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    Clinical Trial Results:
    A Phase 2, Blinded, Randomized, Placebo-Controlled Study Evaluating the Efficacy and Safety of GS-4875 in Subjects with Moderately to Severely Active Ulcerative Colitis

    Summary
    EudraCT number
    		 2019-001430-33
    Trial protocol
    		 AT   FR   GB   DE   PL   BE   IT  
    Global end of trial date
    14 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2022
    First version publication date
    14 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-365-4237
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04130919
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    14 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the efficacy of tilpisertib (formerly GS-4875)‎ compared with placebo control in achieving clinical remission per modified Mayo Clinic Score (MCS) in adults with moderately to severely active ulcerative colitis (UC).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2019
    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
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    19
    EEA total number of subjects
    3
    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)
    15
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Australia, Europe and the United States.

    Pre-assignment
    Screening details
    		 32 participants were screened.

    Period 1
    Period 1 title
    Blinded Treatment Phase
    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
    		 Tilpisertib 300 mg (Blinded Treatment Phase)
    Arm description
    		 Tilpisertib 300 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per Modified Mayo Clinic score (MCS) at Week 10, continued to receive tilpisertib 300 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tilpisertib
    Investigational medicinal product code
    Other name
    GS-4875
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered once daily

    Arm title
    		 Tilpisertib 100 mg (Blinded Treatment Phase)
    Arm description
    		 Tilpisertib 100 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 100 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tilpisertib
    Investigational medicinal product code
    Other name
    GS-4875
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Arm title
    		 Placebo (Blinded Treatment Phase)
    Arm description
    		 Placebo tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive placebo tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Number of subjects in period 1
    		Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase)
    Started
    7
    6
    6
    Completed
    5
    4
    3
    Not completed
    2
    2
    3
         Investigator's decision
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    1
         Study terminated by sponsor
    1
    1
    1
         Disease worsening
    -
    -
    1
         Withdrew consent
    1
    -
    -
    Period 2
    Period 2 title
    Open-label Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tilpisertib 300 mg from Tilpisertib 300 mg (OLTP)
    Arm description
    		 Participants who received tilpisertib 300 mg and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tilpisertib
    Investigational medicinal product code
    Other name
    GS-4875
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered once daily

    Arm title
    		 Tilpisertib 300 mg from Tilpisertib 100 mg (OLTP)
    Arm description
    		 Participants who received tilpisertib 100 mg and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tilpisertib
    Investigational medicinal product code
    Other name
    GS-4875
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered once daily

    Arm title
    		 Tilpisertib 300 mg from Placebo (OLTP)
    Arm description
    		 Participants who received placebo and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tilpisertib
    Investigational medicinal product code
    Other name
    GS-4875
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered once daily

    Number of subjects in period 2 [1]
    		Tilpisertib 300 mg from Tilpisertib 300 mg (OLTP) Tilpisertib 300 mg from Tilpisertib 100 mg (OLTP) Tilpisertib 300 mg from Placebo (OLTP)
    Started
    4
    3
    3
    Completed
    1
    1
    0
    Not completed
    3
    2
    3
         Investigator's decision
    1
    -
    -
         Disease worsening
    1
    -
    1
         Withdrew consent
    1
    1
    1
         Lost to follow-up
    -
    -
    1
         MCS response not achieved at open-label week 10
    -
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who completed the Blinded Treatment phase and did not achieve the clinical response per modified MCS at Week 10 entered in Open-label Treatment phase to receive tilpisertib 300 mg.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tilpisertib 300 mg (Blinded Treatment Phase)
    Reporting group description
    		 Tilpisertib 300 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per Modified Mayo Clinic score (MCS) at Week 10, continued to receive tilpisertib 300 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Tilpisertib 100 mg (Blinded Treatment Phase)
    Reporting group description
    		 Tilpisertib 100 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 100 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Placebo (Blinded Treatment Phase)
    Reporting group description
    		 Placebo tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive placebo tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase) Total
    Number of subjects
    		 7 6 6 19
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51 ( 11.8 ) 49 ( 22.6 ) 43 ( 18.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 1 3 6
        Male
    		 5 5 3 13
    Race
    Not Permitted means local regulators did not allow collection of race information.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Black or African American
    		 0 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        White
    		 7 6 3 16
        Other
    		 0 0 1 1
        Not Permitted
    		 0 0 0 0
    Ethnicity
    Not Permitted means local regulators did not allow collection of ethnicity information.
    Units: Subjects
        Not Hispanic or Latino
    		 6 4 6 16
        Hispanic or Latino
    		 1 2 0 3
        Not Permitted
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Tilpisertib 300 mg (Blinded Treatment Phase)
    Reporting group description
    		 Tilpisertib 300 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per Modified Mayo Clinic score (MCS) at Week 10, continued to receive tilpisertib 300 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Tilpisertib 100 mg (Blinded Treatment Phase)
    Reporting group description
    		 Tilpisertib 100 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 100 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Placebo (Blinded Treatment Phase)
    Reporting group description
    		 Placebo tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive placebo tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.
    Reporting group title
    Tilpisertib 300 mg from Tilpisertib 300 mg (OLTP)
    Reporting group description
    		 Participants who received tilpisertib 300 mg and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).

    Reporting group title
    Tilpisertib 300 mg from Tilpisertib 100 mg (OLTP)
    Reporting group description
    		 Participants who received tilpisertib 100 mg and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).

    Reporting group title
    Tilpisertib 300 mg from Placebo (OLTP)
    Reporting group description
    		 Participants who received placebo and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).

    Primary: Percentage of Participants who Achieved Clinical Remission per Modified Mayo Clinic Score (MCS) at Week 10

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    End point title
    		 Percentage of Participants who Achieved Clinical Remission per Modified Mayo Clinic Score (MCS) at Week 10 [1]
    End point description
    The modified MCS is a scoring system for assessment of ulcerative colitis (UC) activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and physician's global assessment (PGA) (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. Clinical remission per modified MCS is defined as stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 at Week 10. Full analysis set included all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 10
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypotheses were tested for the primary end point.
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase)
    Number of subjects analysed
    7
    6
    6
    Units: percentage of participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved Endoscopic Response at Week 10

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    End point title
    		 Percentage of Participants who Achieved Endoscopic Response at Week 10
    End point description
    Endoscopic response was defined as an endoscopic subscore of ≤ 1 at Week 10. Endoscopic subscore is a part of the modified MCS which is a scoring system for assessment of UC activity. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease, 1 = mild disease (erythema, decreased vascular pattern), 2 = moderate disease (marked erythema, lack of vascular pattern, friability, erosions), and 3 = severe disease (spontaneous bleeding, ulceration). Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase)
    Number of subjects analysed
    7
    6
    6
    Units: percentage of participants
        number (not applicable)
    14.3
    16.7
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved MCS Response at Week 10

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    End point title
    		 Percentage of Participants who Achieved MCS Response at Week 10
    End point description
    The modified MCS is a scoring system for assessment of UC activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS response is defined as a decrease from baseline of ≥ 3 points and at least 30% in MCS, in addition to a ≥ 1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore ≤ 1 at Week 10. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase)
    Number of subjects analysed
    7
    6
    6
    Units: percentage of participants
        number (not applicable)
    28.6
    16.7
    16.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved MCS Remission at Week 10

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    End point title
    		 Percentage of Participants who Achieved MCS Remission at Week 10
    End point description
    The modified MCS is a scoring system for assessment of UC activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS remission is defined as a MCS score of ≤ 2 and no individual subscore > 1 at Week 10. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase)
    Number of subjects analysed
    7
    6
    6
    Units: percentage of participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10

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    End point title
    		 Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10
    End point description
    Geboes histologic remission was assessed by the Geboes histologic scores.Grade 0:Architectural changes(0.0=No abnormality to 0.3=Severe diffuse or multifocal abnormalities); Grade 1:Chronic inflammatory infiltrate(1.0=No increase to 1.3=Marked increase);Grade 2A:Eosinophils in lamina propria(2A.0=No increase to 2A.3-=Marked increase;Grade 2B:Neutrophils in lamina propria(2B.0= No increase to 2B.3=Marked increase);Grade 3:Neutrophils in epithelium (3.0=None to 3.3=>50% crypts involved);Grade 4:Crypt destruction(4.0=none to 4.3=Unequivocal crypt destruction),and Grade 5:Erosions and ulcerations:(5.0=No erosion, ulceration or granulation to 5.4=Ulcer or granulation tissue). Histologic remission defined as having Grade 0 of ≤ 0.3, Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0,Grade 4 of 4.0,andGrade 5 of 5.0. Score ranges from 0 to 5.4. Lower values indicate better outcome.Participants in the Full Analysis Set with at least 1 histological assessment were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 10
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase)
    Number of subjects analysed
    6
    6
    4
    Units: percentage of participants
        number (not applicable)
    16.7
    16.7
    25.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
    End point description
    TEAEs for the Blinded Treatment phase are either defined as AEs with an onset date on or after the Blinded Treatment phase study drug start date and no later than 30 days after permanent discontinuation study drug if no Open-label Treatment phase study drug was taken, or any AEs with an onset date on or after the Blinded Treatment phase study drug start date and before the Open-label Treatment phase study drug start date if Open-label Treatment phase study drug was taken and/or any AEs leading to premature discontinuation of Blinded Treatment phase study drug. TEAEs for the Open-label Treatment phase are either defined as AEs with an onset date on or after the Open-label Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Open-lab Treatment phase study drug and/or any AEs leading to premature discontinuation study drug. Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase) Tilpisertib 300 mg from Tilpisertib 300 mg (OLTP) Tilpisertib 300 mg from Tilpisertib 100 mg (OLTP) Tilpisertib 300 mg from Placebo (OLTP)
    Number of subjects analysed
    7
    6
    6
    4
    3
    3
    Units: percentage of participants
        number (not applicable)
    57.1
    50.0
    50.0
    50.0
    66.7
    66.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Laboratory Abnormalities

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    End point title
    		 Percentage of Participants Who Experienced Laboratory Abnormalities
    End point description
    Treatment-emergent laboratory abnormalities for Blinded Treatment phase are defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of Blinded Treatment phase study drug plus 30 days for participants who permanently discontinued study drug or before the first dose of Open-label Treatment phase study drug. For the Open-label Treatment phase, treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from Open-label baseline at any postbaseline time point, up to and including the date of last dose of Open-label Treatment phase study drug plus 30 days for participants who permanently discontinued study drug. For maximum postbaseline toxicity grade, the most severe graded abnormality from all tests was counted for each patient. Grade 1:mild; Grade 2:moderate; Grade 3:severe; Grade 4:life-threatening. Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days
    End point values
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase) Tilpisertib 300 mg from Tilpisertib 300 mg (OLTP) Tilpisertib 300 mg from Tilpisertib 100 mg (OLTP) Tilpisertib 300 mg from Placebo (OLTP)
    Number of subjects analysed
    7
    6
    6
    4
    3
    3
    Units: percentage of participants
    number (not applicable)
        Grade 1
    42.9
    66.7
    16.7
    25.0
    33.3
    66.7
        Grade 2
    28.6
    33.3
    50.0
    25.0
    0
    33.3
        Grade 3
    14.3
    0
    0
    25.0
    66.7
    0
        Grade 4
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events: Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label Treatment phase: First dose date up to 50.7 weeks plus 30 days; All-Cause Mortality: Enrollment up to Week 70.3
    Adverse event reporting additional description
    Adverse Events: Safety Analysis Set included all participants who received at least one dose of study drug; All-Cause Mortality: All Randomized Analysis Set included all participants who were randomized in the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Tilpisertib 300 mg (Blinded Treatment Phase)
    Reporting group description
    		 Tilpisertib 300 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 300 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Tilpisertib 100 mg (Blinded Treatment Phase)
    Reporting group description
    		 Tilpisertib 100 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 100 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Placebo (Blinded Treatment Phase)
    Reporting group description
    		 Placebo tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive placebo tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase.

    Reporting group title
    Tilpisertib 300 mg From Tilpisertib 300 mg (OLTP)
    Reporting group description
    		 Participants who received tilpisertib 300 mg and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).

    Reporting group title
    Tilpisertib 300 mg From Tilpisertib 100 mg (OLTP)
    Reporting group description
    		 Participants who received tilpisertib 100 mg and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).

    Reporting group title
    Tilpisertib 300 mg From Placebo (OLTP)
    Reporting group description
    		 Participants who received placebo and did not achieve clinical response per modified MCS at Week 10 in the Blinded Treatment phase, received tilpisertib 300 mg tablets orally once daily for up to 50 weeks in the Open-label Treatment phase (OLTP).

    Serious adverse events
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase) Tilpisertib 300 mg From Tilpisertib 300 mg (OLTP) Tilpisertib 300 mg From Tilpisertib 100 mg (OLTP) Tilpisertib 300 mg From Placebo (OLTP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Proctalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Campylobacter infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 100 mg (Blinded Treatment Phase) Placebo (Blinded Treatment Phase) Tilpisertib 300 mg From Tilpisertib 300 mg (OLTP) Tilpisertib 300 mg From Tilpisertib 100 mg (OLTP) Tilpisertib 300 mg From Placebo (OLTP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    2
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    External ear inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemorrhoids thrombosed
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Mastitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2019
    - Minor corrections and language revisions were made to provide clarity and consistency throughout the protocol - Updates to the Glossary of Abbreviations and Definition of Terms as needed per revisions to the protocol - Updated Study Design schema (Section 3) to reflect changes made to dosage in the protocol - Updated Study Procedures Table (Appendix 2 and Appendix 3) to reflect changes made to study visits assessments/procedures in the protocol as described in the summary of changes
    19 Jun 2020
    - Study GS-US-365-4237 is revised to become a blinded study - An unblinded sponsor data review has been added when 90 subjects reach Week 10 - Phase 1 study results from GS-US-365-4235 (Phase 1 CYP3A drug-drug interaction study) and GS-US-365-5588 (Phase 1 iohexol study) - Toxicology study results from TX-457-2018 (phototoxicity study in rats) and TX-365-2016 (39-week chronic toxicology study in monkeys) - Revisions to allowed concomitant medications based on the results of Phase 1 Study GS-US-365-4235

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Nov 2020
    Gilead made the decision to discontinue the development of tilpisertib since a new molecular entity was able to achieve greater target coverage. The decision was not due to any safety concerns.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Since only 19 participants were enrolled, none of the planned statistical analyses were performed. During the COVID-19 pandemic, there were changes to protocol visits and procedures where necessary to mitigate the impact of the pandemic to the study.
    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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