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    Summary
    EudraCT Number:2018-003986-33
    Sponsor's Protocol Code Number:APD334-302
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-22
    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 number2018-003986-33
    A.3Full title of the trial
    A Phase 3, Randomized, Double Blind, Placebo Controlled, 12 Week Study to Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative Colitis
    Studio di fase 3, randomizzato, in doppio cieco, controllato con placebo, della durata di 12 settimane, volto a valutare l’efficacia e la sicurezza di etrasimod in soggetti con colite ulcerosa da moderatamente a gravemente attiva
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study evaluating the efficacy and safety of Etrasimod in the treatment of patients with moderately to severely active Ulcerative Colitis
    Studio per la valutazione dell’efficacia e la sicurezza di etrasimod nel trattamento di soggetti con colite ulcerosa da moderatamente a gravemente attiva
    A.3.2Name or abbreviated title of the trial where available
    ELEVATE UC 12
    ELEVATE UC 12
    A.4.1Sponsor's protocol code numberAPD334-302
    A.5.4Other Identifiers
    Name:IND numberNumber:125154
    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 SponsorARENA PHARMACEUTICALS, INC.
    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 supportArena Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationArena Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointGiles Hulley
    B.5.3 Address:
    B.5.3.1Street Address6154 Nancy Ridge Drive
    B.5.3.2Town/ citySan Diego - CA
    B.5.3.3Post code92121
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018582104528
    B.5.5Fax number000000
    B.5.6E-mailghulley@arenapharm.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 nameEtrasimod
    D.3.2Product code [APD334]
    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 INNetrasimod L-arginine
    D.3.9.1CAS number 1206123-97-8
    D.3.9.2Current sponsor codeAPD334 L-arginine
    D.3.9.3Other descriptive nameAPD334 L-arginine
    D.3.9.4EV Substance CodeSUB171412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ulcerative Colitis
    Colite ulcerosa
    E.1.1.1Medical condition in easily understood language
    Ulcerative Colitis, a form of inflammatory bowel disease
    Colite ulcerosa una forma di malattia infiammatoria intestinale
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045366
    E.1.2Term Ulcerative colitis, unspecified
    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
    To assess the efficacy of etrasimod when administered for 12 weeks on clinical remission in subjects with moderately to severely active ulcerative colitis (UC).
    valutare l’efficacia di etrasimod somministrato per 12 settimane sulla remissione clinica in soggetti con colite ulcerosa (CU) da moderatamente a gravemente attiva.
    E.2.2Secondary objectives of the trial
    Secondary:
    The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks on clinical response, symptomatic response and remission, endoscopic changes, and mucosal healing in subjects
    with moderately to severely active UC.
    Safety:
    The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for 12 weeks in subjects with moderately to severely active UC.
    Other:
    Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of etrasimod on health related subject reported outcomes and biomarkers.
    Secondario:
    L’obiettivo secondario è valutare l’efficacia di etrasimod somministrato per 12 settimane in termini di risposta clinica, risposta e remissione sintomatica, variazioni endoscopiche e guarigione della mucosa in soggetti con CU da moderatamente a gravemente attiva.
    Sicurezza:
    L’obiettivo di sicurezza è valutare la sicurezza di etrasimod in seguito a un dosaggio giornaliero di 2 mg per 12 settimane in soggetti con CU da moderatamente a gravemente attiva.
    Altro:
    Altri obiettivi includono la valutazione della farmacocinetica (PK) di etrasimod e l’effetto di etrasimod sugli esiti correlati alla salute riferiti dal soggetto e sui biomarcatori.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men, women and adolescents 16 to 80 years of age
    2. Ability to provide written informed consent or assent (parent or legal guardian must provide consent for a subject < 18 years of age who has assented to participate in the study or as required per local regulations)
    and to be compliant with the schedule of protocol assessments. Enrollment of subjects < 18 years should be conducted only if acceptable according to local laws and regulations.
    3. Diagnosed with UC = 3 months prior to screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence. The endoscopy and histology report should be present in the source
    documents; however, if not available, the screening endoscopy and histology may serve as such
    4. Active UC confirmed by endoscopy with = 10 cm rectal involvement.
    Inclusion of subjects with proctitis only at baseline will be capped at 15% of the total subjects enrolled.
    c. A male must agree to use condoms during treatment and for 4 weeks following treatment.
    5. Moderately to severely active UC defined as MMS of 4 to 9, including an ES of = 2 and RB score = 1
    6. Received a surveillance colonoscopy (performed according to local standard) within 12 months before baseline to rule out dysplasia in subjects with pancolitis > 8 years duration or subjects with left-sided
    colitis > 12 years duration. Subjects without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening (ie, in place of screening proctosigmoidoscopy). Any adenomatous polyps must be removed prior to their first dose of study treatment.
    7. Demonstrated an inadequate response to, loss of response to, or intolerance to at least 1 of the following therapies as defined below:
    Conventional therapy
    a. Corticosteroids
    b. Thiopurines
    Biologic therapy or JAK inhibitor therapy
    a. Antitumor necrosis factor alpha (TNFa) antibodies (eg, infliximab, adalimumab, golimumab, or biosimilars)
    b. Anti integrin antibodies (eg, vedolizumab)
    c. JAK inhibitors (eg, tofacitinib)
    8. Subjects are permitted to be receiving a therapeutic dose of the following drugs:
    • Oral 5 ASA compounds provided the dose has been stable for = 2 weeks immediately prior to randomization
    • Oral corticosteroid therapy (prednisone at a stable dose = 20 mg/day, budesonide at a stable dose = 9 mg/day, or equivalent steroid) provided the dose has been stable for the 4 weeks immediately prior to the
    screening endoscopy assessment
    • Immunosuppressive agents such as oral azathioprine or 6 mercaptopurine must be discontinued = 2 weeks prior to randomization
    • Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the dose has been stable for the 2 weeks immediately prior to randomization
    • Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea
    If oral aminosalicylates or corticosteroids have been recently discontinued, they must have been stopped for at least 2 weeks prior to the endoscopy used for the baseline MMS.
    9. Vital signs at screening and prerandomization taken in the sitting position: heart rate = 50 bpm, systolic blood pressure (BP) = 90 mm Hg, and diastolic BP = 55 mm Hg
    10. Screening and prerandomization 12 lead electrocardiogram (ECG) showing no clinically significant abnormalities with a PR interval = 200 ms, Fridericia's corrected QT interval (QTcF) < 450 ms (men) or QTcF <
    470 ms (women)
    11. Adequate hematological function
    12. Adequate hepatic function. Subjects with an isolated total bilirubin and normal AST and ALT diagnosed with Gilbert's syndrome may participate
    13. Adequate renal function
    14. Females must meet either a or b of the following criteria and males must meet criterion c to qualify for the study:
    a. A female who is not of childbearing potential must meet 1 of the following:
    Postmenopausal, defined as no menses for 12 months without an alternative medical cause;
    ¿ Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
    1. Uomini, donne e adolescenti di età compresa tra 16 e 80 anni
    2. Capacità di fornire il consenso o l’assenso informato scritto (il genitore o tutore legale deve fornire il consenso in caso di soggetti di età <18 anni che hanno fornito l’assenso a partecipare allo studio o se richiesto dalle normative locali) e di attenersi al programma delle valutazioni previste dal protocollo. I soggetti di età <18 anni possono essere arruolati solo se ciò è accettabile ai sensi delle leggi e dei regolamenti locali
    3. Diagnosi di CU ricevuta =3 mesi prima dello screening. La diagnosi di CU deve essere confermata da evidenze endoscopiche e istologiche. Il referto endoscopico e istologico deve essere presente nei documenti originali; tuttavia, se non disponibile, l’esame endoscopico e istologico eseguito allo screening assolverà a tale funzione
    4. CU attiva confermata tramite endoscopia con coinvolgimento rettale =10 cm. L’inclusione di soggetti con proctite solo al basale sarà limitata al 15% dei soggetti totali arruolati
    5. CU da moderatamente a gravemente attiva definita come un punteggio MMS da 4 a 9, incluso un punteggio ES =2 ed RB =1
    6. Esecuzione di una colonscopia di sorveglianza (effettuata in base agli standard locali) entro 12 mesi prima del basale per escludere una displasia nei soggetti con pancolite di durata >8 anni o soggetti con colite al lato sinistro di durata >12 anni. I soggetti che non dispongono di una colonscopia di sorveglianza nei 12 mesi precedenti saranno sottoposti a una colonscopia allo screening (ossia, in sostituzione della proctosigmoidoscopia di screening). Eventuali polipi adenomatosi devono essere rimossi prima che venga somministrata la prima dose di trattamento dello studio.
    7. Dimostrazione di risposta inadeguata, perdita di risposta o intolleranza ad almeno 1 delle seguenti terapie definite sotto:
    Terapia convenzionale
    a. Corticosteroidi
    b. Tiopurine
    Terapia biologica o terapia con inibitori di JAK
    a. Anticorpi anti-fattore di necrosi tumorale alfa (TNFa) (ad es., infliximab, adalimumab, golimumab o biosimilari)
    b. Anticorpi anti-integrina (ad es., vedolizumab)
    c. Inibitori di JAK (ad es., tofacitinib)
    8. Ai soggetti è consentito di assumere una dose terapeutica dei seguenti farmaci:
    • Composti orali dell’acido 5-aminosalicilico (5-ASA) a condizione che la dose sia rimasta stabile per =2 settimane immediatamente prima della randomizzazione
    • Terapia corticosteroidea orale (prednisone a una dose stabile =20 mg/giorno, budesonide a una dose stabile =9 mg/giorno, o steroide equivalente) a condizione che la dose sia rimasta stabile nelle 4 settimane immediatamente precedenti la valutazione endoscopica di screening
    • I farmaci immunosoppressori quali azatioprina o 6-mercaptopurina devono essere sospesi =2 settimane prima della randomizzazione
    • Probiotici (ad es., Culturelle®, Saccharomyces boulardii) a condizione che la dose sia rimasta stabile nelle 2 settimane immediatamente precedenti la randomizzazione
    • Antidiarroici (ad es., loperamide, difenossilato con atropina) per il controllo della diarrea cronica
    Qualora di recente sia stata interrotta la somministrazione di aminosalicilati o corticosteroidi, l’interruzione deve essere avvenuta almeno 2 settimane prima dell’endoscopia usata per il punteggio MMS al basale.
    9. Segni vitali allo screening e prima della randomizzazione misurati in posizione seduta: frequenza cardiaca =50 bpm, pressione sanguigna sistolica =90 mmHg e diastolica =55 mmHg
    10. Elettrocardiogramma (ECG) a 12 derivazioni eseguito allo screening e prima della randomizzazione che dimostri la totale assenza di anomalie clinicamente significative con un intervallo PR =200 ms, intervallo QT corretto con la formula di Fridericia (QTcF) <450 ms (uomini) o QTcF <470 ms (donne)
    11. Funzione ematologica adeguata
    12. Funzione epatica adeguata. È consentita la partecipaz di soggetti che presentano valori isolati di bilirubina totale e valori normali di AST e ALT con diagnosi di sindrome di Gilbert.
    E.4Principal exclusion criteria
    1. Severe extensive colitis as evidenced by:
    • Physician judgment that the subject is likely to require hospitalization for medical care or surgical intervention of any kind for UC (eg,colectomy) within 12 weeks of baseline
    • Current evidence of fulminant colitis, toxic megacolon or recent history (within last 6 months) of toxic megacolon, or bowel perforation
    • Previous total or partial colectomy
    2. Diagnosis of Crohn's disease or indeterminate colitis or the presence or history of a fistula consistent with Crohn's disease
    3. Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis
    4. Hospitalization for exacerbation of UC requiring intravenous (IV) steroids within 12 weeks of screening (a single dose of IV steroids given is acceptable)
    5. Positive assay or stool culture for pathogens or positive test for Clostridium difficile toxin at screening
    6. Pregnancy, lactation, or a positive serum ß hCG measured during screening
    7. Clinically relevant hematologic, hepatic, neurological, pulmonary, ophthalmological, endocrine, metabolic, psychiatric or other major systemic disease making implementation of the protocol or interpretation of the study difficult or would put the subject at risk
    8. Recent history (within 6 months of the Screening) of cardiovascular disease, including myocardial infarction or unstable angina, stroke/transient ischemic attack, decompensated heart failure (requiring
    inpatient treatment), or New York Heart Association Class III/IV heart failure.
    9. Any history of the following, unless treated with an implanted pacemaker or an implanted cardioverter-defibrillator with pacing:
    • History or presence of symptomatic bradycardia
    • History of sick sinus syndrome or neurocardiogenic syncope
    • Second or third degree AV block
    • Periods of asystole > 3 seconds
    10. Forced expiratory volume at 1 second (FEV1) or forced vital capacity
    (FVC) < 70% of predicted values and FEV1/FVC ratio < 0.70 at screening
    11. Uncontrolled diabetes at screening, or subjects with diabetes with significant comorbid conditions such as retinopathy
    12. History of macular edema or retinopathy
    13. Current or past history of active tuberculosis (TB), history of untreated latent TB infection, or test positive for latent TB infection at screening.
    14. Known active bacterial, viral, fungal, mycobacterial infection, or other infection or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or during screening or oral antibiotics within 14 days prior to screening. Fungal infection of nail beds is allowed
    15. Have HIV/acquired immune deficiency syndrome or test positive for HIV antibodies at screening
    16. Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at screening
    17. Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening
    18. History of an opportunistic infection (eg, pneumocystis carinii, cryptococcal meningitis, progressive multifocal leukoencephalopathy) or serious bacterial, viral, or fungal infections (eg, disseminated herpes
    simplex, disseminated herpes zoster) requiring IV medication(s) = 3 weeks prior to randomization
    19. History of or currently active primary or secondary immunodeficiency
    20. History of cancer within the last 5 years, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic
    mucosal dysplasia
    21. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
    22. History of alcohol or drug abuse within 1 year of randomization
    23. Hypersensitivity to etrasimod or any of the excipients or placebo compounds
    24. Prior treatment with sphingosine 1 phosphate receptor modulators
    25. Treatment with a biologic agent within 8 weeks or 5 elimination half lives, prior to randomization
    1. Colite estesa grave accertata mediante:
    • Parere medico secondo cui è probabile che il soggetto richieda un ricovero per ricevere cure mediche o un intervento chirurgico di qualsiasi tipologia per la CU (ad es., colectomia) entro 12 settimane dal basale
    • Evidenze attuali di colite fulminante, megacolon tossico o anamnesi recente (entro almeno 6 mesi) di megacolon tossico o perforazione intestinale
    • Precedente colectomia parziale o totale
    2. Diagnosi di malattia di Crohn o colite indeterminata oppure presenza o anamnesi di una fistola coerente con malattia di Crohn
    3. Diagnosi di colite microscopica, colite ischemica o colite infettiva
    4. Ricovero per esacerbazione della CU che richieda la somministrazione endovenosa (EV) di steroidi entro 12 settimane dallo screening (è accettabile una singola dose di steroidi somministrata EV)
    5. Positività al test o alla coltura fecale per agenti patogeni (esame di uova e parassiti, batteri) o positività al test per la tossina di Clostridium difficile allo screening (in caso di positività a C. difficile, il soggetto può essere trattato e riesaminato =4 settimane dopo aver completato il trattamento)
    6. Gravidanza, allattamento o positività alla beta-gonadotropina corionica umana sierica misurata durante lo screening
    7. Malattia ematologica, epatica, neurologica, polmonare, oftalmologica, endocrina, metabolica (comprese, senza limitazione, ipo- e iperkaliemia), malattia psichiatrica clinicamente rilevante o altra importante malattia sistemica che possa rendere difficile l’attuazione del protocollo o l’interpretazione dello studio o costituire un rischio per il soggetto
    8. Anamnesi recente (entro 6 mesi dalla visita di screening) di malattie cardiovascolari, inclusi infarto del miocardio, angina instabile, ictus/attacco ischemico transitorio, insufficienza cardiaca scompensata (che abbia richiesto un trattamento ospedaliero) o insufficienza cardiaca di classe III/IV secondo la New York Heart Association
    9. Qualsiasi anamnesi delle seguenti condizioni, salvo se trattate con un pacemaker impiantato o un defibrillatore-cardioverter con stimolazione impiantato:
    • Anamnesi o presenza di bradicardia sintomatica
    • Anamnesi di sindrome del nodo del seno o sincope neurocardiogena
    • Blocco atrioventricolare (AV) di secondo o terzo grado
    • Periodi di asistole >3 secondi
    10. Volume espiratorio forzato in 1 secondo (FEV1) o capacità vitale forzata (FVC) <70% dei valori previsti e rapporto FEV1/FVC <0,70 allo screening
    11. Diabete non controllato, evidenziato da valori di emoglobina A1c (HbA1c) >9% allo screening, o soggetti con diabete associato a comorbilità significative quali retinopatia
    12. Anamnesi di edema o retinopatia maculare
    13. Anamnesi attuale o pregressa di tubercolosi (TBC) attiva, anamnesi di infezione da TBC latente non trattata o positività al test per l’infezione da TBC latente allo screening.
    14. Infezione nota di origine batterica, virale, micotica, micobatterica o di altro tipo in fase attiva o qualsiasi episodio di infezione importante che richieda il ricovero o il trattamento con antibiotici EV nei 30 giorni precedenti lo screening o durante lo screening, oppure antibiotici per via orale nei 14 giorni precedenti lo screening. Sono consentite le infezioni fungine del letto ungueale
    15. Infezione da virus dell’immunodeficienza umana (HIV)/Sindrome da immunodeficienza acquisita o positività al test per gli anticorpi anti-HIV allo screening
    16. Infezione acuta o cronica di epatite B o positività al test per il virus dell’epatite B (HBV) allo screening
    17. Infezione da epatite C in corso o positività al test per il virus dell’epatite C (HCV) allo screening
    18. Anamnesi di un’infezione opportunistica (es., da Pneumocystis carinii, meningite criptococcica, leucoencefalopatia multifocale progressiva) o gravi infezioni di origine batterica, virale o fungina e necessità di uno o più farmaci EV =3 sett prima della randomizzazione
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoints will evaluate etrasimod versus placebo in:
    • The proportion of subjects in clinical remission at Week 12
    Gli endpoints primari di efficacia valuteranno etrasimod verso placebo nella:
    • Percentuale di soggetti in remissione clinica alla Settimana 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    Settimana 12
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints are:
    • The proportion of subjects achieving endoscopic improvement at Week 12
    • Proportion of subjects with mucosal healing at Week 12
    The other secondary endpoints are:
    • Proportion of subjects with a clinical response at Week 12
    • Proportion of subjects with endoscopic improvement at Week 12
    • Proportion of subjects with endoscopic normalization at Week 12
    • Proportions of subjects with clinical response of RB and SF symptom outcomes at each of the following time points: Weeks 2, 4, 8, and 12
    • Proportions of subjects with clinical remission of RB and SF symptom outcomes at each of the following time points: Weeks 2, 4, 8, and 12
    Exploratory efficacy endpoints are:
    • Proportion of subjects with remission and response using total Mayo Clinic score at Weeks 12
    • Proportion of subjects with histologic remission at Week 12 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
    • Proportion of subjects with histologic improvement at Week 12 (as defined by the Geboes, Robarts, and Nancy histopathology scores)
    • Proportion of subjects with improvement in EIMs at Weeks 12 in subjects with EIMs at baseline
    Other Efficacy Related Endpoints
    Health Related Quality of Life
    • Scores and change from baseline to Week 12 in the following:
    - IBDQ total score
    - UC PRO/SS
    - SF 36, version 2, physical and mental component and domain scores
    - WPAI-UC
    - Urgency NRS
    - Abdominal pain NRS
    • Proportion of subjects with UC-related hospitalizations
    • Proportion of subjects requiring UC-related surgeries, including colectomy
    Pharmacokinetics
    • Plasma concentrations of etrasimod, M3 (AR503641), and other metabolite(s) of interest (if warranted) will be assessed from samples collected prior to dosing and 4 hours (± 15 minutes) post dose (after 12-
    lead ECG) on Week 0/Day 1
    • Plasma concentrations of etrasimod, M3 (AR503641), and other metabolite(s) of interest (if warranted) will be assessed from samples collected prior to dosing (trough) at Weeks 2, 4, 8, and 12
    Biomarkers
    • Change from baseline in level of fecal calprotectin at Weeks 4, 8, and 12
    • Change from baseline in level of hs CRP at Weeks 2, 4, 8, and 12
    • Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, and 12
    Safety Endpoints
    • Incidence and severity of adverse events
    • Incidence and severity of laboratory abnormalities, and change from baseline in laboratory values (to include hematology, serum chemistry,coagulation, and urinalysis)
    • Incidence of clinically significant vital sign abnormalities and changes from baseline
    Principali endpoint secondari di efficacia:
    • Percentuale di soggetti che raggiungono il miglioramento endoscopico alla Settimana 12
    • Percentuale di soggetti con guarigione mucosale alla Settimana 12
    Gli altri endpoints secondari sono:
    • Percentuale di soggetti con risposta clinica alla settimana 12
    • Percentuale di soggetti con miglioramento endoscopico alla settimana 12
    • Percentuale di soggetti con normalizzazione endoscopica alla settimana 12
    • Percentuale di soggetti con risposta clinica di sintomo RB e SF risultati di ciascuno dei seguenti punti temporali: settimane 2, 4, 8 e 12
    • Percentuale di soggetti con remissione clinica del sintomo di RB e SF risultati di ciascuno dei seguenti punti temporali: settimane 2, 4, 8 e 12
    Gli endpoint di efficacia esplorativa sono:
    • Percentuale di soggetti con remissione e risposta utilizzando Mayo totale Punteggio clinico alla settimana 12
    • Percentuale di soggetti con remissione istologica alla settimana 12 (come definito dai punteggi di istopatologia di Geboes, Robarts e Nancy)
    • Percentuale di soggetti con miglioramento istologico alla settimana 12 (come definito dai punteggi di istopatologia di Geboes, Robarts e Nancy)
    • Percentuale di soggetti con miglioramento degli EIM alla settimana 12 in soggetti con EIM al basale
    Endpoint di qualità della vita correlata alla salute:
    • Punteggi e variazione rispetto al basale alla Settimana 12 per i seguenti parametri:
    ¿ Punteggio totale del Questionario IBDQ
    ¿ UC-PRO/SS
    ¿ Punteggi di dominio e delle componenti fisiche e mentali della versione 2 del Questionario, SF-36
    ¿ Questionario WPAI UC
    ¿ Scala di valutazione numerica (Numeric Rating Scale, NRS) per le emergenze
    ¿ NRS di valutazione del dolore addominale
    • Percentuale di soggetti con ricoveri ospedalieri correlati alla CU
    • Percentuale di soggetti che richiedono interventi chirurgici correlati alla CU, tra cui colectomia
    Farmacocinetica:
    Le concentrazioni plasmatiche di etrasimod, M3 (AR503641) e di uno o più eventuali altri metaboliti di interesse (se necessario) saranno valutate nei campioni raccolti pre-dose e 4 ore (± 15 minuti) post-dose (dopo l’ECG a 12 derivazioni) alla Settimana 0/Giorno 1
    Le concentrazioni plasmatiche di etrasimod, M3 (AR503641) e di uno o più eventuali altri metaboliti di interesse (se necessario) saranno valutate nei campioni raccolti pre-dose (valore minimo) alle Settimane 2, 4, 8 e 12.
    biomarkers
    • Variazione rispetto al basale del livello di calprotectina fecale alle settimane 4, 8 e 12
    • Variazione rispetto al basale nel livello di hs CRP alle settimane 2, 4, 8 e 12
    • Variazione e variazione percentuale dal basale della conta linfocitaria a Settimane 2, 4, 8 e 12
    Endpoint di sicurezza:
    • Incidenza e gravità degli eventi avversi
    • Incidenza e gravità delle anomalie di laboratorio e variazione rispetto al basale nei valori di laboratorio (incluse ematologia, ematochimica, coagulazione e analisi delle urine)
    • Incidenza di anomalie e variazioni clinicamente significative nei segni vitali rispetto al basale
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 2, 4, 8, and 12
    Settimane 2, 4, 8, e 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 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 No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned19
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA253
    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
    Argentina
    Australia
    Austria
    Belarus
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    China
    Croatia
    Czechia
    Denmark
    Egypt
    Estonia
    France
    Georgia
    Germany
    Hungary
    India
    Israel
    Italy
    Korea, Democratic People's Republic of
    Latvia
    Lebanon
    Lithuania
    Mexico
    Moldova, Republic of
    Netherlands
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Slovakia
    South Africa
    Spain
    Switzerland
    Taiwan
    Thailand
    Turkey
    Ukraine
    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
    LVLS.
    LVLS.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    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 months6
    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.1.1.1In 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: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 290
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 126
    F.4.2.2In the whole clinical trial 330
    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. However eligible participants will be given the opportunity to enter an open label extension study (OLE) with etrasimod
    NESSUNA. Tuttavia, ai partecipanti ammissibili verrà data l'opportunità di partecipare a uno studio di estensione in aperto (OLE) con etrasimod
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-23
    P. End of Trial
    P.End of Trial StatusOngoing
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