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    Summary
    EudraCT Number:2010-022766-27
    Sponsor's Protocol Code Number:B3041001
    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:2012-04-27
    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 number2010-022766-27
    A.3Full title of the trial
    A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY TO INVESTIGATE THE SAFETY AND EFFICACY OF MULTISTEM (PF-05285401) IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS
    STUDIO DI FASE II, RANDOMIZZATO, IN DOPPIO CIECO, CONTROLLATO CON PLACEBO, A GRUPPI PARALLELI, MULTICENTRICO PER DETERMINARE LA SICUREZZA E L'EFFICACIA DI MULTISTEM (PF-05285401) IN SOGGETTI CON COLITE ULCEROSA DA MODERATA A GRAVE.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of safety and effectiveness of human-derived stem cells (multistem, also know as PF-05285401) in the treatment of ulcerative colitis.
    Studio sulla sicurezza ed afficacia di un derivato di cellule staminali di derivazione umana (multistem,anche chiamato PF-05285401) nel trattamento della colite ulcerosa.
    A.4.1Sponsor's protocol code numberB3041001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01240915
    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 SponsorPFIZER LIMITED
    B.1.3.4CountryUnited Kingdom
    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 supportPfizer Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number001 800 7181021
    B.5.5Fax number001 303 739 1119
    B.5.6E-mailclinicaltrials.govcallcenter@pfizer.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 nameMultistem
    D.3.2Product code PF-05285401
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codePF-05285401
    D.3.9.3Other descriptive nameMultistem
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms million organisms
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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 nameMultistem
    D.3.2Product code PF-05285401
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codePF-05285401
    D.3.9.3Other descriptive nameMultistem
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number750
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP 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 Yes
    D.2.1.1.1Trade name Promiten
    D.2.1.1.2Name of the Marketing Authorisation holderMEDA A/S
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDEXTRAN 1 FOR INJECTION
    D.3.9.4EV Substance CodeSUB11894MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ulcerative Colitis
    Colite Ulcerosa
    E.1.1.1Medical condition in easily understood language
    Ulcerative colitis is a type of Inflammatory Bowel Disease (IBD), which involves inflammation of all or part of the colon
    La Colite Ulcerosa è tipo di malattia infimmatoria cronica intestinale che coinvolge l'infiammazione di tutto o in parte il colon
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10045282
    E.1.2Term UC
    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
     To evaluate the safety and tolerability of intravenous doses of MultiStem in moderate-tosevere ulcerative colitis.  To study the efficacy of a single intravenous dose of MultiStem in moderate-to-severe ulcerative colitis measured by an effect on endoscopic and rectal bleeding scores.
    • Valutare la sicurezza e la tollerabilità di dosi endovenose di MultiStem in pazienti affetti da colite ulcerosa da moderata a grave. • Studiare l’efficacia di una singola dose endovenosa di MultiStem nei pazienti affetti da colite ulcerosa da moderata a grave, misurata in base all’effetto sui punteggi endoscopici e di sanguinamento rettale.
    E.2.2Secondary objectives of the trial
    To study the effect of a single intravenous dose of MultiStem on disease severity measured by total and partial Mayo score.  To study the effect of repeat intravenous dose of MultiStem on disease measured by partial Mayo score and by rectal bleeding.  To study the effect of intravenous doses of MultiStem on fecal calprotectin and Creactive protein (CRP) levels.
    •Studiare l’effetto di una singola dose endovenosa di MultiStem sulla gravità della patologia,misurato in base al punteggio Mayo totale e parziale.•Studiare l’effetto di dosi endovenose ripetute di MultiStem sulla malattia,misurato in base al punteggio Mayo parziale e al sanguinamento rettale.•Studiare l’effetto di una singola dose endovenosa di MultiStem sui livelli di calprotectina fecale e proteina C reattiva (CRP).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PHARMACOGENETIC:
    Vers:Am6
    Date:2011/10/18
    Title:EXPLORATORY RESEARCH SAMPLES FOR PFIZER’S BIOBANK
    Objectives:The purpose of this research is to collect, store, and use your sample(s) to study genes, RNA, proteins and metabolites. The samples and data obtained from the research using your samples will be examined only in relation to: • response to the study drugs in the main drug study • Ulcerative Colitis and related conditions; and/or • information from the genes, RNA, proteins and metabolites of other people, including study participants with other conditions or diseases. This research may give rise to new or improved drug treatments.

    FARMACOGENETICA:
    Vers:Am6
    Data:2011/10/18
    Titolo:Ricerca esplorativa su campioni raccolti per la Biobanca di Pfizer.
    Obiettivi:L'obiettivo di questa ricerca è prelevare, conservare e usare i campioni per studiare i geni, l'RNA, le proteine e i metaboliti. I campioni e i dati ottenuti dalla ricerca basata su su di essi verranno esaminati solo in relazione a:  risposta ai farmaci dello studio principale;  colite ulcerosa e disturbi correlati; e/o  informazioni derivanti dai geni, dall'RNA, dalle proteine e dai metaboliti di altre persone, compresi i partecipanti allo studio affetti da altri disturbi o malattie. Questa ricerca potrebbe portare alla scoperta di nuovi trattamenti farmacologici o al miglioramento di quelli esistenti.

    E.3Principal inclusion criteria
    1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. 2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, lifestyle guidelines and other study procedures. 3. Subject must be at least 18 years of age. 4. Males and females with a documented diagnosis (endoscopic or radiographic) of UC 6 months prior to screening. 5. For Cohort 1 and 2 only: Active moderate-to-severe UC defined as Mayo score of 6 and <11. 6. For Cohort 3 only: Active moderate-to-severe UC defined as Mayo score of 6. Modified Baron endoscopic score of 2 determined within 21 days of first dosing for Cohort 1 and within 7 days of first dosing for Cohorts 2 and 3 (flexible sigmoidoscopy unless surveillance colonoscopy clinically indicated). 8. Subjects must have failed or be intolerant (as determined by the investigator) of at least one of the following treatments for UC: Oral corticosteroids, azathioprine or 6- mercaptopurine (6-MP), or anti-tumor necrosis factor (TNF) therapy, eg, infliximab or adalimumab. 9. Subjects currently receiving the following treatment regimens for UC are eligible providing they are on stable dose for designated period of time: a. 5-ASA or sulfasalazine stable dose for at least 3 weeks prior to Day 1 and during the study treatment period. b. Corticosteroids or equivalent at a stable dose for at least 2 weeks prior to Day 1 study visit (Prednisolone 25 mg/day, or equivalent). NOTE: Tapering of corticosteroids or equivalent may only commence at Week 8 (see “Concomitant Medications” section). c. Antibiotics (eg, metronidazole, rifaximin) stable dose for at least 2 weeks prior to Day 1 study visit and during the study treatment period ie, up to Week 8. d. Rectally administered formulation of corticosteroids or 5-ASA stable dose for at least 2 weeks prior to Day 1 study visit and during the study treatment period. e. Methotrexate (up to 15 mg/week subcutaneously) stable for at least 2 months prior to Day 1 study visit. Azathioprine (up to 2.5 mg/kg/day) or 6-mercaptopurine (up to 1.5 mg/kg/day) stable for at least 3 months prior to Day 1 study visit and during the study treatment period. NOTE: excluded medications include anti-TNF therapies used within 8 weeks of Day 1 study visit or cyclosporine, mycophenolate, or tacrolimus used within 4 weeks of Day 1 study visit as described in the exclusion criteria. 10. Subjects willing to use double contraception during the study treatment period and until completion of follow-up procedures ie, Week 52: 11. If the subject is a sexually active woman of childbearing potential, she and her male partner are required to simultaneously use 2 effective contraceptive methods as listed in Section 4.4.2. Female subjects who wish to use non-hormonal contraception must have done so for at least 14 days prior to the Day 1 study visit. 12. Non-vasectomized males with female partners of child bearing potential must be willing to use a condom in addition to having their female partner use another form of contraception as listed in Section 4.4.2. of the Protocol
    1. Evidenza di documento di consenso informato firmato e datato personalmente, indicante che il soggetto (o un legale rappresentante riconosciuto) è stato informato su tutti gli aspetti pertinenti lo studio. 2. Soggetti desiderosi e in grado di attenersi al programma delle visite, al piano di trattamento, alle analisi di laboratorio, alle linee guida per lo stile di vita e alle altre procedure dello studio. 3. Soggetti di età &gt; 18 anni. 4. Maschi e femmine con diagnosi documentata (endoscopia o radiografia) di UC ≥6 mesi prima dello screening. 5. Solo per la Coorte 1 e 2: UC attiva da moderata a grave definita da un punteggio Mayo ≥6 e &lt;11. 6. Solo per la Coorte 3: UC attiva da moderata a grave definita da un punteggio Mayo ≥6. 7. Punteggio endoscopico Baron modificato ≥2 determinato entro 21 giorni dal primo dosaggio per la Coorte 1 ed entro 7 giorni dal primo dosaggio per le Coorti 2 e 3 (sigmoidoscopia flessibile, a meno che non sia indicata clinicamente la colonscopia di sorveglianza). 8. Soggetti non rispondenti o intolleranti (a giudizio dello sperimentatore) ad almeno uno dei seguenti trattamenti per UC: corticosteroidi orali, azatioprina o 6-mercaptopurina (6-MP), oppure terapia contro il fattore di necrosi tumorale (Anti-Tumor Necrosis Factor, TNF), quale per es. infliximab o adlimumab. 9. I soggetti che stanno attualmente assumendo i seguenti regimi di trattamento per UC sono idonei a condizione che stiano assumendo una dose stabile per il periodo di tempo designato: a. Dose stabile di 5-ASA o sulfasalazina per almeno 3 settimane prima del Giorno 1 e durante il periodo di trattamento dello studio. b. Corticosteroidi o farmaci equivalenti a una dose stabile per almeno 2 settimane prima della visita dello studio al Giorno 1 (prednisolone ≤25 mg/die o equivalente). NOTA: la riduzione graduale del regime di corticosteroidi o equivalenti può iniziare solo alla Settimana 8 (fare riferimento alla sezione “Terapie concomitanti”). c. Antibiotici (per es. metronidazolo, rifaximina) a dose stabile per almeno 2 settimane prima della visita dello studio del Giorno 1 e durante il periodo di trattamento con il farmaco dello studio, per es. fino alla Settimana 8. d. Formulazioni di corticosteroidi o 5-ASA per somministrazione rettale a dose stabile per almeno 2 settimane prima della visita dello studio del Giorno 1 e durante il periodo di trattamento con il farmaco dello studio. e. Metotrexato (fino a 15 mg/settimana per via sottocutanea) a dose stabile per almeno 2 mesi prima della visita dello studio del Giorno 1. Azatioprina (fino a 2,5 mg/kg/die) o 6-mercaptopurina (fino a 1,5 mg/kg/die) a dose stabile per almeno 3 mesi prima della visita dello studio del Giorno 1 e durante il periodo di trattamento con il farmaco dello studio. 10. Soggetti che accettano di utilizzare un doppio sistema contraccettivo durante il periodo di trattamento con il farmaco dello studio e fino al completamento delle procedure di follow-up, ovvero alla Settimana 52. 11. Se il soggetto è una donna sessualmente attiva in età fertile, tale soggetto e il suo partner di sesso maschile dovranno utilizzare contemporaneamente 2 metodi contraccettivi efficaci, secondo le indicazioni nella Sezione 4.4.2 del Protocollo. I soggetti femminili che desiderino utilizzare un sistema contraccettivo non ormonale devono avere adottato tale pratica almeno 14 giorni prima della visita del Giorno 1 dello studio. 12. I maschi non sottoposti a vasectomia con partner femmina fertile devono utilizzare un preservativo e la partner adottare un’altra forma di contraccezionecome riportato nel Protocollo alla sezione 4.4.2.
    E.4Principal exclusion criteria
    1. Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial. 2. Abnormal organ and marrow function as defined: a. Leukocytes <4,000/L. b. Platelets <150,000/L. c. AST (SGOT) or ALT (SGPT) >3x institutional upper limit of normal. d. Bilirubin >upper institutional limit of normal. e. Creatinine >1.2 mg/dL. 3. Diagnosis of indeterminate colitis, or clinical findings suggestive of Crohn’s disease, including Crohn’s enterocolitis, ischaemic colitis, radiation colitis, diverticular disease associated colitis as well as microscopic colitis. 4. Subjects with UC, which is confined to a proctitis defined as inflammation limited to less than 15 cm from the anal verge on a flexible sigmoidoscopy. 5. Subjects who meet Truelove-Witts criteria for severe UC. Diarrhea >6 times/day, bloody and any one of the items: a. Hemoglobin 75% or below of normal value. b. Evening temperature >37.5C. c. Pulse rate >90 beats/min. d. ESR >30 mm/h. 6. Subjects who have received i.v. steroids or TPN or have been hospitalized due to UC within 3 weeks prior to screening. 7. Subjects displaying clinical signs of toxic megacolon, ischemic colitis or fulminant colitis. 8. Known allergies to bovine or porcine products, dextran, or H1 blockers. 9. Known intolerance to corticosteroids. 090177e18273d9ff\Approved\Approved On: 18-Oct-2011 10:33 PF-05285401 B3041001 Protocol Amendment 6, 18 October 2011 PFIZER CONFIDENTIAL Page 37 10. Subjects who have previously participated in any study of an allogeneic cell therapy, with the exception of erythrocyte transfusions. 11. Subjects who have received any investigational drug or device within 3 months (or as determined by the local requirement, whichever is longer) prior to Day 1 study visit. 12. History of symptomatic obstructive strictures, an ostomy, extensive bowel resection (>100 cm) or short bowel syndrome. 13. History of bowel surgery within 6 months prior to Day 1 study visit. 14. Subject who have had surgery as a treatment for UC or, in the opinion of the investigator, are likely to require surgery within 16 weeks of informed consent. 15. Subjects diagnosed with primary sclerosing cholangitis. 16. Subjects with active inflammatory eye disease. 17. Subjects with spondylarthropathy and active musculoskeletal manifestation. 18. Subjects with active pyoderma gangrenosum or erythema nodosum lesions. 19. Subjects with clinically significant pulmonary disease (eg, subjects with COPD GOLD stage III or IV). 20. Subjects with NYHA class IV congestive heart failure. 21. Subjects with active systemic or severe local infections. 22. Fecal culture indicating presence of pathogenic infection; positive C. difficile toxin, or positive stool ova and parasite exam. 23. Subjects likely to require any type of surgery within 16 weeks from informed consent. 24. Known collection or abscess on MRI of the pelvis. 25. Pregnant or lactating women. 26. History of alcohol or drug abuse with less than 6 months of abstinence prior to Day 1 study visit. 27. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results. 28. Subjects with a temperature of 38C (100.4F) or higher at screening. 090177e18273d9ff\Approved\Approved On: 18-Oct-2011 10:33 PF-05285401 B3041001 Protocol Amendment 6, 18 October 2011 PFIZER CONFIDENTIAL Page 38 29. Subjects with malignancies or with a history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin
    1. Soggetti membri del personale del centro sperimentale o dipendenti di Pfizer direttamente coinvolti nella conduzione della sperimentazione. 2. Funzione anormale di organo o midollo definita come segue: a. Leucociti &lt;4.000/μl. b. Piastrine &lt;150.000/μl. c. AST (SGOT) o ALT (SGPT) &gt;3x il limite superiore di normalità adottato dall’istituto. d. Bilirubina &gt;limite superiore di normalità adottato dall’istituto. e. Creatinina &gt;1,2 mg/dl. 3. Diagnosi di colite indeterminata o rilevamenti clinici che suggeriscono malattia di Crohn, inclusa enterocolite di Crohn, colite ischemica, colite da radiazione, patologia diverticolare associata a colite e colite microscopica. 4. Soggetti con UC che sia confinata a proctite definita come infiammazione limitata a meno di 15 cm dal limite anale su sigmoidoscopia flessibile. 5. Soggetti che soddisfano i criteri Truelove-Witts per UC grave. Diarrea &gt; 6 volte al giorno, sangue nelle feci e uno qualsiasi dei seguenti: a. Emoglobina 75% o inferiore rispetto al valore normale. b. Temperatura corporea alla sera &gt;37,5 °C. c. Polso &gt; 90 battiti al minuto. d. ESR &gt; 30 mm/h. 6. Soggetti che abbiano ricevuto steroidi o TPN per via endovenosa o siano stati ricoverati a causa di UC nelle 3 settimane precedenti allo screening. 7. Soggetti che mostrino segni clinici di megacolon tossico, colite ischemica o colite fulminante. 8. Allergie note a prodotti bovini o suini o destrano o bloccanti H1. 9. Intolleranza nota ai corticosteroidi. 10. Soggetti che abbiano partecipato in precedenza a qualsiasi studio relativo a terapia cellulare allogenica, a eccezione delle trasfusioni di eritrociti. 11. Soggetti che abbiano ricevuto qualsiasi farmaco o dispositivo sperimentale entro 3 mesi (o entro il limite determinato dalle normative locali, a seconda del periodo più lungo) prima della visita al Giorno 1 dello studio. 12. Anamnesi di stenosi ostruttive sintomatiche, ostomia, resezione intestinale estensiva (&gt;100 cm) o sindrome da intestino corto. 13. Anamnesi di intervento chirurgico all’intestino nei 6 mesi precedenti la visita al Giorno 1 dello studio. 14. Soggetti che siano stati sottoposti a intervento chirurgico per il trattamento di UC o, a giudizio dello sperimentatore, possano necessitare di tale intervento entro 16 settimane dal consenso informato. 15. Soggetti a cui sia stata diagnosticata la colangite sclerosante primaria. 16. Soggetti con patologia infiammatoria oculare attiva. 17. Soggetti con spondilartopatia e manifestazioni muscoloscheletriche attive. 18. Soggetti con lesioni da pioderma cancrenoso o eritema nodoso. 19. Soggetti con pneumopatia clinicamente significativa (per es. soggetti con COPD GOLD di stadio III o IV). 20. Soggetti con insufficienza cardiaca congestizia di classe IV NYHA. 21. Soggetti con infezioni sistemiche o infezioni locali gravi attive. 22. Colture fecali indicanti presenza di infezione patogena; tossina C. difficile positiva o risultato positivo all’esame delle feci per la presenza di uova e parassiti. 23. Soggetti per i quali è probabile che sia necessario un qualsiasi intervento chirurgico entro 16 settimane dal consenso informato. 24. Raccolta o ascesso noti su scansione a RMI della pelvi. 25. Donne in stato di gravidanza o allattamento al seno. 26. Storia di abuso di alcool o droghe con meno di 6 mesi di astinenza prima della visita dello studio al Giorno 1. 27. ECG a 12 derivazioni allo screening che dimostri anomalie clinicamente rilevanti che possano influire sulla sicurezza del soggetto o sull’interpretazione dei risultati dello studio. 28. Soggetti con temperatura corporea pari o superiore a 38 °C (100,4 °F). 29. Soggetti con neoplasie o anamnesi di neoplasia, a eccezione di cancro della pelle a cellule squamose o cellule basali non metastatico trattato o rimosso adeguatamente.
    E.5 End points
    E.5.1Primary end point(s)
    -Incidence and severity of adverse events (at Weeks, 4, 8, 12 and 16).
    -Change from baseline of endoscopic score at Week 8 as measured by modified Baron
    score.
    -Change from baseline of Mayo rectal bleeding sub-score at Week 4.
    -Change from baseline of Mayo rectal bleeding sub-score at Week 8.
    • Incidenza e gravità degli eventi avversi (alle Settimane 4, 8, 12 e 16).

    • Variazione rispetto al basale del punteggio endoscopico alla Settimana 8, misurato in base al punteggio Baron modificato.
    • Variazione rispetto al basale del sottopunteggio Mayo relativo al sanguinamento rettale alla Settimana 4.
    • Variazione rispetto al basale del sottopunteggio Mayo relativo al sanguinamento rettale alla Settimana 8.
    E.5.1.1Timepoint(s) of evaluation of this end point
    weeks 4,8,12 and 16
    Settimane 4,8,12 e 16
    E.5.2Secondary end point(s)
    -Change from baseline of Mayo rectal bleeding sub-score at Weeks 12 and 16.
    -Changes in laboratory measurements of safety and vital signs (at Weeks 4, 8, 12, and 16).
    -Changes from baseline at Weeks 4, 8, 12 and 16 in the following biomarker levels: fecal
    calprotectin, CRP.
    -Proportion of subjects with a Mayo rectal bleeding sub-score equal 0 at Weeks 4, 8, 12 and 16.
    -Proportion of subjects in endoscopic remission at Week 8 (defined as subjects with a
    modified Baron endoscopic score equal 0).
     Proportions of subjects in clinical remission at Week 8 (defined as a total Mayo score of
    2 points or lower, with no individual sub-score exceeding 1 point).
    -Proportions of subjects with a decrease from baseline of at least one point in Mayo rectal
    bleeding sub-score at Weeks 4, 8, 12 and 16.
    -Proportion of subjects with an endoscopic response at Week 8 (defined as a decrease in
    modified Baron endoscopic score from baseline of at least 2 points).
    -Proportion of subjects with a clinical response at Week 8 (defined as a decrease in total
    Mayo score from baseline in Mayo score of at least 3 points and at least 30 percent, with
    an accompanying decrease in the sub-score for rectal bleeding of at least 1 point or an
    absolute sub-score for rectal bleeding of 0 or 1).
    -Changes from baseline in total Mayo score at Week 8.
    -Changes from baseline in partial Mayo score at Weeks 4, 8, 12 and 16.
    -Patient-reported rectal bleeding scores, to be modeled longitudinally up to and including
    Week 16.
    -Changes in biopsy histology score at Week 8 (measured by Riley Index).
    • Variazione rispetto al basale del sottopunteggio Mayo relativo al sanguinamento rettale alle Settimane 12 e 16.
    • Variazione delle misurazioni di laboratorio sulla sicurezza e sui parametri vitali (alle Settimane 4, 8, 12 e 16).
    • Variazioni rispetto al basale alle Settimane 4, 8, 12 e 16 dei livelli dei seguenti biomarcatori: calprotectina fecale, CRP.
    • Percentuali di soggetti con sottopunteggio Mayo relativo al sanguinamento rettale pari a 0 alle Settimane 4, 8, 12 e 16.
    • Percentuale di soggetti in remissione endoscopica alla Settimana 8 (definita sulla base di come soggetti con punteggio endoscopico Baron modificato pari a 0).
    • Percentuale di soggetti in remissione clinica alla Settimana 8 (definita come punteggio Mayo totale pari o inferiore a 2, non nessun sottopunteggio individuale superiore a 1 punto).
    • Percentuale di soggetti con riduzione rispetto al basale di almeno un punto del sottopunteggio Mayo relativo al sanguinamento rettale alle Settimane 4, 8, 12 e 16.
    • Percentuale di soggetti con risposta endoscopica alla Settimana 8 (definita come una riduzione del punteggio endoscopico Baron modificato rispetto al basale di almeno 2 punti).
    • Percentuale di soggetti con risposta clinica alla Settimana 8 (definita come riduzione del punteggio Mayo totale rispetto al basale del punteggio Mayo di almeno 3 punti e di almeno il 30%, con una concomitante riduzione del sottopunteggio di sanguinamento rettale pari ad almeno 1 punto o un sottopunteggio assoluto di sanguinamento rettale pari a 0 o 1).
    • Variazione rispetto al basale del punteggio Mayo totale alla Settimana 8.
    • Variazioni rispetto al basale del punteggio Mayo parziale alla Settimana 4, 8, 12 e 16.
    • Punteggi relativi al sanguinamento rettale riportati dal paziente, modellati in senso longitudinale verso l’alto e che comprendono la Settimana 16.
    • Variazioni del punteggio istologico della biopsia alla Settimana 8 (misurate tramite Indice Riley).
    E.5.2.1Timepoint(s) of evaluation of this end point
    weeks 4,8,12 and 16
    Settimane 4,8,12 e 16
    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 Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    tollerabilità
    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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Canada
    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 years0
    E.8.9.1In the Member State concerned months14
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months29
    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.1.1Number of subjects for this age range: 0
    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: 104
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 55
    F.4.2.2In the whole clinical trial 128
    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)
    Normal treatment of the condition
    Normale trattamento della condizione
    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 Decision2012-02-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-11-19
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