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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Study to Investigate the Safety and Efficacy of APD334 in Patients with Moderately to Severely Active Ulcerative Colitis

    Summary
    EudraCT number
    2015-001942-28
    Trial protocol
    CZ   GB   ES   DE   LV   HU   LT   FR   PL   BG   BE   AT  
    Global end of trial date
    14 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2018
    First version publication date
    16 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APD334-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02447302
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Arena Pharmaceuticals, Inc.
    Sponsor organisation address
    6154 Nancy Ridge Drive, San Diego, United States, CA 92121
    Public contact
    Chris Cabell, Arena Pharmaceuticals, Inc., ct.gov@arenapharm.com
    Scientific contact
    Chris Cabell, Arena Pharmaceuticals, Inc., ct.gov@arenapharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of treatment with APD334 in inducing clinical remission at 12 weeks.
    Protection of trial subjects
    Compliance was assessed using subject data recorded in the drug accountability form of the electronic Case Report Forms (eCRFs). On each day, a subject had to take his or her assigned study drug. The compliance rate for each subject was computed as 100% × (actual number of capsules taken over the study period) / (designated total number of capsules that should have been taken over the study period). There are prohibited medications and medications considered with regard to concomitant procedures.
    Background therapy
    -
    Evidence for comparator
    For all analyses, one model was fitted for the individual treatment comparisons etrasimod 2 mg versus placebo, etrasimod 1 mg versus placebo, and etrasimod 2 mg versus etrasimod 1 mg with the treatment term containing the 3 groups (etrasimod 1 mg, etrasimod 2 mg, and placebo), and the second model was fitted for the pooled treatment comparison (etrasimod 1 mg and etrasimod 2 mg versus placebo) with the treatment term containing 2 treatment groups (pooled 2 mg etrasimod and 1 mg, and placebo).
    Actual start date of recruitment
    01 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    156
    EEA total number of subjects
    66
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    150
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study included a screening period (up to 28 days), a double-blind induction treatment period (12 weeks), and a possible follow-up visit (2 weeks after the last study visit). The target population consisted of male or female subjects aged between 18 and 80 years (inclusive), with moderately to severely active Ulcerative Colitis.

    Pre-assignment
    Screening details
    During the screening period (Days −28 to −1), subjects were evaluated for study entry based on the inclusion and exclusion criteria. Screening procedures to evaluate subject eligibility for the study were to be conducted within 28 days prior to study drug administration on Day 1.

    Period 1
    Period 1 title
    Induction Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Assessor, Subject, Investigator, Monitor
    Blinding implementation details
    All study personnel directly related to this study (investigators, study site personnel, monitors, and CRO and Sponsor personnel), with the exception of the clinical supply staff, safety staff, and the unblinded statistician supporting the DSMB, were blinded to the identity of study drug. Randomization codes were generated by a CRO statistician not directly involved with the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Etrasimod 1 mg
    Arm description
    Etrasimod 1 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.
    Arm type
    Experimental

    Investigational medicinal product name
    Etrasimod 1 mg
    Investigational medicinal product code
    -
    Other name
    APD334, 1 mg
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 × 1 mg etrasimod capsule orally QD for 12 weeks

    Arm title
    Etrasimod 2 mg
    Arm description
    Etrasimod 2 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.
    Arm type
    Experimental

    Investigational medicinal product name
    Etrasimod 2 mg
    Investigational medicinal product code
    -
    Other name
    APD334, 2 mg
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 × 2 mg etrasimod capsule orally QD for 12 weeks

    Arm title
    Placebo
    Arm description
    Placebo was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. Placebo was to be taken on an empty stomach after an overnight fast of approximately 8 hours.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    -
    Other name
    -
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 × matching etrasimod capsule orally QD for 12 weeks

    Number of subjects in period 1
    Etrasimod 1 mg Etrasimod 2 mg Placebo
    Started
    52
    50
    54
    Completed
    47
    46
    48
    Not completed
    5
    4
    6
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    4
    3
    -
         Consent withdrawn by subject
    -
    1
    5
         Sponsor Decision
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Etrasimod 1 mg
    Reporting group description
    Etrasimod 1 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group title
    Etrasimod 2 mg
    Reporting group description
    Etrasimod 2 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. Placebo was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group values
    Etrasimod 1 mg Etrasimod 2 mg Placebo Total
    Number of subjects
    52 50 54 156
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    52 49 49 150
        From 65-84 years
    0 1 5 6
    Age continuous
    Units: years
        median (full range (min-max))
    44.0 (21 to 64) 38.5 (21 to 67) 46.0 (20 to 73) -
    Gender categorical
    Units: Subjects
        Female
    22 23 22 67
        Male
    30 27 32 89
    Subject analysis sets

    Subject analysis set title
    Induction Treatment Period
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The 12-week double-blind induction treatment period started at Week 0 (Day 1) immediately after randomly assigning subjects to a treatment group and ended at Week 12. Eligible subjects were randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups: etrasimod 1 mg, etrasimod 2 mg, or placebo. Randomization was stratified by presence or absence of current oral corticosteroid usage and prior exposure to tumor necrosis factor alpha (TNFα) antagonists. The study drugs were administered orally once daily (QD) for 12 weeks. All doses were administered with approximately 240 mL (8 ounces) of water. The study drugs were to be taken on an empty stomach after an overnight fast of approximately 8 hours. After the first study drug administration (Week 0 [Day 1]), subjects were to return to the study site for 5 evaluation visits (Weeks 1, 2, 4, 8, and 12) during the double-blind treatment period.

    Subject analysis sets values
    Induction Treatment Period
    Number of subjects
    156
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    150
        From 65-84 years
    6
    Age continuous
    Units: years
        median (full range (min-max))
    42.0 (20 to 73)
    Gender categorical
    Units: Subjects
        Female
    67
        Male
    89

    End points

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    End points reporting groups
    Reporting group title
    Etrasimod 1 mg
    Reporting group description
    Etrasimod 1 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group title
    Etrasimod 2 mg
    Reporting group description
    Etrasimod 2 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. Placebo was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Subject analysis set title
    Induction Treatment Period
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The 12-week double-blind induction treatment period started at Week 0 (Day 1) immediately after randomly assigning subjects to a treatment group and ended at Week 12. Eligible subjects were randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups: etrasimod 1 mg, etrasimod 2 mg, or placebo. Randomization was stratified by presence or absence of current oral corticosteroid usage and prior exposure to tumor necrosis factor alpha (TNFα) antagonists. The study drugs were administered orally once daily (QD) for 12 weeks. All doses were administered with approximately 240 mL (8 ounces) of water. The study drugs were to be taken on an empty stomach after an overnight fast of approximately 8 hours. After the first study drug administration (Week 0 [Day 1]), subjects were to return to the study site for 5 evaluation visits (Weeks 1, 2, 4, 8, and 12) during the double-blind treatment period.

    Primary: Adapted Mayo Score (MCS) at Week 12

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    End point title
    Adapted Mayo Score (MCS) at Week 12
    End point description
    Using the multiple imputation method to handle missing data, change from baseline in the adapted MCS at Week 12 was analyzed using ANCOVA on each multiply imputed dataset for the ITT population.
    End point type
    Primary
    End point timeframe
    The primary efficacy endpoint was the change from baseline in the adapted MCS (stool frequency, rectal bleeding, and findings on endoscopy) at Week 12.
    End point values
    Etrasimod 1 mg Etrasimod 2 mg Placebo
    Number of subjects analysed
    52
    50
    54
    Units: mean
        least squares mean (confidence interval 90%)
    -1.94 (-2.45 to -1.42)
    -2.49 (-3.01 to -1.98)
    -1.50 (-2.00 to -1.01)
    Statistical analysis title
    ITT Statistical Analysis Plan
    Statistical analysis description
    The primary efficacy endpoint was analyzed using an analysis of covariance (ANCOVA) model with terms of treatment, current oral corticosteroid use, prior exposure to TNFα antagonists, and baseline value as covariates. Least-squares (LS) mean by treatment group and its 90% confidence interval (CI), and LS mean difference between treatment group and its 90% CI were reported. Same method was applied to analyze change from baseline at Week 12 for score-based endpoints.
    Comparison groups
    Etrasimod 1 mg v Etrasimod 2 mg v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.0091
    Method
    ANCOVA
    Parameter type
    Mean diff. in 2mg etrasimod vs pbo =-.99
    Confidence interval
         level
    90%
         sides
    1-sided
         lower limit
    -1.68
         upper limit
    -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [1] - The proportion of subjects who achieved endoscopic improvement was analyzed individually using the Cochran-Mantel-Haenszel (CMH) test adjusted for the stratification factors of presence or absence of current oral corticosteroid therapy at baseline and previous exposure to TNFα antagonists, to compare the difference of proportions between treatment groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were able to be reported by the subject at any time for the duration of the study. All AEs were monitored up to 30 days after the study drug administration.
    Adverse event reporting additional description
    The Investigator assessed the severity of each Treatment-Emergent Adverse Event (TEAE) using CTCAE criteria v4.03. Most TEAEs were mild (grade 1) or moderate (grade 2) in severity. An independent Data Safety Monitoring Board (DSMB) was established to review safety data from this study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Etrasimod 1 mg
    Reporting group description
    Etrasimod 1 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group title
    Etrasimod 2 mg
    Reporting group description
    Etrasimod 2 mg was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. The study drug was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered orally once daily (QD) for 12 weeks, administered with approximately 240 mL (8 ounces) of water. Placebo was to be taken on an empty stomach after an overnight fast of approximately 8 hours.

    Serious adverse events
    Etrasimod 1 mg Etrasimod 2 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 50 (0.00%)
    6 / 54 (11.11%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 50 (0.00%)
    3 / 54 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 50 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 50 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Etrasimod 1 mg Etrasimod 2 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 52 (55.77%)
    28 / 50 (56.00%)
    24 / 54 (44.44%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 50 (6.00%)
    2 / 54 (3.70%)
         occurrences all number
    3
    3
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 50 (6.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    3
    2
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 50 (4.00%)
    1 / 54 (1.85%)
         occurrences all number
    3
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 50 (2.00%)
    4 / 54 (7.41%)
         occurrences all number
    2
    2
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 50 (4.00%)
    2 / 54 (3.70%)
         occurrences all number
    4
    2
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 May 2015
    The first amendment to the protocol, dated 01 May 2015, included the following important changes: • The term partial MCS was changed to 3-component MCS throughout the protocol. • Use of Inflammatory Bowel Disease Questionnaire and corresponding exploratory objective, endpoint, and analysis were added. • Definition of an intolerable AE was added. • A clarification was made to specify that the stool sample collected during the study was used for the analysis of both the fecal calprotectin assay and for culture, ova, and parasite evaluation and C difficile assay. • Requirement for a chest X-ray to be taken at the Week 12 visit was removed for subjects not continuing into the extension study. • Clarified that study medication should be taken after an overnight fast (~8 hours) and food should be avoided for ~1 hour after dosing. • Inclusion criterion pertaining to corticosteroid usage was updated to remove the references pertaining to the allowance of corticosteroid tapering in the study, with the requirement of stable dosage regimen throughout the study duration for corticosteroid usage. • The requirement of capping the number of subjects with prior exposure to TNFα antagonists for randomization into the study was added. • Information about blinding requirements for analysis of total lymphocyte and white blood cell (WBC) counts to be followed during the study was added. • The ECG assessment information was updated to clarify that the ECGs were to be read and interpreted by both the study physician and centrally. • Reference to “continuous telemetry” in the protocol was corrected to “Holter monitoring.” • The laboratory parameters were updated to add and remove certain evaluation parameters from the assessments. • “Pharmacodynamic” assessments in the study were replaced with “hematologic” assessments. • Subgroup analyses parameters for fecal calprotectin and CRP were defined.
    17 Jun 2015
    The second amendment to the protocol, dated 17 Jun 2015, included the following important changes: • Analysis time points to the efficacy parameters of rectal bleeding, stool frequency, fecal calprotectin, CRP reduction, and 2-component Mayo Score were added. • The following exploratory endpoints were added: (1) change from baseline in Mayo endoscopic subscore at Week 12; (2) change from baseline in Mayo PGA at Week 12; (3) change from baseline in 2-component Mayo score at Weeks 1, 2, 4, 8, and 12; and (4) change from baseline in lymphocyte counts at Weeks 1, 2, 4, 8, 12, and 14. • A secondary method for the primary efficacy analysis was added, which included a logistic regression analysis with terms of treatment, presence or absence of current oral corticosteroid therapy at baseline, previous exposure to TNFα antagonists, and the interaction between 2 stratification factors (if appropriate). • Requirement of clinical laboratory tests to be performed at screening and Week 12 under fasting conditions was removed. • Inclusion criterion related to colonoscopy for subjects with history of extensive pancolitis or left-sided colitis was clarified. • Exclusion criterion pertaining to the serology requirements was updated to exclude subjects without documented varicella zoster virus (VZV) IgG antibody status. • Addition of 3 exclusion criteria: (1) use of moderate to strong inhibitors of CYP2C9; (2) history of severe renal impairment; and (3) history of severe hepatic impairment. • Dosage instructions for study drug administration were clarified to instruct subjects not to take their study drug dose at home on days with scheduled study visits in order to complete predose study procedures and to remain fasted as instructed on the days of scheduled visits prior to dosing. • Moderate to strong inhibitors of CYP2C9 were added to the excluded (i.e., prohibited) medications list.
    30 Jun 2015
    The third amendment to the protocol, dated 30 Jun 2015, included the following important changes: • An exclusion criterion of “previous treatment with 2 or more biologic agents” was added. • Vedolizumab was added to the list of medications that were to be excluded within 60 days prior to randomization. • Consideration for a repeat flexible proctosigmoidoscopy was added.
    21 Sep 2015
    The fourth amendment to the protocol, dated 21 Sep 2015, included the following important changes: • Information on retinal photos to be taken at each ophthalmoscopy was added. Requirement of Week 12 ophthalmoscopy applicable only to subjects who did not enter the extension study was removed. • Inclusion criterion about the permitted use of corticosteroids prior to study entry was updated. • Exclusion criteria related to history or evidence of adenomatous colonic polyps and colonic mucosal dysplasia were updated.
    10 Oct 2016
    The fifth amendment to the protocol, dated 10 Oct 2016, included the following important changes: • Subject entry requirement for participation in the extension Study APD334-005 was updated to include only responders and not both responders and nonresponders. • Blood sample collection at 8 hours postdose for PK assessments was removed. • Added possibility to prolong time window for screening to 35 days. Extended window for specified procedures (proctosigmoidoscopy) to 10 days. Removed all other visit and procedure windows. • The duration within which certain screening procedures were to be completed prior to randomization was updated from 7 to 10 days. • Assessment timings and requirements for heart rate, blood pressure, and ECG measurements were updated. • Exclusion criterion related to use of biologic agents prior to study entry was updated, with subjects who received previous treatment with more than 3 biologics were not to be enrolled. • Additional monitoring considerations for changes in heart rate and ECG parameters were added. • Recipient of notification of SAE was changed from the Sponsor to PPD (contract research organization [CRO]). • Information on extending the screening period window to 35 days and clarification on rescreening procedures was added. • Information about the 2-component May score to be calculated at Weeks 1, 2, 4, and 8 was added. • Added specification that APD334-003 study will remain blinded until completion of the APD334-005 study. • Clarified that clinical laboratory tests and CBC tests should be performed prior to dosing.
    27 Mar 2017
    The sixth amendment to the protocol, dated 27 Mar 2017, included the following important changes: • The primary objective was updated to determine the effect of treatment with etrasimod in improving 3-component MCS (score ranging from 0 to 9, including stool frequency, rectal bleeding, and findings on endoscopy) at Week 12. • The following secondary objectives were added: (1) to determine the effect of treatment with etrasimod on a combination of clinical remission and clinical response reflected by a composite endpoint at 12 weeks; and (2) to determine the effect of treatment with etrasimod in inducing clinical remission at 12 weeks. • The following exploratory objectives were added: (1) to determine the effect of etrasimod treatment on total MCS at 12 weeks; and (2) to determine dose response effect of etrasimod on 3-component MCS, combination of clinical remission and clinical response reflected by a composite endpoint, clinical remission, clinical response, and endoscopic improvement, at 12 weeks. • The primary, secondary, and exploratory efficacy endpoints were updated based on the changes made to the study objectives. • The study design information was updated to designate this study as a proof of concept study. • Subject entry requirement for participation in the extension Study APD334-005 was updated to include both responders and nonresponders. • Inclusion criterion about integrin antagonists was updated to include subjects in the study who had discontinued prior treatment with vedolizumab despite clinical benefit. • The exclusion criterion of “a history of primary nonresponse to a treatment regimen of vedolizumab per the current labeling and/or institutional standard of care. • Sample size language was changed to up to 240, with the added statement that the Sponsor can stop enrollment for any reason prior to that. • Sponsor considerations for conducting interim analysis were added. • Added section that outlined reasons to terminate the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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