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    Summary
    EudraCT Number:2018-003278-28
    Sponsor's Protocol Code Number:204869
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-07-22
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-003278-28
    A.3Full title of the trial
    A multicentre randomized, double-blind, placebo-controlled Phase 2 study to evaluate the safety, tolerability, efficacy, dose-response, pharmacokinetics and pharmacodynamics of repeat dosing of an anti-LAG3 cell depleting monoclonal antibody (GSK2831781) in patients with active ulcerative colitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety, tolerability, efficacy and dose-response of GSK2831781 in ulcerative colitis.
    A.4.1Sponsor's protocol code number204869
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03893565
    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 SponsorGlaxoSmithKline Research & Development 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 supportGlaxoSmithKline Research & Development Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Limited
    B.5.2Functional name of contact pointGSK Clinical Support Help Desk
    B.5.3 Address:
    B.5.3.1Street Address980 Great West Road
    B.5.3.2Town/ cityBrentford, Middlesex
    B.5.3.3Post codeTW8 9GS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4408007839733
    B.5.6E-mailGSKClinicalSupportHD@gsk.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.3.2Product code GSK2831781
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot Assigned
    D.3.9.1CAS number Not assigned
    D.3.9.2Current sponsor codeGSK2831781
    D.3.9.3Other descriptive nameGSK2831781
    D.3.9.4EV Substance CodeSUB130526
    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 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 infusion
    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 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
    Ulcerative Colitis
    E.1.1.1Medical condition in easily understood language
    Ulcerative Colitis
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10045365
    E.1.2Term Ulcerative colitis
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To evaluate the safety and tolerability of repeat doses of GSK2831781
    during the Double-Blind Induction Phase.
    - To characterise the efficacy dose response of GSK2831781 during the
    Double-Blind Induction Phase.
    E.2.2Secondary objectives of the trial
    - To evaluate the safety and tolerability of repeat doses of GSK2831781
    during the Double-Blind Extended Treatment Phase.
    - To investigate the effect of repeat doses of GSK2831781 on clinical
    efficacy including endoscopic mucosal healing during the Double-Blind
    Induction Phase.
    - To investigate the effect of repeat doses of GSK2831781 on UC
    histologic disease activity during the Double-Blind Induction Phase.
    - To investigate the effect of repeat doses of GSK2831781 on biomarkers
    of UC disease activity during the Double-Blind Induction Phase.
    - To investigate the pharmacokinetics of GSK2831781 following
    subcutaneous dosing.
    - To investigate the immunogenicity of repeat doses of GSK2831781
    during the Double-Blind Induction Phase.
    - To evaluate the safety and tolerability of repeat doses of GSK2831781
    in all trial phases.
    - To investigate the immunogenicity of repeat doses of GSK2831781 in
    all trial phases
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    AGE and WEIGHT: Participant must be 18 years of age or older and >40kg at the time of signing the informed consent.

    TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS:
    Participants who have a:
    -Diagnosis of ulcerative colitis, established at least 3 months prior to screening, as documented by diagnostic sigmoidoscopy or colonoscopy, and biopsy.
    -Complete 4-domain Mayo Score of 6 to 12, with disease extending ≥15cm from the anal verge, with a centrally read endoscopic subscore of ≥2 at screening endoscopy, and a rectal bleeding subscore ≥1.
    -A history of at least one of the following:
    (1) Inadequate response to, loss of response to, or intolerance to azathioprine or mercaptopurine (including thiopurine methyltransferase (TPMT) and NUDT15 genetic mutations precluding use), ciclosporin, tacrolimus or methotrexate.
    (2) Inadequate response to, loss of response to, intolerance to, or demonstrated dependence on oral corticosteroids.
    (3) Inadequate response to, loss of response to, or intolerance to at least one approved advanced therapy for UC, including anti-TNF therapies, anti-integrin therapies, anti-IL-12/23 monoclonal antibodies or JAK inhibitors.
    - Surveillance colonoscopy (performed according to local standards) within 12 months of screening (or during screening, if required) for participants with:
    (1) Pancolitis of >8 years duration; or
    (2) Patients with left-sided colitis of >12 years duration; or
    (3) For patients for whom this criterion does not apply, colorectal cancer surveillance should be undertaken according to local or national guidelines for patients with age ≥50, or with other known risk factors for colorectal cancer.

    SEX
    Both male and female participants are eligible to participate.
    Female participants:
    - A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
    (1) Not a woman of childbearing potential (WOCBP),
    OR
    (2) A WOCBP who agrees to use a highly effective contraceptive method for at least 4 weeks prior to dosing, until the Follow-Up visit.

    INFORMED CONSENT
    -Capable of giving signed informed consent as described in the protocol
    E.4Principal exclusion criteria
    Medical Conditions:
    1)Current diagnosis of indeterminate colitis, inflammatory bowel disease-unclassified, CD, infectious colitis, or ischaemic colitis
    2)Fulminant UC (as defined by 6 bloody stools daily AND 1 or more of: i) body temperature ≥100.4°F (or 38°C) or ii) heart rate >90 beats per minute),or toxic megacolon
    3)Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or planned surgery for UC
    4)Any uncontrolled medical conditions, other than active UC, that in the opinion of the investigator put the participant at unacceptable risk or interfere w/ study assessments or integrity of the data. Other medical conditions should be stable at the time of screening and be expected to remain stable for the duration of the study
    5)Unstable lifestyle factors, such as alcohol use to excess or recreational drug use, to the extent that in the opinion of the investigator they would interfere w/ the ability of a participant to complete the study
    6)An active infection or a history of serious infections as described in the protocol
    7)Current or history of chronic liver or biliary disease w/ the exception of Gilbert’s syndrome, asymptomatic gallstones or uncomplicated fatty liver disease
    8)Hereditary/acquired immunodeficiency disorder, including immunoglobulin deficiency unless the participant has a documented history of elective IgA deficiency
    9)A major organ transplant or haematopoietic stem cell/marrow transplant
    10)Any planned major surgical procedure during the study
    11)A history of malignant neoplasm w/in the last 5 yrs, except for adequately treated non-metastatic basal or squamous cell cancers of the skin (w/in 1 yr) or carcinoma in situ of the uterine cervix (w/in 3 yrs) that has been fully treated and shows no evidence of recurrence
    PRIOR/CONCOMITANT THERAPY:
    12)A change in dose of oral sulfasalazine or aminosalicylate w/in 2 wks prior to baseline endoscopy
    13)≥20mg/day oral prednisolone, or a change in dose of corticosteroid w/in 2 wks prior to baseline endoscopy, or anticipated inability to maintain a stable dose of corticosteroids (≤20 mg oral prednisolone or equivalent) until Wk12
    14)Topical(rectal) corticosteroids or topical(rectal) aminosalicylate w/in 2 wks prior to baseline endoscopy
    15)Initiation/change in dose of mercaptopurine or azathioprine (including initiation/discontinuation of allopurinol) or methotrexate w/in 8 wks prior to baseline endoscopy
    16)Treatment w/ ciclosporin, tacrolimus or thalidomide w/in 4 wks prior to baseline endoscopy
    17)Treatment w/ an anti-TNF biologic w/in 8 wks prior to baseline endoscopy, anti-integrin or anti-IL-12/23 biologics w/in 12 wks prior to baseline endoscopy, or a JAK inhibitor w/in 4 wks prior to baseline endoscopy
    18)History of inadequate response, loss of response, or intolerance to more than 3 classes of approved advanced therapies for UC (including anti-TNF therapies, anti-integrin therapies, anti-IL-12/23 monoclonal antibodies, or JAK inhibitors; but excluding exposure w/in a clinical trial setting), of which participants must not have had inadequate response to more than 2 classes
    19)Received faecal microbiota transplantation w/in 4 wks prior to baseline endoscopy
    20 Received live vaccination w/in 4 wks of Day 1 or plan to receive during the study until Follow-Up
    PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE:
    21)Participated in a clinical trial and received an IP w/in the following time period prior to this study’s screening endoscopy day: Biologics: 3 mths, 5 half-lives, or twice the duration of the biological effect of the IP (whichever is longer); NCEs: 30 days, 5 half-lives or twice the duration of the biological effect (whichever is longer)
    DIAGNOSTIC ASSESSMENTS:
    22)Absolute neutrophil count <1.5x10^9/L or a haemoglobin <80g/L or lymphocyte count <0.8x10^9/L
    23)Estimated GFR by Chronic Kidney Disease Epidemiology Collaboration equation calculation <60 ml/min/1.73m^2 at screening
    24)ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening
    25)Other clinically significant abnormalities of lab assessments, as judged by the investigator and/or GSK Medical Monitor, that could affect the safety of the participant, or the interpretation of the data from the study
    26) Presence of hep-B surface antigen or Hep-B core antibody, or positive hep-C antibody result at screening
    27) Positive serology for HIV at screening
    28) Where participation in the study would result in donation of blood or blood products in excess of 500ml w/in 3 mths
    29) QTc >450msec or QTc >480msec for participants w/ bundle branch block at screening and Day 1. The QTc is the QT interval corrected for heart rate according to either Bazett’s formula, Fridericia’s formula, or another method, machine or over read
    Other Exclusion Criteria:
    30) Participants w/ hypersensitivity to GSK2831781 or any excipients in the clinical formulation of GSK2831781
    E.5 End points
    E.5.1Primary end point(s)
    - Incidence of adverse events and serious adverse events during the
    Double-Blind Induction Phase.
    - Incidence of findings of potential clinical importance during the
    Double-Blind Induction Phase for: Vital Signs; Clinical laboratory values
    (haematology, clinical chemistry and urinalysis); QTc.
    - Change from baseline in Complete 4-domain Mayo score at Week 10.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 10 and end Double-Blind Induction Phase (safety endpoints)
    E.5.2Secondary end point(s)
    - Incidence of adverse events and serious adverse events in the Double-
    Blind Extended Treatment Phase.
    - Incidence of findings of potential clinical importance during the
    Double-Blind Extended Treatment Phase for: Vital signs; Clinical
    laboratory values (haematology, clinical chemistry and urinalysis); QTc
    - Adapted Mayo endoscopic score of 0 or 1 at Week 10.
    - Adapted Mayo clinical remission at Week 10.
    - Adapted Mayo clinical response at Week 10.
    - Symptomatic remission over time.
    - Change from baseline in partial Mayo score over time.
    - Change from baseline in Adapted Mayo endoscopic score and Ulcerative
    Colitis Endoscopic Index of Severity (UCEIS) at Week 10.
    - Histological severity as determined by the Robarts Histopathology
    Index at Week 10.
    - Histological severity as determined by the Nancy Histological Index at
    Week 10
    - Histological severity as determined by the Geboes Histological Index at
    Week 10.
    - Change from baseline in serum C-reactive protein over time.
    - Change from baseline in faecal calprotectin over time.
    - GSK2831781 PK parameters: AUC(0-tau), Cmax, tmax.
    - Incidence of anti-drug antibodies at each visit.
    - Adverse events, vital signs, clinical laboratory values (haematology,
    clinical chemistry, and urinalysis), 12-lead ECG.
    - Incidence of anti-drug antibodies at each visit.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 10 and end of study (safety endpoints)
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other 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 trial5
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    India
    Korea, Republic of
    Mexico
    Russian Federation
    Serbia
    South Africa
    Ukraine
    United States
    Belgium
    Bulgaria
    Czechia
    Estonia
    France
    Hungary
    Netherlands
    Poland
    Slovakia
    Slovenia
    United Kingdom
    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 years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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: 202
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 320
    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)
    Study intervention will cease at the end of a participant’s Follow-Up period. GSK2831781 will not be made available to participants after the end of the study due to the early stage of development, and because other treatments are available. The investigator is responsible for ensuring that consideration has been given to the post-study care of the participant’s medical 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 Decision2019-07-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-05-17
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