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    Summary
    EudraCT Number:2012-000529-31
    Sponsor's Protocol Code Number:20110232
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-09-21
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-000529-31
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 in Subjects with Moderate to Severe Crohn’s Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to find out more about the effect of AMG 181 in people with moderate to severe Crohn's Disease
    A.4.1Sponsor's protocol code number20110232
    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 SponsorAmgen 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 supportAmgen Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ Medical Info - Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.4Telephone numberN/A
    B.5.5Fax numberN/A
    B.5.6E-mailMedinfoInternational@amgen.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 nameAMG 181
    D.3.2Product code AMG 181
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMG 181
    D.3.9.2Current sponsor codeAMG 181
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    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) Yes
    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 Yes
    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 placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate to severe Crohn's Disease
    E.1.1.1Medical condition in easily understood language
    Crohn's Disease
    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 17.0
    E.1.2Level LLT
    E.1.2Classification code 10011402
    E.1.2Term Crohn's disease (colon)
    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 evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving Crohn’s Disease Activity Index (CDAI) remission (CDAI < 150) at week 8
    E.2.2Secondary objectives of the trial
    Key Secondary:
    - To evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving CDAI remission (CDAI < 150) at week 12
    - To evaluate the efficacy of AMG 181 as measured by the proportion of subjects with a CDAI response (defined as either remission or a CDAI reduction from baseline of ≥ 100) at week 12
    - To evaluate the efficacy of AMG 181 as measured by the proportion
    of subjects with a CDAI response (defined as either remission or a CDAI reduction from baseline of ≥ 100) at week 8

    Other Secondary:
    - To evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving sustained remission at both week 12 and week 24
    - To evaluate the efficacy of AMG 181 as measured by the proportion of subjects achieving sustained remission, defined as achieving the criteria for remission (CDAI < 150) at both week 8 and week 24
    - To evaluate change from baseline in CDAI score at week 12
    - To evaluate change from baseline in CDAI at week 8
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There are 4 substudies for sites in Europe
    - PK Substudy: Participation in the PK substudy is optional. Subjects will visit the clinic for additional pharmacokinetic samples
    - Biomarker Development Blood and Stool Samples Substudy: A subgroup of subjects who provide additional informed consent will participate in the biomarker development substudy. Additional blood samples will be collected for assessment of transcript markers and plasma protein analytes. No additional stools samples will be collected other than those described for the main study
    - Pharmacogenetic Substudy:A subgroup of subjects who provide additional informed consent will participate in the pharmacogenetic substudy. Participation in this substudy is optional. Subjects can only participate in the pharmacogenetic substudy if they have also provided consent for the biomarker substudy. No additional blood samples will be collected.
    - Immunophenotyping and Absolute Counting (IPAC) PD Assay Substudy: A subgroup of subjects who provide additional informed consent will participate in the IPAC PD assay substudy for enumeration of, and assessment of α4β7 occupancy by AMG 181 on, naïve and memory CD4+ T cell subsets by flow cytometry. Participation in the IPAC substudy is limited to selected sites.
    E.3Principal inclusion criteria
    - Subject has provided informed consent
    - Subject is ≥ 18 and ≤ 65 years of age at screening
    - Subject has diagnosis of ileal, ileo-colonic, or colonic Crohn’s disease for a minimum of 6 months prior to baseline
    - Subject has moderately to severely active Crohn’s disease, as defined by a CDAI score ≥ 220 and ≤ 450 at baseline
    - Subject has evidence of active inflammation, as demonstrated by at least one of the following:
    • Elevated C-Reactive Protein (CRP) at screening (≥ 5 mg/L)
    • Elevated fecal calprotectin at screening (≥ 200 μg/g)
    • Endoscopic evidence of inflammation within 12 weeks prior to baseline as demonstrated by photographic documentation of a minimum of 3 nonanastomotic ulcerations (each > 0.5 cm in diameter) or 10 aphthous ulcerations (involving a minimum of 10 contiguous cm of intestine)
    - Subject has demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following agents: Immunomodulators or Anti-TNF agents or to corticosteroids (non-US sites only)
    - Subject can be receiving the following treatments:
    • 5-aminosalicylates, oral prednisone or equivalent ≤ 20 mg/day, budesonide (≤ 9 mg/day), oral antibiotics for treatment of Crohn’s disease (ie, ciprofloxacin, metronidazole) if stable dosage for ≥ 2 weeks prior to baseline
    • Methotrexate (≤ 25 mg/week), azathioprine, 6-mercaptopurine if stable dosage for ≥ 8 weeks prior to baseline
    • Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the dose has been stable for the 2 weeks prior to baseline
    • Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea
    - Subject has neurological exam free of clinically significant, unexplained signs or symptoms in the opinion of the investigator during screening and no clinically significant change prior to randomization
    -Subject has no known history of active tuberculosis
    -Subject has a negative test for tuberculosis during screening

    For a full list of inclusion criteria, please refer to section 4.1 of the protocol

    E.4Principal exclusion criteria
    Disease Specific
    - Subject has clinical manifestations of short bowel syndrome (defined as requiring oral or parenteral supplemental or total nutrition in order to maintain stable body weight)
    - Subject had stricture with obstructive symptoms within 3 months prior to baseline
    - Subject has ileostomy and/or colostomy, or gastric or intestinal pouch
    - Subject has evidence of an infected abscess
    - Subject had bowel perforation or evidence of noninflammatory obstruction during the 6 months prior to baseline
    - Subject has stool positive for C. difficile toxin at screening

    Excluded Medications
    - Subject received an anti-TNF agent within 8 weeks or 5 times the respective elimination half-life, whichever is longer (eg, 8 weeks for infliximab, 10 weeks for adalimumab or certolizumab pegol), prior to baseline
    - Subject received cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, or tacrolimus within 1 month prior to baseline
    - Subject received topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to baseline
    - Subject received intravenous or intramuscular corticosteroids within 2 weeks prior to screening and during screening
    - Subject had any prior exposure to antagonists of integrins or integrin ligands (eg, natalizumab, efalizumab, or vedolizumab), rituximab, or TNF kinoid immunotherapies
    - Subject had any prior exposure to AMG 181

    Laboratory Abnormalities
    - Subject has abnormal laboratory results at screening:
    • Liver tests: either aspartate aminotransferase (AST), alanine transaminase (ALT), or alkaline phosphatase (ALP) > 2.0 Upper Limit of Normal (ULN) or total bilirubin (TBL) > 1.5 ULN (except for subjects with Gilbert Syndrome)
    • White blood cell count < 3,000 cells/mm3 (< 3 x 109/L in SI units)
    • Hemoglobin < 10 g/dL

    General
    - Female subject is not willing to prevent pregnancy from occurring during treatment and for 7 months after the last dose of investigational product (except if ≥ 2 years postmenopausal or surgically sterile). Prevention of pregnancy involves a female subject not having intercourse during treatment and for 7 months after the last dose of investigational product, or the use of two methods of birth control. This means the simultaneous use of: Two highly effective methods of birth control, or one highly effective method of birth control and one effective method of birth control. Highly effective methods (≥ 99% effective when used correctly) of birth control include: hormonal birth control methods (pills, shots, implants or patches), intrauterine devices, sexual activity with a male partner who has had a vasectomy, tubal sterilization (tie, clip, band, burn), or tubal occlusion (insert placed in tube, after confirmed occlusion). Effective methods (< 99% effective) of birth control include: barrier method of condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide.
    - Subject is pregnant, breast feeding, or might become pregnant within 7 months after the last dose of investigational product

    For a full list of exclusion criteria, please refer to section 4.2 of the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Remission at week 8, as defined by a CDAI score of < 150
    E.5.1.1Timepoint(s) of evaluation of this end point
    at week 8
    E.5.2Secondary end point(s)
    Key Secondary Endpoints:
    - Remission at week 12, as defined by a CDAI score of < 150
    - Response at week 12, as defined by either remission or a CDAI reduction from baseline of ≥ 100
    - Response at week 8, as defined by either remission or a CDAI reduction from baseline of ≥ 100

    Other Secondary Endpoints:
    - Sustained remission at both week 12 and week 24
    - Sustained remission, defined as achieving the criteria for remission at both week 8 and week 24
    - Change from baseline in CDAI score at week 12
    - Change from baseline in CDAI score at week 8
    E.5.2.1Timepoint(s) of evaluation of this end point
    refer to E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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
    placebo-controlled period followed by open label period (see Protocol section 3.1)
    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 trial4
    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 EEA54
    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
    Austria
    Belgium
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Netherlands
    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
    "LVLS"
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    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: 242
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 171
    F.4.2.2In the whole clinical trial 252
    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)
    Plans for treatment of care after the subject has ended participation
    are not different from the expected normal treatment for this condition.
    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 Decision2012-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-09-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-04-10
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