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    Clinical Trial Results:
    An Open-Label Phase 2 Study of Itacitinib (INCB039110) in Combination With Low-Dose Ruxolitinib or Itacitinib Alone Following Ruxolitinib in Subjects With Myelofibrosis

    Summary
    EudraCT number
    		 2017-005109-11
    Trial protocol
    		 NL   AT  
    Global end of trial date
    01 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2022
    First version publication date
    02 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    INCB 39110-209
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03144687
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Incyte Corporation
    Sponsor organisation address
    1801 Augustine Cutoff, Wilmington, United States, 19803
    Public contact
    Study Director, Incyte Corporation, 1 8554633463, medinfo@incyte.com
    Scientific contact
    Study Director, Incyte Corporation, 1 8554633463, medinfo@incyte.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
    01 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy and safety of itacitinib combined with low-dose ruxolitinib or itacitinib alone in participants with myelofibrosis (MF).
    Protection of trial subjects
    This study was to be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the United States Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as International Conference on Harmonization Good Clinical Practice consolidated guidelines (E6) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    23
    EEA total number of subjects
    2
    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)
    4
    From 65 to 84 years
    18
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 9 study centers in the United States, 1 study center in Austria, and 1 study center in the Netherlands.

    Pre-assignment
    Screening details
    		 A total of 23 participants with Myelofibrosis (MF) were enrolled in the study and received itacitinib + ruxolitinib (Cohort A) or itacitinib monotherapy (Cohort B).

    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
    		 Cohort A
    Arm description
    		 Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of itacitinib at the dose of 200 mg, orally, once daily (QD) and ruxolitinib, orally, twice daily (BID) at their previous stable dose (must had been < 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5, 10, and 15 mg tablets

    Investigational medicinal product name
    Itacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg tablets

    Arm title
    		 Cohort B
    Arm description
    		 Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Itacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg tablets

    Number of subjects in period 1
    		Cohort A Cohort B
    Started
    13
    10
    Completed
    10
    3
    Not completed
    3
    7
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    1
    3
         Physician decision
    -
    1
         Not Reported
    2
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of itacitinib at the dose of 200 mg, orally, once daily (QD) and ruxolitinib, orally, twice daily (BID) at their previous stable dose (must had been < 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Reporting group title
    Cohort B
    Reporting group description
    		 Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Reporting group values
    		 Cohort A Cohort B Total
    Number of subjects
    		 13 10 23
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 3 1 4
        From 65-84 years
    		 10 8 18
        85 years and over
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.8 ± 6.20 72.0 ± 7.33 -
    Sex: Female, Male
    Units: participants
        Female
    		 6 7 13
        Male
    		 7 3 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 12 9 21
        Unknown or Not Reported
    		 0 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        White/Caucasian
    		 13 8 21
        Other
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of itacitinib at the dose of 200 mg, orally, once daily (QD) and ruxolitinib, orally, twice daily (BID) at their previous stable dose (must had been < 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Reporting group title
    Cohort B
    Reporting group description
    		 Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Subject analysis set title
    PK: Cohort A (Itacitinib)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received itacitinib at the dose of 200 mg, orally, QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Subject analysis set title
    PK: Cohort A (Ruxolitinib)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ruxolitinib, orally, BID at their previous stable dose (must have been < 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Subject analysis set title
    PK: Cohort B (Itacitinib)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Primary: Change in spleen volume at Week 24 compared to baseline

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    End point title
    		 Change in spleen volume at Week 24 compared to baseline [1]
    End point description
    Spleen volume was measured using magnetic resonance imaging (MRI) or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. Here, Overall Number of participants analyzed (“N”) signifies participants who were evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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: Statistical analysis was not conducted.
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    9
    5
    Units: cubic centimeter (cm^3)
        arithmetic mean (standard deviation)
    88.7 ± 563.5
    -207 ± 571.3
    No statistical analyses for this end point

    Primary: Percentage change in spleen volume at Week 24 compared to baseline

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    End point title
    		 Percentage change in spleen volume at Week 24 compared to baseline [2]
    End point description
    Spleen volume was measured using MRI or CT scan in participants who were not candidates for MRI or when MRI was not readily available. The MRIs or CTs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. Here, “N” signifies participants who were evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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: Statistical analysis was not conducted.
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    9
    5
    Units: percentage change
        arithmetic mean (standard deviation)
    6.9 ± 27.49
    -3.0 ± 34.67
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether considered drug related, that occurs after a participant provides informed consent. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug. An SAE is an AE resulting in: death; initial/prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly.
    End point type
    Secondary
    End point timeframe
    up to approximately 40 months (3.3 years)
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    13
    10
    Units: participants
        TEAE
    13
    10
        SAE
    3
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters

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    End point title
    		 Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
    End point description
    Laboratory investigation included hematology, clinical chemistry, coagulation and urinalysis. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.
    End point type
    Secondary
    End point timeframe
    up to approximately 40 months (3.3 years)
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    13
    10
    Units: participants
        Hemoglobin: High Direction
    0
    0
        Hemoglobin: Low Direction
    4
    4
        Leukocytes: High Direction
    0
    1
        Leukocytes: Low Direction
    0
    0
        Lymphocytes: High Direction
    0
    0
        Lymphocytes: Low Direction
    3
    1
        Neutrophils
    0
    1
        Platelets
    3
    4
        Alanine Aminotransferase
    0
    0
        Albumin
    0
    0
        Alkaline Phosphatase
    0
    0
        Aspartate Aminotransferase
    0
    0
        Bilirubin
    1
    0
        Calcium: High Direction
    0
    0
        Calcium: Low Direction
    0
    0
        Cholesterol
    0
    0
        Creatinine
    0
    0
        Glucose: High Direction
    0
    0
        Glucose: Low Direction
    0
    0
        Phosphate
    0
    1
        Potassium: High Direction
    0
    0
        Potassium: Low Direction
    0
    0
        Sodium: High Direction
    0
    0
        Sodium: Low Direction
    0
    0
        Triglycerides
    0
    1
        Urate
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes From Baseline in Vital Signs

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    End point title
    		 Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
    End point description
    Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported.
    End point type
    Secondary
    End point timeframe
    up to approximately 40 months (3.3 years)
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    13
    10
    Units: participants
        Systolic blood pressure, Week 12
    1
    1
        Systolic blood pressure, Week 24
    0
    1
        Systolic blood pressure, Week 36
    0
    1
        Systolic blood pressure, End of Treatment
    1
    0
        Diastolic blood pressure, Week 12
    0
    1
        Pulse, Week 84
    1
    0
        Pulse, Follow-up
    1
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)

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    End point title
    		 Change from Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)
    End point description
    Spleen volume was measured using magnetic resonance imaging (or CT scan in applicable participants). MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. MRI was performed with a body coil. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. Here, “N” signifies participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 12
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    11
    8
    Units: cm^3
        arithmetic mean (standard deviation)
    -29.2 ± 349.3
    -608 ± 669.6
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)

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    End point title
    		 Percentage Change From Baseline Through Week 12 in SVR as Measured by MRI (or CT Scan in Applicable Participants)
    End point description
    Spleen volume was measured using magnetic resonance imaging (or CT scan in applicable participants). MRI of the upper and lower abdomen and pelvis was performed, to assess spleen volumes. MRI was performed with a body coil. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred. Here, “N” signifies participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 12
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    11
    8
    Units: percentage change
        arithmetic mean (standard deviation)
    -1.6 ± 14.69
    -24.6 ± 21.72
    No statistical analyses for this end point

    Secondary: Change from Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation

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    End point title
    		 Change from Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation
    End point description
    Measurement of spleen length below the left costal margin was measured by palpation. Spleen size was determined at every physical examination with the participant in the recumbent (not left decubitus) position. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The measurements should be noted and the site at which it was determined listed (eg, anterior axillary line, midclavicular line, and/or subxiphoid). A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. Here, “N ”signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline through Weeks 12 and 24
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    12
    7
    Units: cm
    arithmetic mean (standard deviation)
        Week 12, n=12, 7
    -0.2 ± 2.17
    -3.6 ± 6.73
        Week 24, n=9, 5
    -0.4 ± 5.41
    -2.6 ± 3.44
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation

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    End point title
    		 Percentage Change From Baseline Through Week 12 and Week 24 on Spleen Length as Measured by Palpation
    End point description
    Measurement of spleen length below the left costal margin was measured by palpation. Spleen size was determined at every physical examination with the participant in the recumbent (not left decubitus) position. The edge of the spleen was determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The measurements should be noted and the site at which it was determined listed (eg, anterior axillary line, midclavicular line, and/or subxiphoid). A positive value indicates an increase in spleen volume and a negative value indicates a decrease in spleen volume. Here, "N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline through Weeks 12 and 24
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    12
    7
    Units: percentage change
    arithmetic mean (standard deviation)
        Week 12, n=12, 7
    8.8 ± 40.83
    -14.4 ± 49.89
        Week 24, n=9, 5
    2.5 ± 50.72
    -21.3 ± 27.94
    No statistical analyses for this end point

    Secondary: Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary

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    End point title
    		 Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 Symptom Diary
    End point description
    Symptoms of myelofibrosis were assessed using a modified MFSAF Version 2.0 diary. Using the diary, participants rated the following symptoms on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be): itching, night sweats, abdominal discomfort/bloating, early satiety, pain under the ribs on left side and bone/muscle pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms. Here, "N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 12 and 24
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    12
    7
    Units: score on scale
    arithmetic mean (standard deviation)
        Change at Week 12, n=12, 7
    1.4 ± 6.06
    -4.7 ± 12.50
        Change at Week 24, n=9, 5
    -1.0 ± 9.88
    -0.3 ± 10.14
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as measured by the MFSAF v2.0 Symptom Diary

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    End point title
    		 Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as measured by the MFSAF v2.0 Symptom Diary
    End point description
    Symptoms of myelofibrosis were assessed using a modified MFSAF Version 2.0 diary. Using the diary, participants rated the following symptoms on a scale from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be): itching, night sweats, abdominal discomfort/bloating, early satiety, pain under the ribs on left side and bone/muscle pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms. Here, “N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 12 and 24
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    12
    6
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage Change at Week 12, n=12, 6
    0.7 ± 69.57
    -1.8 ± 116.6
        Percentage Change at Week 24, n=9, 4
    -5.6 ± 95.56
    33.7 ± 142.3
    No statistical analyses for this end point

    Secondary: Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF)

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    End point title
    		 Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF)
    End point description
    Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS assessed by the participants themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). A higher score indicates worse symptoms. Here, “N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 12 and Week 24
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    11
    7
    Units: score on scale
    arithmetic mean (standard deviation)
        Change at Week 12, n=11, 7
    2.0 ± 9.76
    -3.7 ± 12.91
        Change at Week 24, n=9, 4
    -1.6 ± 11.11
    -6.0 ± 8.76
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF

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    End point title
    		 Percentage Change From Baseline Through Week 12 and Week 24 in Total Symptom Score as Measured by the MPN-SAF
    End point description
    Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS assessed by the participants themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). A higher score indicates worse symptoms. Note that the mean percentage change can vary in direction from the mean absolute change because percent increases (but not decreases) can exceed 100%. Here, “N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 12 and Week 24
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    11
    7
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage Change at Week 12, n=11, 7
    3.8 ± 47.25
    -6.1 ± 51.24
        Percentage Change at Week 24, n=9, 4
    5.8 ± 46.85
    -22.7 ± 29.62
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) Score at Each Visit

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    End point title
    		 Patient Global Impression of Change (PGIC) Score at Each Visit
    End point description
    Symptoms of myelofibrosis were assessed using the PGIC questionnaire. Using the questionnaire, participants rated the overall sense of treatment effect on their symptoms on a scale of 1 (very much improved)- 7(very much worse). The specific wording was: Since the start of the treatment you have received in this study, your myelofibrosis symptoms are: 1) Very much improved, 2) Much improved, 3) Minimally improved, 4) No change, 5) Minimally worse, 6) Much worse, 7) Very much worse. A higher score indicates worse symptoms. 9999=no participants were analyzed at this time point. 99999=Standard deviation was not estimable since only 1 participant was evaluable. Here, “N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point. Here, “N” signifies number of participants analyzed for this outcome measure and “n” signifies number of participants with data available at a particular time point.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 168
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    11
    9
    Units: score on scale
    arithmetic mean (standard deviation)
        Week 4, n=11, 8
    3.6 ± 0.81
    3.5 ± 0.93
        Weeks 8, n=11, 9
    3.3 ± 0.90
    3.3 ± 1.22
        Weeks 12, n=11, 7
    3.2 ± 0.98
    3.6 ± 0.98
        Weeks 16, n=9, 6
    3.0 ± 1.00
    4.2 ± 1.47
        Weeks 20, n=8, 6
    3.3 ± 0.71
    3.2 ± 0.75
        Weeks 24, n=9, 4
    3.2 ± 1.09
    2.8 ± 0.96
        Weeks 36, n=6, 3
    3.2 ± 0.98
    3.0 ± 1.00
        Weeks 48, n=4, 1
    2.5 ± 1.00
    2.0 ± 99999
        Weeks 60, n=3, 1
    3.0 ± 1.73
    3.0 ± 99999
        Weeks 72, n=4, 1
    3.3 ± 1.50
    3.0 ± 99999
        Weeks 84, n=1, 1
    2.0 ± 99999
    3.0 ± 99999
        Weeks 96, n=0, 1
    9999 ± 9999
    2.0 ± 99999
        Weeks 108, n=0, 1
    9999 ± 9999
    4.0 ± 99999
        Week 120, n=0, 1
    9999 ± 9999
    3.0 ± 99999
        Week 132, n=0, 1
    9999 ± 9999
    3.0 ± 99999
        Week 168, n=0, 1
    9999 ± 9999
    3.0 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Participants with Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response

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    End point title
    		 Number of Participants with Responses According to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Consensus Criteria for Treatment Response
    End point description
    Treatment response (complete remission [CR] or partial remission [PR]) graded per IWG-MRT. CR: Bone marrow (BM): < 5% blasts; ≤ Grade 1 MF, Peripheral blood: Hemoglobin (Hb) ≥ 100 grams per liter (g/L), < upper normal limit (UNL); neutrophil count ≥ 1 × 10^9/L and < UNL; Platelet count ≥ 100 × 10^9/L and < UNL; < 2% immature myeloid cells (IMCs) and Clinical: Resolution of disease symptoms; spleen, liver not palpable; no evidence of extramedullary hematopoeisis (EMH). PR: Peripheral blood: Hb ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 10^9/L and < UNL; platelet count ≥ 100 × 10^9/L and < UNL; < 2% IMCs and Clinical: Resolution of symptoms; spleen and liver not palpable; no evidence of EMH or BM: < 5% blasts; ≤ Grade 1 MF; and peripheral blood: Hb≥ 85 g/L but < 100 g/L and < UNL; neutrophil count ≥ 1 × 10^9/L and < UNL; platelet count ≥ 50 × 10^9/L but < 100 × 10^9/L and < UNL; < 2% IMCs and Clinical: Resolution of symptoms; spleen, liver not palpable; no evidence of EMH.
    End point type
    Secondary
    End point timeframe
    up to approximately 40 months (3.3 years)
    End point values
    		 Cohort A Cohort B
    Number of subjects analysed
    13
    10
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib

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    End point title
    		 Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Itacitinib
    End point description
    AUCtau defined as area under the concentration-time curve over a dosing interval for Itacitinib. The concentrations of itacitinib in plasma were determined using a validated Liquid Chromatography with tandem mass spectrometry (LC/MS/MS) method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). 9999=itacitinib PK data for Cohort A on Week 2 were not available as itacitinib was to be held until the completion of PK sample collection. Here, “N ” signifies number of participants analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Itacitinib) PK: Cohort B (Itacitinib)
    Number of subjects analysed
    12
    8
    Units: nanomolar* hour (nM*h)
    arithmetic mean (standard deviation)
        Week 2, n=0, 8
    9999 ± 9999
    24100 ± 6600
        Week 4, n=12, 7
    2540 ± 2020
    28900 ± 11200
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib

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    End point title
    		 Area Under the Concentration-time Curve Over a Dosing Interval (AUCtau) for Ruxolitinib
    End point description
    AUCtau defined as area under the concentration-time curve over a dosing interval for ruxolitinib. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Here, “N ” signifies number of participants analyzed for this outcome measure. Only the data from 15 mg QD is shown as it is the only dose level with at least 3 participants at both Week 2 and Week 4.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Ruxolitinib)
    Number of subjects analysed
    4
    Units: nM*h
    arithmetic mean (standard deviation)
        Week 2
    2930 ± 486
        Week 4
    2350 ± 635
    No statistical analyses for this end point

    Secondary: Apparent Oral Dose Clearance (CL/F) of Itacitinib

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    End point title
    		 Apparent Oral Dose Clearance (CL/F) of Itacitinib
    End point description
    Clearance of a drug was measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). 9999=Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. Here, “N ” signifies number of participants analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Itacitinib) PK: Cohort B (Itacitinib)
    Number of subjects analysed
    12
    8
    Units: liters per hour (L/h)
    arithmetic mean (standard deviation)
        Week 2, n=0, 8
    9999 ± 9999
    48.5 ± 14.9
        Week 4, n=12, 7
    203 ± 97.4
    42.4 ± 15.8
    No statistical analyses for this end point

    Secondary: Apparent Oral Dose Clearance (CL/F) of Ruxolitinib

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    End point title
    		 Apparent Oral Dose Clearance (CL/F) of Ruxolitinib
    End point description
    Clearance of a drug was measure of the rate at which a drug is metabolized or eliminated by normal biological processes. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Only the data from 15 mg QD is shown as it is the only dose level with at least 3 participants at both Week 2 and Week 4.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Ruxolitinib)
    Number of subjects analysed
    4
    Units: L/h
    arithmetic mean (standard deviation)
        Week 2, n=3
    17.0 ± 3.12
        Week 4, n=4
    22.2 ± 6.82
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Itacitinib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Itacitinib
    End point description
    The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). 9999=Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. Here, “N ” signifies number of participants analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Itacitinib) PK: Cohort B (Itacitinib)
    Number of subjects analysed
    12
    8
    Units: nanometer (nM)
    arithmetic mean (standard deviation)
        Week 2, n=0, 8
    9999 ± 9999
    3570 ± 1280
        Week 4, n=12, 7
    559 ± 518
    4460 ± 2470
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Ruxolitinib
    End point description
    The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Only the data from 15 mg QD is shown as it is the only dose level with at least 3 participants at both Week 2 and Week 4.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Ruxolitinib)
    Number of subjects analysed
    4
    Units: nM
    arithmetic mean (standard deviation)
        Week 2, n=3
    695 ± 111
        Week 4, n=4
    677 ± 118
    No statistical analyses for this end point

    Secondary: Time to Maximum Concentration (Tmax) of Itacitinib

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    End point title
    		 Time to Maximum Concentration (Tmax) of Itacitinib
    End point description
    The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). 9999=Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. Here, “N ” signifies number of participants analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Itacitinib) PK: Cohort B (Itacitinib)
    Number of subjects analysed
    12
    8
    Units: hour (hr)
    median (full range (min-max))
        Week 2, n=0, 8
    9999 (9999 to 9999)
    2.0 (1.0 to 5.0)
        Week 4, n=12, 7
    2.0 (1.0 to 2.3)
    2.0 (2.0 to 4.6)
    No statistical analyses for this end point

    Secondary: Time to Maximum Concentration (Tmax) of Ruxolitinib

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    End point title
    		 Time to Maximum Concentration (Tmax) of Ruxolitinib
    End point description
    The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Only the data from 15 mg QD is shown as it is the only dose level with at least 3 participants at both Week 2 and Week 4.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Ruxolitinib)
    Number of subjects analysed
    4
    Units: hr
    median (full range (min-max))
        Week 2, n=3
    1.0 (1.0 to 1.1)
        Week 4, n=4
    1.0 (1.0 to 1.1)
    No statistical analyses for this end point

    Secondary: Concentration at the end of the Dosing Interval (Ctau) of Itacitinib

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    End point title
    		 Concentration at the end of the Dosing Interval (Ctau) of Itacitinib
    End point description
    Ctau is defined as concentration at the end of the dosing interval of ruxolitinib.The concentrations of itacitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 5 to 5000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). 9999=Data for Cohort A (Itacitinib) on Week 2 was not available as Cohort A, itacitinib was to be held on Week 2 until the completion of the PK sample collection. Here, “N ” signifies number of participants analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose on Week 2 and Week 4
    End point values
    		 PK: Cohort A (Itacitinib) PK: Cohort B (Itacitinib)
    Number of subjects analysed
    12
    9
    Units: nM
    arithmetic mean (standard deviation)
        Week 2, n=0, 8
    9999 ± 9999
    102 ± 120
        Week 4, n=12, 9
    10.2 ± 8.67
    108 ± 85.4
    No statistical analyses for this end point

    Secondary: Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib

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    End point title
    		 Concentration at the End of the Dosing Interval (Ctau) of Ruxolitinib
    End point description
    Ctau is defined as concentration at the end of the dosing interval of ruxolitinib. The concentrations of ruxolitinib in plasma were determined using a validated LC/MS/MS method with an assay range of 1 to 1000 nM. The PK parameters were calculated using standard noncompartmental analysis in Phoenix WinNonlin® v8.2 (Certara USA Inc., Princeton, NJ). Only the data from 15 mg QD is shown as it is the only dose level with at least 3 participants at both Week 2 and Week 4.
    End point type
    Secondary
    End point timeframe
    0 (pre-dose), 1, 2, 5 and 8 hours post-dose Week 2 and Week 4
    End point values
    		 PK: Cohort A (Ruxolitinib)
    Number of subjects analysed
    4
    Units: nM
    arithmetic mean (standard deviation)
        Week 2, n=3
    16.6 ± 14.5
        Week 4, n=4
    19.7 ± 28.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to approximately 40 months (3.3 years)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Participants with MF who were tolerating a ruxolitinib dose of less than 20 milligrams (mg) daily with no dose increase or no dose modification in the 8 weeks before screening visit received a combination of itacitinib at the dose of 200 mg, orally, once daily (QD) and ruxolitinib, orally, twice daily (BID) at their previous stable dose (must had been < 20 mg daily). Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Cohort B
    Reporting group description
    		 Participants with MF who progressed after initial reduction in spleen with ruxolitinib treatment, progressed or discontinued for hematologic toxicities received treatment with itacitinib alone at the dose of 600 mg QD. Participants continued study treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other Protocol-specified criteria to stop treatment were met.

    Serious adverse events
    		 Cohort A Total Cohort B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 13 (23.08%)
    8 / 23 (34.78%)
    5 / 10 (50.00%)
         number of deaths (all causes)
    0
    2
    2
         number of deaths resulting from adverse events
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulse absent
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Stent removal
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic lesion
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Total Cohort B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    23 / 23 (100.00%)
    10 / 10 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Skin papilloma
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Hypotension
         subjects affected / exposed
    2 / 13 (15.38%)
    4 / 23 (17.39%)
    2 / 10 (20.00%)
         occurrences all number
    2
    4
    2
    Thrombophlebitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Calcinosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Chest discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Chills
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Fatigue
         subjects affected / exposed
    3 / 13 (23.08%)
    8 / 23 (34.78%)
    5 / 10 (50.00%)
         occurrences all number
    3
    9
    6
    Influenza like illness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Malaise
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
         occurrences all number
    2
    3
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 23 (21.74%)
    4 / 10 (40.00%)
         occurrences all number
    1
    7
    6
    Thirst
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    2
    4
    2
    Dyspnoea
         subjects affected / exposed
    2 / 13 (15.38%)
    5 / 23 (21.74%)
    3 / 10 (30.00%)
         occurrences all number
    2
    5
    3
    Epistaxis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Haemoptysis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Hypoxia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Pleural effusion
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Depressive symptom
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Dysphoria
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
         occurrences all number
    3
    4
    1
    Blood chloride increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    2
    4
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    3
    2
    Reticulocyte count increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Serum ferritin increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Weight decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 13 (15.38%)
    4 / 23 (17.39%)
    2 / 10 (20.00%)
         occurrences all number
    2
    5
    3
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 23 (17.39%)
    3 / 10 (30.00%)
         occurrences all number
    1
    4
    3
    Skin abrasion
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Skin laceration
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Cardiac failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Diabetic neuropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Dizziness
         subjects affected / exposed
    4 / 13 (30.77%)
    6 / 23 (26.09%)
    2 / 10 (20.00%)
         occurrences all number
    4
    6
    2
    Dysarthria
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
         occurrences all number
    2
    3
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 13 (30.77%)
    8 / 23 (34.78%)
    4 / 10 (40.00%)
         occurrences all number
    4
    14
    10
    Hypofibrinogenaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Increased tendency to bruise
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Splenic infarction
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 13 (15.38%)
    4 / 23 (17.39%)
    2 / 10 (20.00%)
         occurrences all number
    5
    7
    2
    Thrombocytosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Abdominal distension
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Abdominal pain
         subjects affected / exposed
    4 / 13 (30.77%)
    7 / 23 (30.43%)
    3 / 10 (30.00%)
         occurrences all number
    4
    7
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
         occurrences all number
    1
    5
    4
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
         occurrences all number
    1
    4
    3
    Diarrhoea
         subjects affected / exposed
    4 / 13 (30.77%)
    8 / 23 (34.78%)
    4 / 10 (40.00%)
         occurrences all number
    4
    12
    8
    Dry mouth
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Nausea
         subjects affected / exposed
    2 / 13 (15.38%)
    5 / 23 (21.74%)
    3 / 10 (30.00%)
         occurrences all number
    2
    7
    5
    Stomatitis
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Tooth disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
         occurrences all number
    1
    3
    2
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Dermatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 23 (13.04%)
    0 / 10 (0.00%)
         occurrences all number
    4
    4
    0
    Rash
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Chronic kidney disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Dysuria
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Micturition urgency
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Pollakiuria
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Urinary retention
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Urinary tract pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    2
    3
    1
    Back pain
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Bone pain
         subjects affected / exposed
    2 / 13 (15.38%)
    3 / 23 (13.04%)
    1 / 10 (10.00%)
         occurrences all number
    2
    3
    1
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Muscle spasms
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 23 (13.04%)
    0 / 10 (0.00%)
         occurrences all number
    3
    3
    0
    Muscular weakness
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Posterior tibial tendon dysfunction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Rash pustular
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    3
    3
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 13 (23.08%)
    5 / 23 (21.74%)
    2 / 10 (20.00%)
         occurrences all number
    6
    9
    3
    Vaginal infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 13 (15.38%)
    4 / 23 (17.39%)
    2 / 10 (20.00%)
         occurrences all number
    2
    4
    2
    Dehydration
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 23 (8.70%)
    0 / 10 (0.00%)
         occurrences all number
    2
    2
    0
    Gout
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
         occurrences all number
    2
    5
    3
    Hypokalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 23 (13.04%)
    2 / 10 (20.00%)
         occurrences all number
    1
    3
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    Iron deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 23 (8.70%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    1
    Lactic acidosis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2017
    The primary purpose of this amendment was to clarify exclusion criterion 16 and correct discrepancies between the Protocol text and the schedule of assessments.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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