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    Summary
    EudraCT Number:2014-002981-64
    Sponsor's Protocol Code Number:CC-10004-UC-001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-11-05
    Trial results View 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-002981-64
    A.3Full title of the trial
    A Phase 2, randomized, placebo-controlled, multicenter study to investigate the efficacy and safety of apremilast (CC-10004) for treatment of subjects with active ulcerative colitis
    Studio di fase 2, randomizzato, controllato con placebo, multicentrico per valutare l¿efficacia e la sicurezza di Apremilast (CC-10004) per il trattamento di soggetti con colite ulcerosa attiva
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial that will compare the efficacy and safety of apremilast versus placebo, in patients with active ulcerative colitis, a chronic inflammatory of the colon of unknown origin
    Studio clinico per mettere a confronto l'efficacia e la sicurezza di apremilast rispetto al placebo in pazienti affetti da colite ulcerosa attiva, un'infiammazione cronica del colon di origine sconosciuta
    A.3.2Name or abbreviated title of the trial where available
    na
    na
    A.4.1Sponsor's protocol code numberCC-10004-UC-001
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN00000000
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00000000
    A.5.3WHO Universal Trial Reference Number (UTRN)U0000-0000-0000
    A.5.4Other Identifiers
    Name:INDNumber:119696
    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 CORPORATION
    B.1.3.4CountryUnited States
    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 Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018882601599
    B.5.5Fax number0019132663094
    B.5.6E-mailClinicalTrialDisclosure@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 nameApremilast
    D.3.2Product code CC-10004
    D.3.4Pharmaceutical form 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 INNAPREMILAST
    D.3.9.1CAS number 608141-41-9
    D.3.9.2Current sponsor codeCC-10004
    D.3.9.3Other descriptive nameAPREMILAST
    D.3.9.4EV Substance CodeSUB130837
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 nameApremilast
    D.3.2Product code [CC-10004]
    D.3.4Pharmaceutical form 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 INNApremilast
    D.3.9.1CAS number 608141-41-9
    D.3.9.2Current sponsor codeCC-10004
    D.3.9.3Other descriptive nameAPREMILAST
    D.3.9.4EV Substance CodeSUB130837
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameApremilast
    D.3.2Product code CC-10004
    D.3.4Pharmaceutical form 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 INNAPREMILAST
    D.3.9.1CAS number 608141-41-9
    D.3.9.2Current sponsor codeCC-10004
    D.3.9.3Other descriptive nameAPREMILAST
    D.3.9.4EV Substance CodeSUB130837
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Subjects with active ulcerative colitis
    Soggetti affetti da colite ulcerosa attiva
    E.1.1.1Medical condition in easily understood language
    Ulcerative colitis is a chronic inflammatory condition of the colon of unknown origin, that is characterized by bloody diarrhea and pain in the lower abdomen.
    La colite ulcerosa ¿ una condizione infiammatoria cronica del colon di origine sconosciuta, caratterizzata da diarrea sanguinolenta e dolori al basso addome.
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045365
    E.1.2Term Ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the clinical efficacy of
    apremilast (30 mg BID and 40 mg BID), compared with placebo, in
    subjects with active ulcerative colitis (UC).
    L'obiettivo primario dello studio ¿ valutare l'efficacia clinica di
    apremilast (30 mg BID e 40 mg BID), rispetto al placebo in soggetti affetti da colite ulcerosa attiva (UC).
    E.2.2Secondary objectives of the trial
    The secondary objective of the study is to evaluate the safety and
    tolerability of apremilast (30 mg BID and 40 mg BID), compared with
    placebo, in subjects with active UC.
    L'obiettivo secondario dello studio ¿ valutare la sicurezza e la tollerabilit¿ di apremilast (30 mg BID e 40 mg BID), rispetto al placebo, nei soggetti con UC attiva.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must satisfy the following criteria to be enrolled in the study:
    1. Male or female aged 18 and over at the time of signing the informed consent.
    2. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
    3. Must be able to adhere to the study visit schedule and other protocol requirements.
    4. Diagnosis of UC with a duration of at least 3 months prior to the Screening Visit
    5. TMS = 6 to = 11 (range: 0-12) prior to randomization in the study.
    6. Endoscopic subscore = 2 (range: 0-3) on the Mayo score
    prior to randomization in the study.
    7. Subjects are required to have a colonoscopy if not performed within 12 months of the Screening Visit.
    8. Subjects must have had a therapeutic failure, been intolerant to, or have a contraindication to, at least one of the following: oral aminosalicylates (ie, 5-aminosalicylic acid [5-ASA] compounds or sulfasalazine [SSZ]), budesonide, systemic corticosteroids, or immunosuppressants (eg, 6 mercaptopurine [6 MP], azathioprine [AZA], or methotrexate [MTX]).
    9. 8.9. Subjects receiving oral corticosteroids may continue their use during the study, provided that the dose (prednisone = 20 mg/day or equivalent, budesonide = 9 mg/day) has been stable for 3 weeks prior to the Screening Visit. If oral corticosteroids were recently discontinued, discontinuation must have been completed at least 3 weeks prior to the Screening Visit. Corticosteroid doses should remain stable until the subject is eligible to start corticosteroids tapering, beginning at the Week 12 Visit.
    10. Oral aminosalicylates are permitted during the study, provided that treatment started at least 6 weeks prior to screening with a stable dose of at least 14 days prior to the Screening Visit. The dose of oral aminosalicylates must remain stable through Week 52 or early termination from the study.
    11. Must meet the following laboratory criteria:
    • White blood cell count = 3000/mm3 (= 3.0 X 109/L) and < 14,000/mm3
    (< 14 X 109/L)
    • Platelet count = 100,000/mm3 (= 100 X 109/L)
    • Serum creatinine = 1.5 mg/dL (= 132.6 µmol/L)
    • AST (SGOT) and ALT (SGPT) ¿ 2 X upper limit of normal (ULN). If initial test shows ALT or AST > 2 times the ULN, one repeat test is allowed during the screening period
    • Total bilirubin = 2 mg/dL (= 34 µmol/L) or albumin > lower limit of normal (LLN). If initial test result is > 2 g/dL, one repeat test is allowed during the screening period
    • Hemoglobin = 9 g/dL (= 5.6 mmol/L)
    12. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and the Baseline Visit. While on IP and for at least 28 days after taking the last dose of IP, FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below:
    Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner’s vasectomy
    OR
    Option 2: Male or female condom (latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]; PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide
    13. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on investigational product and for at least 28 days after the last dose of investigational product.
    Per essere arruolati nello studio, i soggetti devono soddisfare i seguenti criteri:
    1. Soggetti di sesso maschile o femminile, di età pari o superiore a 18 anni al momento della firma del consenso informato.
    2. Devono comprendere e sottoscrivere volontariamente un documento di consenso informato prima che venga effettuata qualsiasi valutazione/procedura legata allo studio.
    3. Devono essere in grado di aderire al programma di visite dello studio e ad altri requisiti del protocollo.
    4. 4. Diagnosi di UC con una durata di almeno 3 mesi prima della Visita di Screening.
    5. TMS da = 6 a = 11 (gamma: 0-12), prima della randomizzazione nello studio.
    6. Sottopunteggio endoscopico = 2 (gamma: 0-3) sul punteggio Mayo prima della randomizzazione nello studio.
    7. I soggetti devono sottoporsi a colonscopia qualora non ne abbiano già effettuata una entro 12 mesi dalla Visita di Screening.
    8. I soggetti devono aver subito un fallimento terapeutico, essere intolleranti o presentare una controindicazione ad almeno una delle terapie seguenti: aminosalicilati orali (cioè composti di acido 5-aminosalicilico [5-ASA] oppure sulfasalazina [SSZ]), budesonide, corticosteroidi sistemici oppure agenti immunosoppressori (ad es. 6 mercaptopurina [6 MP], azatioprina [AZA] o metotrexato [MTX]).
    9. 9. I soggetti che ricevono trattamento con corticosteroidi orali possono continuare ad assumerli durante lo studio, a condizione che il dosaggio (prednisone = 20 mg/die o equivalente, budesonide = 9 mg/die) sia rimasto stabile da 3 settimane prima della Visita di Screening. Se il trattamento con corticosteroidi orali è stato interrotto di recente, l'interruzione deve essere stata completata almeno 3 settimane prima della visita di screening. Il dosaggio dei corticosteroidi deve rimanere stabile finché il soggetto sarà eleggibile per iniziare la diminuzione graduale dei corticosteroidi, che avrà inizio alla Visita della Settimana 12.
    10. Gli aminosalicilati orali sono ammessi durante lo studio, a condizione che il trattamento sia iniziato almeno 6 settimane prima dello screening con il raggiungimento di una dose stabile almeno 14 giorni prima della Visita di Screening. La dose di aminosalicilati orali deve rimanere stabile fino alla Settimana 52 o all'interruzione anticipata dello studio.
    11. Devono soddisfare i criteri di laboratorio seguenti:
    • Conta dei globuli bianchi = 3000/mm3 (= 3,0 X 109/l) e
    < 14.000/mm3 (< 14 X 109/l)
    • Conta piastrinica =100.000/mm3 (= 100 X 109/l)
    • Creatinina nel siero <1,5 mg/dl (=132,6 µmol/l)
    • AST (SGOT) e ALT (SGPT) ¿ 2 x il limite superiore di normalità (ULN). Se dal test iniziale emerge un valore ALT o AST > 2 volte il limite superiore di normalità, è consentita una ripetizione del test durante il periodo di screening
    • Bilirubina totale = 2 mg/dl (= 34 µmol/l) o albumina > limite inferiore di normalità (LLN). Se dal test iniziale emerge un valore > 2 g/dl, è consentita una ripetizione del test durante il periodo di screening
    • Emoglobina = 9 g/dl (= 5,6 mmol/l)
    12. Le donne in età fertile (FCBP) devono sottoporsi a un test di gravidanza con esito negativo alla visita di screening e alla visita basale. Durante il trattamento con IP e per almeno 28 giorni dopo l'assunzione dell'ultima dose di IP, le donne in età fertile che praticano attività in cui è possibile il concepimento devono utilizzare uno dei metodi contraccettivi approvati descritti di seguito:
    Opzione 1: Uno qualsiasi dei seguenti metodi altamente efficaci: contraccezione ormonale (orale, iniezione, impianto, cerotto transdermico, anello vaginale); dispositivo intrauterino (IUD); legatura delle tube o vasectomia del partner
    OPPURE
    Opzione 2: Profilattico maschile o femminile (profilattico in lattice o altro profilattico non in lattice NON realizzato in membrana naturale [animale] [ad esempio, poliuretano]) PIÙ un metodo di barriera aggiuntivo: (a) diaframma con spermicida; (b) cappuccio cervicale con spermicida oppure (c) spugna contraccettiva con spermicida.
    13. I soggetti di sesso maschile (compresi coloro che sono stati sottoposti a vasectomia) che praticano attività in cui è possibile il concepimento devono utilizzare un metodo contraccettivo di barriera (profilattico maschile in lattice o altro profilattico non in lattice che NON sia costituito da membrana naturale [animale] [ad esempio, poliuretano]) nel periodo di assunzione del prodotto sperimentale e per almeno 28 giorni dopo l’assunzione dell’ultima dose dello stesso.
    E.4Principal exclusion criteria
    The presence of any of the following will exclude a subject from enrollment:
    1. Diagnosis of Crohn's disease, indeterminate colitis, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis.
    2. Ulcerative colitis restricted to the distal 15 cm or less (eg, ulcerative proctitis).
    3. Subjects who have had surgery as a treatment for UC or who, in the opinion of the Investigator, are likely to require surgery for UC during the study.
    4. Clinical signs suggestive of fulminant colitis or toxic megacolon.
    5. Evidence of pathogenic enteric infection.
    6. History of colorectal cancer or colorectal dysplasia.
    7. Prior use of any TNF inhibitor (or any biologic agent).
    8. Prior use of mycophenolic acid, tacrolimus, sirolimus, cyclosporine or thalidomide..
    9. Use of IV corticosteroids within 2 weeks of the Screening Visit.
    12. Use of immunosuppressants (AZA, 6-MP or MTX) within 8 weeks of the Screening Visit
    11. Use of topical treatment with 5-ASA or corticosteroid enemas or suppositories within 2 weeks of the Screening Visit
    12. History of any clinically significant neurological, renal, hepatic, gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine, hematological disorder or disease, or any other medical condition that, in the investigator's opinion, would preclude participation in the study.
    13. Prior history of suicide attempt at any time in the subject’s lifetime prior to randomization in the study or major psychiatric illness requiring hospitalization within 3 years of study randomization.
    14. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she was to participate in the study or confounds the ability to interpret data from the study.
    15. Pregnant or breast feeding.
    16. History of any of the following cardiac conditions within 6 months of screening: myocardial infarction, acute coronary syndrome, unstable angina, new onset atrial fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery, interventional cardiac catheterization (with or without a stent placement), interventional electrophysiology procedure, or presence of implanted defibrillator.
    17. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease and herpes zoster), human immunodeficiency virus (HIV), or any major episode of infection requiring hospitalization or treatment with intravenous (IV) or oral antibiotics within 4 weeks of screening.
    18. Subjects with active hepatitis B infection as described in Appendix E are ineligible for the study. Subjects without current hepatitis B infection described in Appendix F may participate in the study.
    19. Subjects who are positive for the hepatitis C antibody are not eligible for the study.
    20. History of congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease).
    21. History of malignancy, except for:
    a. Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas
    b. Treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years
    22. Any condition that could affect oral drug absorption, including gastric resections, gastroparesis or bariatric surgery, such as gastric bypass.
    23. Subjects who have received any investigational drug or device within 3 months of study randomization.
    24. History of alcohol, drug, or chemical abuse within the 6 months prior to screening.
    25. Known hypersensitivity to apremilast or any excipients in the formulation.
    La presenza di uno qualsiasi dei seguenti criteri escluderà il soggetto dall'arruolamento:
    1. Diagnosi di morbo di Crohn, colite indeterminata, colite ischemica, colite microscopica, colite da radiazioni o colite associata a diverticoli.
    2. Colite ulcerosa limitata ai 15 cm distali o meno (ad es. proctite ulcerosa).
    3. I soggetti che hanno subito un intervento chirurgico per trattare l'UC o coloro i quali, secondo il giudizio dello sperimentatore, probabilmente richiederanno un intervento chirurgico per UC durante lo studio.
    4. Segni clinici indicativi di colite fulminante o megacolon tossico.
    5. Evidenza di infezione enterica patogena.
    6. Anamnesi di cancro del colon-retto o displasia del colon-retto.
    7. Uso precedente di inibitori del TNF (o agenti biologici).
    8. Uso precedente di acido micofenolico, tacrolimo, sirolimo, ciclosporina o talidomide.
    9. Uso di corticosteroidi endovenosi entro 2 settimane dalla Visita di Screening.
    10. Uso di agenti immunosoppressori (AZA, 6-MP o MTX) entro 8 settimane dalla Visita di Screening.
    11. Uso di trattamento topico con 5-ASA oppure corticosteroidi in clistere o supposta entro 2 settimane dalla Visita di Screening.
    12. Anamnesi di qualsiasi disturbo o patologia clinicamente significativo/a di natura neurologica, renale, epatica, gastrointestinale, polmonare, metabolica, cardiovascolare, psichiatrica, endocrina, ematologica oppure qualsiasi altra condizione medica che, a giudizio dello sperimentatore, precluderebbe la partecipazione allo studio.
    13. Anamnesi di precedente tentativo di suicidio in qualsiasi momento della vita del soggetto prima della randomizzazione nello studio oppure malattia psichiatrica importante che abbia richiesto il ricovero ospedaliero entro 3 anni dalla randomizzazione nello studio.
    14. Qualsiasi condizione, inclusa la presenza di anomalie di laboratorio che esponga il soggetto a rischi inaccettabili qualora dovesse partecipare allo studio oppure che pregiudichi l'interpretazione dei dati ottenuti con lo studio.
    15. Gravidanza o allattamento.
    16. Anamnesi di una qualsiasi delle condizioni cardiache seguenti entro 6 mesi dallo screening: infarto miocardico, sindrome coronarica acuta, angina instabile, fibrillazione atriale di recente insorgenza, flutter atriale di recente insorgenza, blocco atrioventricolare di II o III grado, fibrillazione ventricolare, tachicardia ventricolare, insufficienza cardiaca, intervento cardiochirurgico, cateterismo cardiaco intervenzionale (con o senza posizionamento di uno stent), procedura di elettrofisiologia intervenzionale o presenza di defibrillatore impiantato.
    17. Infezioni note attualmente attive o anamnesi di ricorrenti infezioni batteriche, virali, fungine, micobatteriche o altre infezioni (incluse ma non limitate a tubercolosi e malattia micobatterica atipica e herpes zoster), virus dell'immunodeficienza umana (HIV) o qualsiasi episodio rilevante di infezione che richieda ricovero ospedaliero o trattamento con antibiotici per via endovenosa (IV) o orale entro 4 settimane dalla fase di screening.
    18. I soggetti con infezione attiva da virus dell'epatite B come descritto nell'Appendice E non sono idonei allo studio. I soggetti senza infezione in corso da virus dell'epatite B di cui all'Appendice F possono partecipare allo studio.
    19. I soggetti positivi all'anticorpo per l'epatite C non sono idonei allo studio.
    20. Anamnesi di immunodeficienza congenita o acquisita (ad es. malattia dell'immunodeficienza comune variabile).
    21. Anamnesi di neoplasia maligna fatta eccezione per:
    a. carcinomi basocellulari o squamocellulari cutanei in situ trattati (ossia curati);
    b. neoplasia intraepiteliale cervicale (CIN) trattata (ossia curata) o carcinoma in situ della cervice che non presenta evidenza di recidiva entro i 5 anni precedenti
    22. Qualsiasi condizione che potrebbe pregiudicare l'assorbimento di farmaci assunti per via orale, tra cui resezioni gastriche, gastroparesi o interventi di chirurgia bariatrica, come bypass gastrico.
    23. Soggetti che hanno ricevuto un dispositivo o un farmaco sperimentale entro 3 mesi dalla randomizzazione nello studio.
    24. Anamnesi di abuso di alcolici, stupefacenti o sostanze chimiche nei 6 mesi precedenti lo screening.
    25. Sensibilità nota ad apremilast o a uno qualsiasi degli eccipienti della formulazione
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this study is the proportion of subjects achieving a clinical remission in the TMS at Week 12, defined as a TMS of = 2, with no individual subscore > 1.
    L’endpoint primario di questo studio è la proporzione di soggetti che ottengono una remissione clinica del TMS alla settimana 12, definita come un TMS < 2, con nessun sottopunteggio singolo > 1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    settimana 12
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are:
    ¿ The proportion of subjects achieving clinical response at Week 12, defined as a decrease from baseline in the TMS of at least 3 points and at least 30%, along with a reduction in the rectal bleeding subscore (RBS) of at least 1 point or an absolute RBS of = 1
    ¿ The proportion of subjects achieving endoscopic remission at Week 12, defined as a Mayo endoscopic subscore of 0
    ¿ The proportion of subjects achieving endoscopic response at Week 12, defined as a decrease from baseline of at least 1 point in the Mayo endoscopic subscore
    ¿ The proportion of subjects achieving a RBS = 1 at Week 12
    ¿ The proportion of subjects achieving clinical remission in the modified Mayo Score (range: 0 to 9, based on stool frequency (SFS), RBS and endoscopy) at Week 12, defined as a score of 2 points or lower, with no individual subscore exceeding 1 point
    ¿ The proportion of subjects achieving clinical response in the modified Mayo Score at Week 12, defined as a decrease from baseline at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS of = 1 point
    ¿ The proportion of subjects achieving clinical remission at Week 12 defined as a PMS of = 2, with no individual subscore > 1
    ¿ The proportion of subjects achieving clinical response at Week 12 defined as a decrease from baseline in the PMS of at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS of = 1 point
    ; The following safety parameters will be evaluated for the duration of the study: -
    ¿ Type, frequency, severity, and relationship of AEs to IP
    ¿ Number of subjects who discontinue IP due to any AE
    ¿ Frequency of clinically significant changes in physical examination, vital signs, and/or laboratory findings
    ; Exploratory efficacy endpoints
    ¿ The proportion of subjects who are in clinical remission per the TMS, PMS, or modified Mayo score, as applicable, over time, except at Week 12
    ¿ The proportion of subjects who are in clinical response per the TMS, PMS, or modified Mayo score, as applicable, over time, except at Week 12.
    ¿ The proportion of subjects achieving a RBS = 1 over time, except at Week 12
    ¿ The proportion of subjects achieving SFS = 1 over time
    ¿ The proportion of subjects achieving a physician's global assessment (PGA) = 1 Week 2 through Week 52
    ¿ The proportion of subjects who achieve corticosteroid-free clinical remission at Week 52 among subjects receiving oral corticosteroids at baseline
    ¿ The change from baseline in the PMS at Week 2 through Week 52
    ¿ The change from baseline in the TMS at Week 12 and Week 52
    ¿ The change from baseline in the SF-12v2 score over time
    Gli endpoint di efficacia secondari sono:
    La proporzione di soggetti con una risposta clinica alla settimana 12, definita come una riduzione dal basale del TMS di almeno 3 punti e di almeno il 30% congiuntamente a una riduzione del sottopunteggio del sanguinamento rettale (RBS) di almeno 1 punto o un RBS assoluto di < 1
    La proporzione di soggetti con una remissione endoscopica alla settimana 12, definita come un sottopunteggio endoscopico Mayo pari a 0
    La proporzione di soggetti con una risposta endoscopica alla settimana 12, definita come una riduzione dal basale di almeno 1 punto nel sottopunteggio endoscopico Mayo
    La proporzione di soggetti che raggiungono un RBS < 1 alla settimana 12
    La proporzione di soggetti che raggiungono una remissione clinica nel punteggio Mayo modificato (intervallo: da 0 a 9, sulla base della frequenza di evacuazione (SFS), RBS ed endoscopia) alla settimana 12, definito come un punteggio pari a 2 o inferiore, con nessun sottopunteggio singolo che supera 1 punto
    La proporzione di soggetti che raggiungono una risposta clinica nel punteggio Mayo modificato alla settimana 12, definita come una riduzione dal basale di almeno 2 punti e almeno il 25%, congiuntamente a una riduzione dell'RBS di almeno 1 punto o un RBS assoluto di < 1 punto
    La proporzione di soggetti che raggiungono la remissione clinica alla settimana 12, definita come un PMS < 2, con nessun sottopunteggio singolo > 1
    La proporzione di soggetti con una risposta clinica alla settimana 12, definita come una riduzione dal basale del PMS di almeno 2 punti e di almeno il 25% congiuntamente a a una riduzione dell'RBS di almeno 1 punto o un RBS assoluto < 1 punto
    ; Durante la durata dello studio saranno valutati i seguenti parametri di sicurezza:
    ¿ Tipo, frequenza, gravit¿ e relazione degli AE con il prodotto sperimentale
    ¿ Numero di soggetti che hanno interrotto l¿assunzione del prodotto sperimentale a causa di un qualsiasi AE
    ¿ Frequenza delle variazioni clinicamente significative riguardanti esame obiettivo, funzioni vitali,e/o esami di laboratorio
    ; Endpoint di efficacia esplorativi
    ¿ La proporzione di soggetti in remissione clinica per TMS, PMS, o punteggio Mayo modificato, come applicabile, nel tempo, eccetto alla settimana 12.
    ¿ La proporzione di soggetti in risposta clinica per TMS, PMS o punteggio Mayo modificato, come applicabile, nel tempo, eccetto alla settimana 12.
    ¿ La proporzione di soggetti che un RBS < 1 nel tempo, eccetto alla settimana 12
    ¿ La proporzione di soggetti con un SFS < 1 nel tempo
    ¿ La proporzione di soggetti con una valutazione globale del medico (PGA) <1 dalla settimana 2 alla settimana 52
    ¿ La proporzione di soggetti che raggiungono la remissione clinica libera da corticosteroidi alla Settimana 52 tra i soggetti che ricevono corticosteroidi orali alla baseline
    ¿ La variazione del PMS rispetto al basale dalla settimana 2 alla 52
    ¿ La variazione del TMS rispetto al basale dalla settimana 12 alla 52
    ¿ La variazione del punteggio SF-12v2 rispetto al basale nel tempo
    E.5.2.1Timepoint(s) of evaluation of this end point
    study duration; study duration; study duration
    durata dello studio; durata dello studio; durata dello studio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.7.1Other trial design description
    studio di definizione della dose
    dose-ranging study
    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 trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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 Information not present in EudraCT
    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
    Bulgaria
    Canada
    Czechia
    France
    Germany
    Hungary
    Italy
    Netherlands
    New Zealand
    Poland
    Slovakia
    Spain
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The End of Trial is defined as either the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan, whichever is the later date.
    La Fine della sperimentazione ¿ definita come la data dell'ultima visita dell'ultimo soggetto che completa lo studio o la data di ricevimento dell'ultimo dato rilevato, relativo all'ultimo soggetto, necessario per un'analisi primaria, secondaria e/o esplorativa, come preliminarmente specificato nel protocollo e/o nel Piano di analisi statistica, a seconda di quale delle due date sia successiva.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 165
    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 who complete the Double-blind Placebo-controlled Phase, as well as subjects who prematurely discontinue from the study will enter
    the Post-treatment Observational Follow-up Phase, the 4-week period after the last dose of investigational product (IP). The long term care of the participant will remain the responsibility of
    the primary treating physician once the trial has ended.
    I soggetti che completano la fase in doppio cieco controllata con placebo e i soggetti che interrompono prematuramente lo studio entreranno nella fase di follow-up osservazionale post-trattamento, il periodo di 4 settimane a seguito della somministrazione dell'ultima dose di prodotto sperimentale. L'assistenza a lungo termine del partecipante continuer¿ a essere responsabilit¿ del medico curante una volta concluso lo studio clinico
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-09
    P. End of Trial
    P.End of Trial StatusCompleted
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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