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    Summary
    EudraCT Number:2017-003649-10
    Sponsor's Protocol Code Number:CA40192
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-12-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2017-003649-10
    A.3Full title of the trial
    A PHASE I, OPEN–LABEL, RANDOMIZED, PHARMACOKINETIC, PHARMACODYNAMIC, AND SAFETY STUDY OF ETROLIZUMAB FOLLOWED BY OPEN–LABEL EXTENSION AND SAFETY MONITORING IN PEDIATRIC PATIENTS FROM 4 YEARS TO LESS THAN 18 YEARS OF AGE WITH MODERATE TO SEVERE ULCERATIVE COLITIS OR MODERATE TO SEVERE CROHN’S DISEASE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Pharmacokinetic, Pharmacodynamic, and Safety Study of Etrolizumab Followed by Open-Label Extension and Safety Monitoring in Pediatric Patients From 4 Years to Less Than 18 Years of Age with Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn’s Disease
    A.4.1Sponsor's protocol code numberCA40192
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/148/2015
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 nameEtrolizumab
    D.3.2Product code 549-0261/F02-01
    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 INNETROLIZUMAB
    D.3.9.1CAS number 1044758-60-2
    D.3.9.2Current sponsor codeRO5490261/F02-01
    D.3.9.3Other descriptive nameETROLIZUMAB
    D.3.9.4EV Substance CodeSUB75320
    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 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 Yes
    D.3.11.13.1Other medicinal product typeHumanized monoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate to severe ulcerative colitis (UC); moderate to severe Crohn’s disease (CD)
    E.1.1.1Medical condition in easily understood language
    UC and CD are types of inflammatory bowel disease (IBD) that affects the lining of the digestive tract
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10011401
    E.1.2Term Crohn's disease
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10009900
    E.1.2Term Colitis ulcerative
    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 pharmacokinetics (PK) and pharmacodynamics (PD)of etrolizumab in a pediatric IBD patient population (Randomized Treatment Phase)
    E.2.2Secondary objectives of the trial
    •To evaluate the overall safety and tolerability of etrolizumab in pediatric population (Randomized Treatment Phase)
    •To evaluate long-term safety and efficacy of etrolizumab in pediatric population (Open–label Extension Phase)
    •Post-trial safety surveillance with focus on progressive multifocal leukoencephalopathy (PML) monitoring in patients who have stopped treatment (PML Monitoring Phase)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age of 4 years to < 18 years
    - Weight of 13 kg or more
    - Diagnosis of UC or CD confirmed by biopsy and established for >= 3 months prior to screening
    - Inadequate response, loss of response or intolerance to prior immunosuppressants and/or corticosteroid treatment and/or anti-TNF therapy
    - For patients with UC: moderately to severely active UC as determined by an MCS of 6-12 with an endoscopic subscore >= 2 and a rectal bleeding subscore >= 1
    - For patients with CD: moderately to severely active CD as determined by a Pediatric Crohn’s Disease Activity Index (PCDAI) score of >30 at baseline
    - Patients must meet the surveillance colonoscopy requirements such as document evidence of surveillance for dysplasia every 1 to 2 years, beginning approximately 7 to 10 years after their initial diagnosis
    - For postpubertal females of childbearing potential: agreement to remain abstinent or use acceptable contraceptive methods during the treatment period and for at least 24 weeks after the last dose of etrolizumab
    - For male patients: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm for at least 24 weeks after the last dose of study drug to avoid exposing the embryo to study drug
    E.4Principal exclusion criteria
    For IBD
    - Prior extensive colonic resection, subtotal or total colectomy, or planned surgery
    - Past or present ileostomy or colostomy and a history or current evidence of colonic mucosal dysplasia
    - Diagnosis of indeterminate colitis, toxic megacolon within 12 months of initial screening visit
    - Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
    - Abdominal abscessl
    - Patients with fixed symtomatic stenosis of the intestine and having history or evidence of adenomatous colonic polyps that have not been removed and who are not up to date on vaccinations per the local vaccine schedule will be excluded

    For UC
    - Severe extensive colitis per investigator judgment that colectomy is imminent or the patient has two of the mentioned five symptoms at screening or baseline visit such as 6 bowel movements daily with obvious blood, abdominal examination worrisome for imminent surgery, persistent fever, tachycardia and anemia

    For CD
    - Sinus tract with evidence for infection in the clinical judgment of the investigator, short-bowel syndrome and evidence of abdominal or perianal abscess
    - Expected to require surgery to manage CD-related complications during the study

    For Prior or Concomitant Therapy
    - Any prior treatment with anti-integrins, ustekinumab,anti-adhesion molecules and rituximab
    - Use of intravenous (IV) steroids within 30 days prior to screening with the exception of a single administration of IV steroid, use of agents that deplete B or T cells within 12 months prior to Day (D)1, with the exception of azathioprine and 6 mercaptopurine; use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 4 weeks prior to D1, other biologics within 8 weeks before dosing (unless drug level is below detectability before completion of the 8-week interval) and use of chronic nonsteroidal anti-inflammatory drug and anticoagulants and apheresis within 2 weeks prior to D1
    - Received any investigational treatment including investigational vaccines within 12 weeks prior to D1 of the study or 5 half-lives of the investigational product
    - History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to etrolizumab or any of excipients

    For General Safety
    - Lack of peripheral venous access
    - Congenital or acquired immune deficiency
    - Significant uncontrolled comorbidity, such as cardiac, pulmonary, renal, hepatic, endocrine, or gastrointestoinal disorders (excluding UC and CD) and clinically significant abnormalities on the screening PML Subjective Checklist
    - Neurological conditions or diseases that may interfere with PML monitoring
    - History of demyelinating disease , major neurological disorder and cancer
    - Conditions other than UC or CD that could require treatment with >10 mg/day of prednisone during course of the study

    For Infection Risk
    - Congenital or acquired immune deficiency
    - Patients must undergo screening for HIV and test positive for preliminary, confirmatory tests and hepatitis B virus
    - Positive hepatitis C virus (HCV) antibody test result, unless patient who has undetectable HCV RNA levels for >6 months after completing a successful course of HCV anti-viral treatment and an undetectable HCV RNA at screening or who has a known history of HCV antibody positivity with a history of undetectable HCV RNA and undetectable HCV RNA at screening in absence of history of HCV anti-viral treatment
    - Positive stool test result for ova or parasites or positive stool culture for pathogens at time of screening
    - Evidence of or treatment for Clostridium difficile, other intestinal pathogens and clinically significant cytomegalovirus colitis within 60,30 and 60 days prior to D1 respectively. Laboratory confirmation of CMV from colon biopsy sample is required during screening evaluation only if clinical suspicion is high and to determine the need for CMV treatment
    - History of active or latent treated tuberculosis (TB) and organ transplant and recurrent opportunistic and/or history of severe disseminated viral infections
    - Suspicion of active TB on chest radiograph taken within 3 months of randomization
    - Any major episode of infection requiring treatment with IV antibiotics or oral antibiotics within 8 and within 4 weeks prior to screening and received a live attenuated vaccine within 4 weeks prior to D1
    For Laboratory Values (at Screening)
    - Serum creatinine >1.5 times upper limit of normal (ULN), alanine transaminase or aspartate transaminase >3 ULN, or alkaline phosphatase >3 ULN, or total bilirubin >2.5 ULN
    - In patients with diabetes: glycosylated hemoglobin > 8.0%, platelet count <100,000/mL, hemoglobin <8 g/dL, absolute neutrophil count <1500/mL, absolute lymphocyte count <500/mL
    E.5 End points
    E.5.1Primary end point(s)
    1.Maximum concentration observed (Cmax) (Randomized Treatment Phase)
    2.Area under the concentration-time curve within a dosing interval (AUCtau) (Randomized Treatment Phase)
    3.Elimination half-life (t1/2) (Randomized Treatment Phase)
    4.Steady-state concentration at the end of a dosing interval (Ctrough) (Randomized Treatment Phase)
    5.PD parameters: β7 receptor occupancy by flow cytometry on peripheral blood lymphocytes (Randomized Treatment Phase)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-4. Treatment period: D1 of Week (W)0;D4;D28 (W4); D56 (W8); D60 and 70; D84 (W12); D88 and 98; D112 (W16) and at unscheduled visit and early withdrawal from treatment or discontinuation
    Safety follow-up period: At D126 (W18), D140 (W20) and D168 (W24) or early withdrawal visit
    5. Treatment period: D1 (W0), D4, D56 (W8), D84 (W12), D98, D112 (W16) and at unscheduled visit and early withdrawal from treatment or discontinuation
    Safety follow-up period: At D126 (W18), D140 (W20) and D168 (W24) or early withdrawal visit
    E.5.2Secondary end point(s)
    1.Incidence and severity of infection-related adverse events (Randomized Treatment and Open–Label Extension Phase)
    2.Incidence of immunogenic responses (anti-drug antibodies [ADAs]) (Randomized Treatment Phase)
    3.Incidence and severity of hypersensitivity reaction events (Randomized Treatment and Open–Label Extension Phase)
    4.Incidence and severity of malignancies (Open–Label Extension Phase)
    5.Incidence of ADAs to etrolizumab (Open–Label Extension Phase)
    6.Clinical response at W132, as assessed by the Pediatric Ulcerative Colitis Activity Index (UC) and Pediatric Crohn's Disease Activity Index (CD) (Open–Label Extension Phase)
    7.Occurrence of confirmed PML events (PML Monitoring Phase)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-5. Up to 5 years
    6. At W132
    7. Up to 104 weeks
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    pediatric
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Belgium
    Germany
    Poland
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for PK/PD or statistical analysis or safety follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur 60 months after the last patient is enrolled. The total length of the study, from screening of the first patient to the end of the study, is expected to be
    approximately 5 years.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 60
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 45
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects under age incapable of giving consent personally - Signed Informed Consent Form by parent or legal guardian
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 55
    F.4.2.2In the whole clinical trial 60
    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)
    The Sponsor will offer continued access to Roche IMP etrolizumab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to IMP: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf.
    In addition, patients that are >18 years of age have the option to enroll in the adult open–label extension studies of GA28951 for UC and GA29145 for CD if they meet eligibility criteria
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-15
    P. End of Trial
    P.End of Trial StatusOngoing
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