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    Clinical Trial Results:
    A Phase 1/2 Pharmacokinetic Multi-tumor Study of Subcutaneous Formulation of Ipilimumab Monotherapy and in Combination with Subcutaneous Nivolumab

    Summary
    EudraCT number
    		 2019-004380-40
    Trial protocol
    		 GB   IT  
    Global end of trial date
    18 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2024
    First version publication date
    06 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-76U
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04311710
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    06 Apr 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the PK, safety, and tolerability of high concentrations of ipilimumab administered subcutaneously with and without rHuPH20 as monotherapy and in combination with SC nivolumab with rHuPH20 in participants with one of the following advanced or metastatic tumor types: melanoma, HCC, mUC, NSCLC, and RCC.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2020
    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
    Italy: 14
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    21
    EEA total number of subjects
    14
    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)
    13
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 21 participants were treated.

    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
    Arm title
    		 Part 1 Arm A
    Arm description
    		 4 mg/kg ipilimumab (BMS-734016) + rHuPH20 administered subcutaneously every 3 weeks X 1 cycle (one cycle is 21 days) followed by 3 mg/kg ipilimumab + 1 mg/kg nivolumab (BMS-936558) administered intravenously every 3 weeks X 3 cycles followed by 480 mg nivolumab administered intravenously every 4 weeks for up to 104 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-734016 + BMS-936558
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg (BMS-734016) + 1 mg/kg (BMS-936558) Q3W x 3 cycles

    Investigational medicinal product name
    BMS-936558
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg monotherapy Q4W until completion for 104 weeks

    Investigational medicinal product name
    BMS-734016+ rHuPH20
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    4 mg/kg Q3W x 1 cycle

    Number of subjects in period 1
    		Part 1 Arm A
    Started
    21
    Completed
    3
    Not completed
    18
         Adverse event, non-fatal
    1
         Death
    1
         Other Reason
    2
         Study Drug Toxicity
    10
         Disease Progression
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 Arm A
    Reporting group description
    		 4 mg/kg ipilimumab (BMS-734016) + rHuPH20 administered subcutaneously every 3 weeks X 1 cycle (one cycle is 21 days) followed by 3 mg/kg ipilimumab + 1 mg/kg nivolumab (BMS-936558) administered intravenously every 3 weeks X 3 cycles followed by 480 mg nivolumab administered intravenously every 4 weeks for up to 104 weeks.

    Reporting group values
    		 Part 1 Arm A Total
    Number of subjects
    		 21 21
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ( 13.04 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 14 14
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 18 18
        Not reported
    		 3 3
    Race (NIH/OMB)
    Units: Subjects
        White
    		 21 21

    End points

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    End points reporting groups
    Reporting group title
    Part 1 Arm A
    Reporting group description
    		 4 mg/kg ipilimumab (BMS-734016) + rHuPH20 administered subcutaneously every 3 weeks X 1 cycle (one cycle is 21 days) followed by 3 mg/kg ipilimumab + 1 mg/kg nivolumab (BMS-936558) administered intravenously every 3 weeks X 3 cycles followed by 480 mg nivolumab administered intravenously every 4 weeks for up to 104 weeks.

    Primary: AUC (0-21d) of ipilimumab

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    End point title
    		 AUC (0-21d) of ipilimumab [1]
    End point description
    Area under the concentration-time curve from time 0 to 21 days postdose
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 1 pre-dose, 24, 48, 72, 168, 336 hours post-dose. End-of-infusion on Cycle 2 Day 1 (Cycle 1 = 3 weeks)
    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: Only summary statistics planned for this endpoint.
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    16
    Units: h*ug/mL
        geometric mean (geometric coefficient of variation)
    9931.24 ( 25 )
    No statistical analyses for this end point

    Primary: Time of Maximum Observed Concentration (Tmax) of Ipilimumab

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    End point title
    		 Time of Maximum Observed Concentration (Tmax) of Ipilimumab [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 1 pre-dose, 24, 48, 72, 168, 336 hours post-dose. End-of-infusion on Cycle 2 Day 1 (Cycle 1 = 3 weeks)
    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: Only summary statistics planned for this endpoint.
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    18
    Units: hours
        median (full range (min-max))
    72.08 (48.00 to 168.13)
    No statistical analyses for this end point

    Primary: Cmax

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    End point title
    		 Cmax [3]
    End point description
    Maximum observed serum concentration of ipilimumab
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 1 pre-dose, 24, 48, 72, 168, 336 hours post-dose. End-of-infusion on Cycle 2 Day 1 (Cycle 1 = 3 weeks)
    Notes
    [3] - 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: Only summary statistics planned for this endpoint.
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    18
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    28.91 ( 27 )
    No statistical analyses for this end point

    Primary: Cavg21d

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    End point title
    		 Cavg21d [4]
    End point description
    Average concentration of ipilimumab during 21 days post-first dose
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 1 pre-dose, 24, 48, 72, 168, 336 hours post-dose. End-of-infusion on Cycle 2 Day 1 (Cycle 1 = 3 weeks)
    Notes
    [4] - 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: Only summary statistics planned for this endpoint.
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    16
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    19.47 ( 24 )
    No statistical analyses for this end point

    Primary: C21d

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    End point title
    		 C21d [5]
    End point description
    Observed concentration of ipilimumab at 21 days postdose
    End point type
    Primary
    End point timeframe
    Day 1 Cycle 1 pre-dose, 24, 48, 72, 168, 336 hours post-dose. End-of-infusion on Cycle 2 Day 1 (Cycle 1 = 3 weeks)
    Notes
    [5] - 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: Only summary statistics planned for this endpoint.
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    18
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    12.03 ( 29 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days post last dose (up to approximately 25 months)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
        Total
    21
    No statistical analyses for this end point

    Secondary: Number of Participants with Serious AEs (SAEs)

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    End point title
    		 Number of Participants with Serious AEs (SAEs)
    End point description
    A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: -Results in death -Is life-threatening -Requires inpatient hospitalization or causes prolongation of existing hospitalization -Results in persistent or significant disability/incapacity -Is a congenital anomaly/birth defect -Is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the participant or may require intervention to prevent one of the other serious outcomes listed in the definition above.)
    End point type
    Secondary
    End point timeframe
    From first dose up to 100 days post last dose (up to approximately 27 months)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
        Total
    16
    No statistical analyses for this end point

    Secondary: Number of Participants with Laboratory Abnormalities

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    End point title
    		 Number of Participants with Laboratory Abnormalities
    End point description
    The number of participants experiencing laboratory test abnormalities. Laboratory analysis was performed on the following: hematology, liver and kidney function, and other chemistry testing.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days post last dose (up to approximately 25 months)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
        Hemoglobin (g/L) Grades 1-3
    15
        Platelet Count (10^9/L) Grades 1-4
    9
        Leukocytes (10^9/L) Grades 1-4
    5
        Lymphocytes (Absolute) (10^9/L) Grades 1-4
    8
        Neutrophil (Absolute) (10^9/L) Grades 1-4
    4
        Alkaline Phosphatase (g/L) Grades 1-4
    6
        Aspartate Aminotransferase (U/L) Grades 1-4
    10
        Alanine Aminotransferase (U/L) Grades 1-4
    9
        Bilirubin (Total) (umol/L) Grades 1-4
    6
        Creatinine (umol/L) Grades 1-4
    8
        Hypernatremia (mmol/L) Grades 1-4
    1
        Hyponatremia (mmol/L) Grades 1-4
    11
        Hyperkalemia (mmol/L) Grades 1-4
    0
        Hypokalemia (mmol/L) Grades 1-4
    7
        Hypercalcemia (mmol/L) Grades 1-4
    2
        Hypocalcemia (mmol/L) Grades 1-4
    11
        Hypermagnesemia (mmol/L) Grades 1-4
    0
        Hypomagnesemia (mmol/L) Grades 1-4
    6
        Hypoglycemia (mmol/L) Grades 1-4
    2
    No statistical analyses for this end point

    Secondary: Number of Participants who Died During the Study

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    End point title
    		 Number of Participants who Died During the Study
    End point description
    Number of participants who died
    End point type
    Secondary
    End point timeframe
    From first dose up to 100 days post last dose (up to approximately 27 months)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
    5
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation

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    End point title
    		 Number of Participants with Adverse Events (AEs) Leading to Discontinuation
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days post last dose (up to approximately 25 months)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
        Total
    11
    No statistical analyses for this end point

    Secondary: Number of Participants with Anaphylactic, Hypersensitivity, Injection, and Infusion Reactions

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    End point title
    		 Number of Participants with Anaphylactic, Hypersensitivity, Injection, and Infusion Reactions
    End point description
    The number of participants with AEs in the broad standardized MedDRA query (SMQ) of Anaphylactic Reaction and the select AE hypersensitivity/ injection/infusion reaction category. MedDRA = Medical Dictionary for Regulatory Activities SMQ = standardized MedDRA queries
    End point type
    Secondary
    End point timeframe
    From first dose up to 2 days after study drug administration (up to approximately 24 months)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
        Anaphylactic reaction
    0
        Hypersensitivity reaction
    0
        Injection reaction
    2
        Infusion-related reaction
    1
    No statistical analyses for this end point

    Secondary: Number of Participants who Develop Anti-ipilimumab Antibodies

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    End point title
    		 Number of Participants who Develop Anti-ipilimumab Antibodies
    End point description
    -ADA (anti-drug antibody)-positive: A subject with at least one ADA-positive sample relative to baseline (ADA-negative at baseline or ADA titer to be at least 4-fold or greater (≥) than baseline positive titer at any time after initiation of treatment) -Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected post-baseline -ADA-negative: A participant with no ADA-positive sample after initiation of treatment
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1 pre-dose, 24 hours post-dose, and Day 1 pre-dose of Cycles 2-6 (Cycle 1-4 = 3 weeks each and cycle 5-26 = 4 weeks each)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    21
    Units: participants
        ADA Negative
    21
        ADA Positive
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-nivolumab Antibodies

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    End point title
    		 Number of Participants with Anti-nivolumab Antibodies
    End point description
    -ADA (anti-drug antibody)-positive: A subject with at least one ADA-positive sample relative to baseline (ADA-negative at baseline or ADA titer to be at least 4-fold or greater (≥) than baseline positive titer at any time after initiation of treatment) -Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected post-baseline -ADA-negative: A participant with no ADA-positive sample after initiation of treatment
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose of Cycles 2-6, 10, 14, 18, 22, and 26 (Cycle 1-4 = 3 weeks each and cycle 5-26 = 4 weeks each)
    End point values
    		 Part 1 Arm A
    Number of subjects analysed
    14
    Units: participants
        ADA Positive
    6
        Neutralizing Positive
    2
        ADA Negative
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from first dose to study completion (up to approximately 30 months) SAEs and NSAEs were assessed from first dose to 100 days following last dose (up to approximately 27 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    PART 1 ARM A
    Reporting group description
    		 4 mg/kg ipilimumab (BMS-734016) + rHuPH20 administered subcutaneously every 3 weeks X 1 cycle (one cycle is 21 days) followed by 3 mg/kg ipilimumab + 1 mg/kg nivolumab (BMS-936558) administered intravenously every 3 weeks X 3 cycles followed by 480 mg nivolumab administered intravenously every 4 weeks for up to 104 weeks.

    Serious adverse events
    		 PART 1 ARM A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 21 (76.19%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Immune-mediated myositis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PART 1 ARM A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 21 (28.57%)
         occurrences all number
    7
    Pyrexia
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    5
    Oedema peripheral
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Feeling cold
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Blood albumin decreased
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 21 (33.33%)
         occurrences all number
    11
    Amylase increased
         subjects affected / exposed
    6 / 21 (28.57%)
         occurrences all number
    22
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 21 (33.33%)
         occurrences all number
    11
    Blood bilirubin increased
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    5
    Blood phosphorus decreased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    6
    Blood magnesium decreased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    7
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    4
    Blood creatinine increased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    7
    Blood chloride decreased
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Blood calcium decreased
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    6
    Blood sodium decreased
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    7
    Lipase increased
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    10
    Protein total decreased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Blood urea increased
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 21 (47.62%)
         occurrences all number
    13
    Thrombocytopenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    4
    Neutropenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Lymphopenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    7
    Leukopenia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Abdominal pain
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    8
    Diarrhoea
         subjects affected / exposed
    9 / 21 (42.86%)
         occurrences all number
    18
    Dyspepsia
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    5 / 21 (23.81%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    5
    Colitis
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Vitiligo
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Papule
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Hyperthyroidism
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 21 (14.29%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 21 (19.05%)
         occurrences all number
    4
    Hyperglycaemia
         subjects affected / exposed
    6 / 21 (28.57%)
         occurrences all number
    8
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Vitamin D deficiency
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2

    More information

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

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

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