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    Clinical Trial Results:
    Randomized, placebo-controlled trial of YF476, a gastrin receptor antagonist, in Barrett’s esophagus (10-505; T-016)

    Summary
    EudraCT number
    		 2014-002418-22
    Trial protocol
    		 GB  
    Global end of trial date
    27 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2021
    First version publication date
    03 Feb 2021
    Other versions
    Summary report(s)
    		 10-505 SOTR

    Trial information

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    Trial identification
    Sponsor protocol code
    T-016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01298999
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 HMR code: 10-505
    Sponsors
    Sponsor organisation name
    Trio Medicines Ltd
    Sponsor organisation address
    Cumberland Avenue, London, United Kingdom, NW10 7EW
    Public contact
    Dr Malcolm Boyce, Trio Medicines Ltd, +44 2089614130, mboyce@triomedicines.com
    Scientific contact
    Dr Malcolm Boyce, Trio Medicines Ltd, +44 2089614130, mboyce@triomedicines.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
    10 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To determine if administration of YF476 (a CCK2R antagonist) to patients with Barrett's esophagus (BE) decreases tissue Ki67 expression, a marker of cellular proliferation. Secondary: To assess the effects of YF476 on biomarkers potentially associated with esophageal adenocarcinoma. To assess the effects of YF476 on fasting serum gastrin, a marker of gastric acid suppression, and plasma chromogranin A (CgA), a marker of ECL cell hyperplasia. To determine whether YF476 is safe in patients with BE.
    Protection of trial subjects
    Before the trial started, we did a risk assessment to identify and manage risks to the trial patients. We determined that the overall risk to the patients was negligible because: 1. netazepide has a good safety profile in non-clinical and clinical studies; 2. the expected netazepide exposure during the study was within the safe limits seen in non-clinical studies; 3. the safety testing and assessments were adequate based on our clinical experience of netazepide; and 4. any risks were adequately mitigated by safety assessments, and by the medical cover provided by the investigator site. All study procedures and information given to the subjects were reviewed and approved by a research ethics committee. To minimise anxiety in the subjects and to ensure that they were fully informed about the trial, subjects were asked to read and sign an information and consent form (ICF). The ICF gave details: 1. about netazepide, including risks of taking it; 2. of inclusion and exclusion criteria; 3. of lifestyle restrictions and risks/disadvantages of taking part in the study; 4. of procedures during the study, including the amount of blood to be donated; and 5. about payment and clinical studies in general.
    Background therapy
    		 There was no background therapy used in the trial.
    Evidence for comparator
    		 There were no comparators used in the trial.
    Actual start date of recruitment
    01 May 2013
    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
    United States: 12
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    24
    EEA total number of subjects
    12
    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)
    6
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Screening started on 15 May 2013.

    Pre-assignment
    Screening details
    		 Confirmation of Barrett's esophagus with no dysplasia (review of endoscopy); review of medication history; medical history, physical examination, ECG and vital signs; laboratory safety tests; and urine pregnancy test. 27 patients were enrolled and 3 failed screening due to elevated lipase, prolonged QTc and being diagnosed with lymphoma.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment
    Arm description
    		 Patients taking 25 mg netazepide (gastrin receptor antagonist) once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Netazepide
    Investigational medicinal product code
    YF476
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Netazepide 25 mg was taken by mouth once daily for 12 weeks. A single capsule was taken with breakfast except on clinic visit days, when patients fasted overnight and took netazepide after completing study procedures.

    Arm title
    		 Placebo
    Arm description
    		 Patients taking matching placebo once daily for 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    YF476 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was taken by mouth once daily for 12 weeks. A single capsule was taken with breakfast except on clinic visit days, when patients fasted overnight and took netazepide after completing study procedures.

    Number of subjects in period 1
    		Treatment Placebo
    Started
    13
    11
    Completed
    10
    10
    Not completed
    3
    1
         Recurrent metastatic prostate cancer
    -
    1
         Baseline pathology low grade dysplasia
    1
    -
         Baseline pathology indefinite for dysplasia
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Patients taking 25 mg netazepide (gastrin receptor antagonist) once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients taking matching placebo once daily for 12 weeks

    Reporting group values
    		 Treatment Placebo Total
    Number of subjects
    		 13 11 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 4 2 6
        From 65-84 years
    		 9 9 18
        85 years and over
    		 0 0 0
    Age continuous
    For the treatment arm, data has been summarised for 10 patients that completed the trial and excludes 3 patients that were withdrawn after the first study visit, due to reasons unrelated to the treatment.
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ( 8.1 ) 68.6 ( 6.6 ) -
    Gender categorical
    F
    Units: Subjects
        Female
    		 2 1 3
        Male
    		 11 10 21
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 13 11 24
        More than one race
    		 0 0 0
        Unknown or not reported
    		 0 0 0
    Height
    For the treatment arm, data has been summarised for 10 patients that completed the trial and excludes 3 patients that were withdrawn after the first study visit, due to reasons unrelated to the treatment.
    Units: cm
        arithmetic mean (standard deviation)
    		 172.9 ( 10.8 ) 171.1 ( 6.5 ) -
    Weight
    For the treatment arm, data has been summarised for 10 patients that completed the trial and excludes 3 patients that were withdrawn after the first study visit, due to reasons unrelated to the treatment.
    Units: kg
        arithmetic mean (standard deviation)
    		 83.5 ( 11.1 ) 78.5 ( 12.4 ) -
    Body mass index
    For the treatment arm, data has been summarised for 10 patients that completed the trial and excludes 3 patients that were withdrawn after the first study visit, due to reasons unrelated to the treatment.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 28.2 ( 5.1 ) 26.7 ( 3.1 ) -
    Fasting serum gastrin concentration
    For the treatment arm, data has been summarised for 10 patients that completed the trial and excludes 3 patients that were withdrawn after the first study visit, due to reasons unrelated to the treatment.
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 66.7 ( 45.5 ) 51.9 ( 29.1 ) -
    Fasting plasma CgA concentration
    For the treatment arm, data has been summarised for 10 patients that completed the trial and excludes 3 patients that were withdrawn after the first study visit, due to reasons unrelated to the treatment.
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 14.5 ( 19.4 ) 9.1 ( 5.0 ) -
    Ki67 expression
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    		 1539 ( 514 ) 1556 ( 622 ) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Patients taking 25 mg netazepide (gastrin receptor antagonist) once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients taking matching placebo once daily for 12 weeks

    Primary: Change in Ki67 expression

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    End point title
    		 Change in Ki67 expression
    End point description
    Results are reported as mean increase in Ki67 positive cells per mm^2 of BE epithelium after 12 weeks netazepide treatment.
    End point type
    Primary
    End point timeframe
    Biopsies were taken at baseline and Week 12 to assess Ki67 expression levels.
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    10 [1]
    10 [2]
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    35.6 ( 620.7 )
    307.8 ( 640.3 )
    Notes
    [1] - 3 patients were withdrawn
    [2] - 1 patient was withdrawn
    Statistical analysis title
    		 Two sample t-tests
    Statistical analysis description
    Two sample t-test to compare placebo and treatment groups. Nominal p-value and 95% confidence intervals for treatment difference were reported.
    Comparison groups
    Placebo v Treatment
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Fasting serum gastrin concentration

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    End point title
    		 Fasting serum gastrin concentration
    End point description
    After 6 patients (3 per treatment) had their Week 4 and 8 visits, the protocol was amended so that those visits were replaced by a single visit at Week 6 in order to reduce the total number of visits. The number of patients included in the analysis for each study visit is outlined below: Week 4 - 3 patients per arm Week 6 - 7 patients in the treatment arm, 8 patients in the placebo arm Week 8 - 3 patients per arm Week 12 - 10 patients per arm Follow up - 10 patients per arm
    End point type
    Secondary
    End point timeframe
    Blood samples were taken periodically for 12 weeks, and at the follow-up visit to measure fasting serum gastrin concentrations.
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    10 [3]
    10 [4]
    Units: pmol/L
    arithmetic mean (standard deviation)
        Week 4
    242.6 ( 142.3 )
    43.6 ( 9.9 )
        Week 6
    103.3 ( 89.9 )
    63.9 ( 32.2 )
        Week 8
    234.3 ( 156.5 )
    96.4 ( 54.2 )
        Week 12
    146.8 ( 112.8 )
    49.2 ( 20.4 )
        Follow up
    94.9 ( 78.8 )
    64.7 ( 37.7 )
    Notes
    [3] - The number of patients analysed at each visit differs due to the protocol amendment.
    [4] - The number of patients analysed at each visit differs due to the protocol amendment.
    No statistical analyses for this end point

    Secondary: Fasting plasma CgA concentration

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    End point title
    		 Fasting plasma CgA concentration
    End point description
    After 6 patients (3 per treatment) had their Week 4 and 8 visits, the protocol was amended so that those visits were replaced by a single visit at Week 6 in order to reduce the total number of visits. The number of patients included in the analysis for each study visit is outlined below: Week 4 - 3 patients per arm Week 6 - 7 patients in the treatment arm, 8 patients in the placebo arm Week 8 - 3 patients per arm Week 12 - 10 patients per arm Follow up - 10 patients per arm
    End point type
    Secondary
    End point timeframe
    Blood samples were taken periodically for 12 weeks, and at the follow-up visit to measure fasting plasma CgA concentrations.
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    10 [5]
    10 [6]
    Units: nmol/L
    arithmetic mean (standard deviation)
        Week 4
    3.9 ( 1.8 )
    8.8 ( 3.7 )
        Week 6
    1.8 ( 0.9 )
    16.9 ( 9.8 )
        Week 8
    3.8 ( 1.8 )
    10.9 ( 6.0 )
        Week 12
    2.9 ( 2.5 )
    10.6 ( 7.4 )
        Follow up
    19.8 ( 26.1 )
    11.9 ( 7.2 )
    Notes
    [5] - The number of patients analysed at each visit differs due to the protocol amendment.
    [6] - The number of patients analysed at each visit differs due to the protocol amendment.
    No statistical analyses for this end point

    Secondary: Expression of Biomarkers potentially associated with Esophageal Adenocarcinoma (EAC)

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    End point title
    		 Expression of Biomarkers potentially associated with Esophageal Adenocarcinoma (EAC) [7]
    End point description
    Results are reported as log-fold change in biomarker expression after 12 weeks netazepide treatment. Results for patients in the placebo arm were not provided.
    End point type
    Secondary
    End point timeframe
    Blood samples were taken for assay of biomarkers at baseline and Week 12 to assess the change in expression.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results from patients in the placebo arm were not provided, so only data for the treatment are reported.
    End point values
    		 Treatment
    Number of subjects analysed
    10 [8]
    Units: log-fold change
    number (not applicable)
        CCK2R expression
    -1.19
        PTGS2 expression
    0.31
        DCLK1 expression
    -0.34
    Notes
    [8] - Results for patients in the placebo arm were not provided.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Each patient was monitored throughout the study (from screening until follow-up).
    Adverse event reporting additional description
    The investigator or delegate questioned the patients about adverse events (AEs) using non-leading questions, such as 'How are you feeling?'. The investigator also recorded AEs reported spontaneously. Other clinically significant changes in the safety assessments could also be recorded as an AE if criteria, described in the protocol, were met.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    		 Netazepide 25 mg once daily by mouth for 12 weeks.

    Reporting group title
    Placebo group
    Reporting group description
    		 Matching placebo once daily by mouth for 12 weeks.

    Serious adverse events
    		 Treatment group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Scrotal abscess
    Additional description: The patient did not withdraw from the study as the event was concluded to be unrelated to treatment and recovery was seen after 17 days.
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 13 (76.92%)
    7 / 11 (63.64%)
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 11 (27.27%)
         occurrences all number
    3
    3
    Presyncope
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 11 (9.09%)
         occurrences all number
    3
    1
    Abdominal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Abdominal distension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    3
    Epistaxis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    Arthralgia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Rash pustular
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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