das células escamosas in situ da pele ou displasia/cancro do colo do útero que tenha sido excisado e resolvido); ou displasia do cólon que não tenha sido completamente removida.
    16. O indivíduo tem uma história de abuso de álcool ou drogas no prazo de 1 ano antes do início da selecção. 17. Hipersensibilidade aos ingredientes ativos ou aos excipientes do ozanimod ou do placebo. 17. Hipersensibilidade aos ingredientes ativos ou aos excipientes do ozanimod ou do placebo.18. O indivíduo tem uma história de ausência de resposta primária para 2 ou mais terapêuticas biológicas aprovadas utilizadas no tratamento da DC.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects with a CDAI score < 150 at Week 12
    Proporção de indivíduos com uma pontuação do CDAI < 150 na semana 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Subjects will be deemed a responder with respect to this endpoint if they meet the definition for CDAI Clinical Remission at Week 12.
    Os indivíduos serão considerados respondedores em relação a este parâmetro de avaliação se cumprirem a definição CDAI para a Remissão Clínica na Semana 12.
    E.5.2Secondary end point(s)
    Major Secondary Endpoints:
    - Proportion of subjects with average daily abdominal pain score ¿ 1 point, and average daily stool frequency score ¿ 3 points with abdominal
    pain and stool frequency no worse than baseline at Week 12
    - Proportion of subjects with a Simple Endoscopic Score for Crohn¿s Disease (SES-CD) score decrease from baseline of ¿ 50% at Week 12
    - Proportion of subjects with CDAI reduction from baseline of ¿ 100 points or CDAI score < 150 at Week 12
    - Proportion of subjects with CDAI reduction from baseline of ¿ 100 points or CDAI score < 150 and SES-CD decrease from baseline of ¿ 50% at Week 12
    Principais parâmetros de avaliação secundários:
    ¿ Proporção de indivíduos com uma pontuação de dor abdominal diária, média ¿ 1 ponto e uma pontuação de frequência de fezes diária, média ¿ 3 pontos e uma pontuação de frequência de fezes, não pior, do que no início do estudo na semana 12
    ¿ Proporção de indivíduos com uma diminuição da Pontuação Endoscópica Simples para a Doença de Crohn (SES-CD) em relação ao início do estudo ¿ 50% na semana 12
    ¿ Proporção de indivíduos com redução do CDAI em relação ao início do estudo ¿ 100 pontos ou pontuação do CDAI < 150 na semana 12
    ¿ Proporção de indivíduos com redução do CDAI em relação ao início do estudo ¿ 100 pontos ou pontuação do CDAI < 150 e diminuição da SES-CD em relação ao início do estudo ¿ 50% na semana 12
    E.5.2.1Timepoint(s) of evaluation of this end point
    at Week 12
    na semana 12
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA109
    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
    Bulgaria
    Canada
    China
    Finland
    France
    Georgia
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Korea, Republic of
    Lithuania
    Mexico
    Netherlands
    Poland
    Portugal
    Russian Federation
    Saudi Arabia
    Serbia
    Singapore
    Slovakia
    Slovenia
    South Africa
    Spain
    Sweden
    Turkey
    Ukraine
    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
    The end of study is defined as either the date of the last visit of the last subject to complete the safety follow-up, or the date of receipt of the last datapoint from the last subject that is required for primary or secondary analysis, as prespecified in the protocol, whichever is the later date.
    O final do estudo é definido como a data da última consulta do último indivíduo a concluir o acompanhamento de segurança ou a data de recepção do último ponto de dados do último indivíduo, necessário para a análise primária ou secundária, conforme especificado previamente no protocolo, o que ocorrer mais tarde.
    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 months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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 Yes
    F.1.1Number of subjects for this age range: 30
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 585
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 251
    F.4.2.2In the whole clinical trial 675
    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)
    Subjects will be entering the Maintenance Study or Open-label Extension Study. If not entering these studies they will have a Safety Follow-Up Visit (30 to 90 days after the last dose of IP).
    Os indivíduos entrarão no Estudo de Manutenção ou no Estudo de Extensão Aberto. Se não entrarem nestes estudos, realizarão uma consulta de acompanhamento de segurança (30 a 45 dias após a última dose do medicamento experimental [ME])
    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 Decision2018-05-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-06
    P. End of Trial
    P.End of Trial StatusOngoing
    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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