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    Clinical Trial Results:
    A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects with PIK3CA-related Overgrowth Spectrum and Proteus Syndrome

    Summary
    EudraCT number
    		 2016-000558-37
    Trial protocol
    		 IT   FR   ES   GB   DE  
    Global end of trial date
    11 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    7075-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03094832
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol Number: MK-7075-002
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    In this study, oral miransertib (MK-7075, formerly called ARQ 092) was administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3 kinase, catalytic subunit alpha (PIK3CA)-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS) (MOSAIC). The study consists of two parts: Part A and Part B. In Part A, participants with either PROS or PS received miransertib orally once daily (QD) for first 3 cycles (each cycle length=28 days) with an option to increase the dose at the investigator's discretion. Part A was closed to enrollment under Amendment 6. In Part B Cohorts 1, 2, and 3 participants received a starting dose of miransertib QD for the first 3 cycles and then the dose was increased at the investigator's discretion, provided no clinically significant drug related toxicity was observed. In Part B Cohort 4 participants previously treated with miransertib or currently receiving miransertib were enrolled under Compassionate Use/Expanded Access.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2017
    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: 1
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    50
    EEA total number of subjects
    13
    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)
    29
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 50 participants were enrolled in the study of which 49 participants received at least one dose of treatment and was used for safety analysis.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Miransertib PROS/PS
    Arm description
    		 During Cycles 1-3, participants with either PROS (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA]-related Overgrowth Spectrum) or PS (Proteus syndrome) received miransertib 15 mg/m^2 once daily (QD) (each cycle length = 28 days). From Cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 and then titrated to 35 mg/m^2 orally QD at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Miransertib
    Investigational medicinal product code
    Other name
    MK-7075, ARQ 092
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose of 15 mg/m^2 or 25 mg/m^2 orally QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 orally QD at the investigator's discretion.

    Arm title
    		 Part B: Miransertib PROS (Cohort 1)
    Arm description
    		 During Cycles 1-3, participants with PROS who have a measurable lesion by volumetric magnetic resonance imaging (MRI) received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Miransertib
    Investigational medicinal product code
    Other name
    MK-7075, ARQ 092
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose of 15 mg/m^2 or 25 mg/m^2 orally QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 orally QD at the investigator's discretion.

    Arm title
    		 Part B: Miransertib PS (Cohort 2)
    Arm description
    		 During Cycles 1-3, participants with PS who have a measurable lesion by standardized digital photography received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Miransertib
    Investigational medicinal product code
    Other name
    MK-7075, ARQ 092
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose of 15 mg/m^2 or 25 mg/m^2 orally QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 orally QD at the investigator's discretion.

    Arm title
    		 Part B: Miransertib PROS/PS (Cohort 3)
    Arm description
    		 During Cycles 1-3, participants with PROS or PS who do not meet all the eligibility criteria for Cohorts 1 or 2 received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Miransertib
    Investigational medicinal product code
    Other name
    MK-7075, ARQ 092
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose of 15 mg/m^2 or 25 mg/m^2 orally QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 orally QD at the investigator's discretion.

    Arm title
    		 Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Arm description
    		 During cycles 1-48 (each cycle length = 28 days) or until disease progression, unacceptable toxicity, or discontinuation, participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access continued to receive the current dose of miransertib (did not exceed 25 mg/m^2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Miransertib
    Investigational medicinal product code
    Other name
    MK-7075, ARQ 092
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial dose of 15 mg/m^2 or 25 mg/m^2 orally QD and then titrated up to 25 mg/m^2 or 35 mg/m^2 orally QD at the investigator's discretion.

    Number of subjects in period 1
    		Part A: Miransertib PROS/PS Part B: Miransertib PROS (Cohort 1) Part B: Miransertib PS (Cohort 2) Part B: Miransertib PROS/PS (Cohort 3) Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Started
    17
    22
    1
    8
    2
    Treated
    17
    22
    1
    8
    1
    Completed
    2
    2
    0
    0
    0
    Not completed
    15
    20
    1
    8
    2
         Other
    13
    20
    1
    7
    1
         Death
    1
    -
    -
    -
    -
         Withdrawal by Parent/Guardian
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Miransertib PROS/PS
    Reporting group description
    		 During Cycles 1-3, participants with either PROS (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA]-related Overgrowth Spectrum) or PS (Proteus syndrome) received miransertib 15 mg/m^2 once daily (QD) (each cycle length = 28 days). From Cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 and then titrated to 35 mg/m^2 orally QD at the investigator’s discretion.

    Reporting group title
    Part B: Miransertib PROS (Cohort 1)
    Reporting group description
    		 During Cycles 1-3, participants with PROS who have a measurable lesion by volumetric magnetic resonance imaging (MRI) received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B: Miransertib PS (Cohort 2)
    Reporting group description
    		 During Cycles 1-3, participants with PS who have a measurable lesion by standardized digital photography received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B: Miransertib PROS/PS (Cohort 3)
    Reporting group description
    		 During Cycles 1-3, participants with PROS or PS who do not meet all the eligibility criteria for Cohorts 1 or 2 received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Reporting group description
    		 During cycles 1-48 (each cycle length = 28 days) or until disease progression, unacceptable toxicity, or discontinuation, participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access continued to receive the current dose of miransertib (did not exceed 25 mg/m^2).

    Reporting group values
    		 Part A: Miransertib PROS/PS Part B: Miransertib PROS (Cohort 1) Part B: Miransertib PS (Cohort 2) Part B: Miransertib PROS/PS (Cohort 3) Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4) Total
    Number of subjects
    		 17 22 1 8 2 50
    Age Categorical
    Units: Participants
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Standard deviation was not calculatable when n<2 for Part B Miransertib PS Cohort 2 arm
    Units: years
        arithmetic mean (standard deviation)
    		 8.2 ( 9.9 ) 9.9 ( 6.7 ) 12.0 ( 9999 ) 12.5 ( 9.1 ) 20.0 ( 1.4 ) -
    Gender Categorical
    Units: Participants
        Female
    		 9 10 0 3 1 23
        Male
    		 8 12 1 5 1 27
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 3 0 1 0 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 5 0 1 0 6
        White
    		 17 13 1 6 2 39
        More than one race
    		 0 1 0 0 0 1
        Unknown or Not Reported
    		 0 0 0 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 2 1 0 0 0 3
        Not Hispanic Or Latino
    		 15 20 1 8 2 46
        Not Reported
    		 0 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Part A: Miransertib PROS/PS
    Reporting group description
    		 During Cycles 1-3, participants with either PROS (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA]-related Overgrowth Spectrum) or PS (Proteus syndrome) received miransertib 15 mg/m^2 once daily (QD) (each cycle length = 28 days). From Cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 and then titrated to 35 mg/m^2 orally QD at the investigator’s discretion.

    Reporting group title
    Part B: Miransertib PROS (Cohort 1)
    Reporting group description
    		 During Cycles 1-3, participants with PROS who have a measurable lesion by volumetric magnetic resonance imaging (MRI) received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B: Miransertib PS (Cohort 2)
    Reporting group description
    		 During Cycles 1-3, participants with PS who have a measurable lesion by standardized digital photography received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B: Miransertib PROS/PS (Cohort 3)
    Reporting group description
    		 During Cycles 1-3, participants with PROS or PS who do not meet all the eligibility criteria for Cohorts 1 or 2 received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Reporting group description
    		 During cycles 1-48 (each cycle length = 28 days) or until disease progression, unacceptable toxicity, or discontinuation, participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access continued to receive the current dose of miransertib (did not exceed 25 mg/m^2).

    Primary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE) [1]
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality. The analysis population included all participants who have received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 48 months
    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: There was no statistical analysis planned for this endpoint.
    End point values
    		 Part A: Miransertib PROS/PS Part B: Miransertib PROS (Cohort 1) Part B: Miransertib PS (Cohort 2) Part B: Miransertib PROS/PS (Cohort 3) Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Number of subjects analysed
    17
    22
    1
    8
    1
    Units: Participants
    17
    20
    0
    6
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Study Treatment Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE [2]
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality. The analysis population included all participants who have received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 45 months
    Notes
    [2] - 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: There was no statistical analysis planned for this endpoint.
    End point values
    		 Part A: Miransertib PROS/PS Part B: Miransertib PROS (Cohort 1) Part B: Miransertib PS (Cohort 2) Part B: Miransertib PROS/PS (Cohort 3) Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Number of subjects analysed
    17
    22
    1
    8
    1
    Units: Participants
    2
    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
    Up to approximately 48 months
    Adverse event reporting additional description
    All cause mortality was reported on all enrolled participants and non-serious and serious AEs were reported on all participants who received at lease one dose of study treatment. Per protocol, disease progression (DP) was not considered an AE unless related to treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Part A: Miransertib PROS/PS
    Reporting group description
    		 During Cycles 1-3, participants with either PROS (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA]-related Overgrowth Spectrum) or PS (Proteus syndrome) received miransertib 15 mg/m^2 once daily (QD) (each cycle length = 28 days). From Cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 and then titrated to 35 mg/m^2 orally QD at the investigator’s discretion.

    Reporting group title
    Part B: Miransertib PROS (Cohort 1)
    Reporting group description
    		 During Cycles 1-3, participants with PROS who have a measurable lesion by volumetric magnetic resonance imaging (MRI) received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B: Miransertib PS (Cohort 2)
    Reporting group description
    		 During Cycles 1-3, participants with PS who have a measurable lesion by standardized digital photography received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B: Miransertib PROS/PS (Cohort 3)
    Reporting group description
    		 During Cycles 1-3, participants with PROS or PS who do not meet all the eligibility criteria for Cohorts 1 or 2 received miransertib 15 mg/m^2 QD (each cycle length = 28 days). From cycles 4-48 or until disease progression, unacceptable toxicity, or discontinuation, participants received miransertib dose titrated to 25 mg/m^2 orally QD at the investigator's discretion.

    Reporting group title
    Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Reporting group description
    		 During cycles 1-48 (each cycle length = 28 days) or until disease progression, unacceptable toxicity, or discontinuation, participants previously treated with miransertib or currently receiving miransertib under Compassionate Use/Expanded Access continued to receive the current dose of miransertib (did not exceed 25 mg/m^2).

    Serious adverse events
    		 Part A: Miransertib PROS/PS Part B: Miransertib PROS (Cohort 1) Part B: Miransertib PS (Cohort 2) Part B: Miransertib PROS/PS (Cohort 3) Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Miransertib PROS/PS Part B: Miransertib PROS (Cohort 1) Part B: Miransertib PS (Cohort 2) Part B: Miransertib PROS/PS (Cohort 3) Part B:Miransertib Compassionate Use/Expanded Access(Cohort 4)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    18 / 22 (81.82%)
    0 / 1 (0.00%)
    6 / 8 (75.00%)
    1 / 1 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    Hypotension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Venous haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Lymphorrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Face oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Fatigue
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    4
    0
    2
    0
    Inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Lithiasis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Mucosal inflammation
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    15 / 17 (88.24%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    74
    3
    0
    8
    0
    Suprapubic pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Swelling
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Thirst
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Reproductive system and breast disorders
    Oedema genital
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Perineal erythema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Perineal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Testicular oedema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    2
    0
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    10 / 17 (58.82%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    17
    4
    0
    4
    1
    Dysphonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    7
    0
    Hiccups
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Laryngeal inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    6
    3
    0
    4
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    5
    3
    0
    2
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Tachypnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tonsillolith
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Delirium
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Enuresis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    Anion gap
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    2
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Blood fibrinogen increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blood insulin increased
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    4 / 8 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    6
    0
    Bone density decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Fibrin D dimer decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haematocrit increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Haemoglobin increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    4 / 8 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    8
    1
    0
    10
    0
    Lymphocyte count increased
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Monocyte count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    4 / 17 (23.53%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    17
    2
    0
    5
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Platelet count decreased
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    5
    1
    0
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    4
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Urine ketone body present
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    5
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Head injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Scratch
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Wound dehiscence
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vascular malformation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    3
    5
    0
    3
    0
    Headache
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    9
    3
    0
    3
    0
    Paraesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Petit mal epilepsy
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Presyncope
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    3
    0
    6
    0
    Eosinophilia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    3
    0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Ear and labyrinth disorders
    Excessive cerumen production
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Ear pain
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye discharge
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 17 (41.18%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    4 / 8 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    11
    5
    0
    7
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    6 / 17 (35.29%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    20
    1
    0
    4
    0
    Cheilitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    8 / 17 (47.06%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    4 / 8 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    12
    3
    0
    10
    0
    Dental caries
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Food poisoning
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 22 (18.18%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    6
    0
    7
    0
    Oral pain
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    4
    0
    Salivary duct obstruction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 22 (18.18%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    2
    6
    0
    3
    0
    Swollen tongue
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    11 / 17 (64.71%)
    5 / 22 (22.73%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    24
    13
    0
    6
    1
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Blister
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Bullous haemorrhagic dermatosis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    3
    0
    Eczema
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    Perioral dermatitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Petechiae
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Pityriasis rosea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    4
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    5 / 17 (29.41%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    0
    1
    0
    Skin disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin hypopigmentation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Skin mass
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Renal disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 17 (23.53%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    14
    3
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    Bone pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Osteochondrosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    5 / 17 (29.41%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 1 (0.00%)
         occurrences all number
    27
    4
    0
    3
    0
    Scoliosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Spinal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 22 (18.18%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    10
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Coxsackie viral infection
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Eye infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    0
    0
    0
    Impetigo
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Laryngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Otitis media acute
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Paronychia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    5 / 17 (29.41%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    0
    0
    0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    5 / 17 (29.41%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    0
    0
    0
    Scarlet fever
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Soft tissue infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Tracheitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 17 (17.65%)
    7 / 22 (31.82%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    6
    13
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    0
    1
    0
    Viraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Metabolism and nutrition disorders
    Alkalosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 22 (13.64%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    0
    5
    0
    Dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Hyperinsulinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 22 (9.09%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    4
    5
    0
    2
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 22 (0.00%)
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 22 (4.55%)
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2017
    Major changes of Amendment (AM) 1 include modification to the definition of drug related toxicity to include any toxicities considered related, probably related, or possibly related to miransertib, updates to toxicities that prevent dose titrations, updates to dose limiting toxicity criteria for discontinuation of study treatment and modifications to the blood sample collection schedule for pharmacokinetic (PK) evaluation.
    27 Jul 2017
    Major changes of AM 2 include the possibility to open the miransertib capsule and administering it with a sweetened semiliquid, expanding window to collect overgrowth tissue, include blood sample collection for potential biomarkers during Cycle 1 Day 1 and removing fasting glucose requirements and electrocardiogram (ECG) for Cycle 1 Day 1 and expansion in contraception methods in accordance with clinical trials facilitation and coordination Group (CTFG) guidelines.
    13 Dec 2017
    Major changes of AM 3 include changing the eligibility criteria from 6 years to 2 years of age and removing phosphatase and tensin on chromosome 10 (PTEN) as an eligible mutation, adding of pain scale and to remove PK collection on Day 8, making biopsies optional, adding clarification that maximum dose titrations were not required if efficacy was seen at the lower dose levels and permitting intermittent use of high dose steroids as required.
    20 Sep 2018
    Major changes of AM 4 include updating inclusion criteria for participant population extending duration of treatment to 48 cycles and evaluating accumulated outcomes data, allowing surgical procedures as long as the procedures did not meet the discontinuation criteria, and increasing the enrollment number for participants in the study.
    16 Sep 2019
    Major changes of AM 6 include closing participant enrollment to Part A of the study, including Part B Cohort 4, updating study efficacy and exploratory endpoints, and increasing number of global sites.
    08 Oct 2021
    Major changes of AM 7 include removing all primary efficacy endpoints and all secondary endpoints, changing sponsor to ArQule, Inc (A Wholly owned subsidiary to Merch Sharp & Dohme, a subsidiary of Merck & Co., Inc), and updating primary objective to reflect safety and tolerability of miransertib.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Mar 2022
    Business reasons
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination due to business reasons
    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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