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    Clinical Trial Results:
    A Phase 1/2 multicenter, open-label study to determine the recommended dose and regimen of Durvalumab (MEDI4736) in combination with Lenalidomide (LEN) with and without Dexamethasone (DEX)in subjects with newly diagnosed multiple myeloma (NDMM)

    Summary
    EudraCT number
    		 2015-004831-11
    Trial protocol
    		 DE   ES   DK   FI   NL  
    Global end of trial date
    06 Sep 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Oct 2023
    First version publication date
    17 Sep 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MEDI4736-MM-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    16 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the recommended dose and regimen of durvalumab in combination with LEN with and without DEX in subjects with newly diagnosed multiple myeloma (NDMM).
    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 Apr 2016
    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
    Canada: 13
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    56
    EEA total number of subjects
    39
    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)
    17
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 56 subjects treated

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: High risk, TNE
    Arm description
    		 High risk, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    LEN
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/day on days 1 to 21 of each 28-day treatment cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    DEX
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1500 mg on day 1 of each 28-day cycle

    Arm title
    		 Cohort B: >=65 years old, TNE
    Arm description
    		 >= 65 years old, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were not high risk were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle, up to 12 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1500 mg on day 1 of each 28-day cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    DEX
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    LEN
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/day on days 1 to 21 of each 28-day treatment cycle

    Arm title
    		 Cohort C: High risk, Post-transplant
    Arm description
    		 High risk, post-transplant NDMM participants were administered the following as maintenance therapy: • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 10 mg/day on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    LEN
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg/day on days 1 to 21 of each 28-day treatment cycle

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1500 mg on day 1 of each 28-day cycle

    Number of subjects in period 1
    		Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Started
    25
    10
    21
    Completed
    0
    0
    0
    Not completed
    25
    10
    21
         Consent withdrawn by subject
    2
    -
    -
         Adverse event, non-fatal
    2
    -
    1
         Progressive Disease
    2
    1
    -
         Full Clinical Hold by FDA
    19
    9
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: High risk, TNE
    Reporting group description
    		 High risk, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.

    Reporting group title
    Cohort B: >=65 years old, TNE
    Reporting group description
    		 >= 65 years old, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were not high risk were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle, up to 12 cycles.

    Reporting group title
    Cohort C: High risk, Post-transplant
    Reporting group description
    		 High risk, post-transplant NDMM participants were administered the following as maintenance therapy: • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 10 mg/day on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant Total
    Number of subjects
    		 25 10 21 56
    Age Categorical
    Units: participants
        <=75 years
    		 12 7 20 39
        >75 years
    		 13 3 1 17
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75.4 ( 4.17 ) 72.5 ( 5.25 ) 59.6 ( 7.52 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 15 0 4 19
        Male
    		 10 10 17 37
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 1 1 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 0 0 1
        White
    		 21 9 17 47
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 2 0 4 6

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: High risk, TNE
    Reporting group description
    		 High risk, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.

    Reporting group title
    Cohort B: >=65 years old, TNE
    Reporting group description
    		 >= 65 years old, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were not high risk were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle, up to 12 cycles.

    Reporting group title
    Cohort C: High risk, Post-transplant
    Reporting group description
    		 High risk, post-transplant NDMM participants were administered the following as maintenance therapy: • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 10 mg/day on Days 1 to 21 of each 28-day treatment cycle.

    Primary: Participants with Dose-Limiting Toxicities (DLTs) During the Dose-Determining Timeframe (Day 1 – Day 28)

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    End point title
    		 Participants with Dose-Limiting Toxicities (DLTs) During the Dose-Determining Timeframe (Day 1 – Day 28) [1]
    End point description
    A Dose Review Team (DRT) evaluated DLTs to determine the recommended dose (RD) of Durvalumab to use in the Expansion Period. A DLT was defined as: a. Grade 4 neutropenia for >= 5 days. b. Grade 3 neutropenia associated with fever (≥ 38.5°C / 101.3°F) of any duration. c. Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or platelets transfusion. d. Grade 4 hematologic toxicity that does not resolve to baseline level <=72 hours. e. Grade 4 anemia, unexplained by underlying disease. f. Any nonhematologic toxicity Grade ≥ 3 except for alopecia and nausea. g. Treatment interruption >= 2 weeks due to AE. If ≤ 1 of the 6 initial participants in each cohort experience a DLT during cycle 1, the RD was Durvalumab 1500 mg; If >=2 of the 6 initial participants in any cohort experience a DLT during cycle 1, the maximum tolerated dose (MTD) was exceeded and the dose level of Durvalumab was de-escalated to 750 mg
    End point type
    Primary
    End point timeframe
    First treatment cycle: Day 1 to Day 28
    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 analysis planned for this endpoint.
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    6
    7
    6
    Units: Count of participants
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Participants with Treatment Emergent Adverse Events (TEAE)

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    End point title
    		 Participants with Treatment Emergent Adverse Events (TEAE)
    End point description
    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. A TEAE includes AEs between the first dose date of either study drug and 90 days after the last dose of study drug. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required) - Grade 3 = Severe (limitation in activity; medical intervention required) - Grade 4 = Life-threatening - Grade 5 = Death 99999=NA
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 84 (the longer of 90 days after discontinuing treatment with DURVA, or 28 days after the last dose of LEN or dex)
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    25
    10
    21
    Units: Count of participants
        >= 1 TEAE
    24
    9
    18
        >=1 treatment-related TEAE
    22
    8
    17
        >=1 related to DURVA
    16
    4
    15
        >=1 related to LEN
    22
    8
    15
        >=1 related to dex
    16
    6
    99999
        >=1 TEAE of severity grade 3 or 4
    19
    8
    7
        >=1 severity 3/4, related to study drug
    13
    8
    6
        >=1 severity 3/4, related to DURVA
    7
    4
    4
        >=1 severity 3/4, related to LEN
    11
    8
    4
        >=1 severity 3/4, related to dex
    5
    2
    99999
        >=1 Grade 5 TEAE (Death)
    1
    0
    1
        >=1 Grade 5 TEAE related to study drug
    0
    0
    1
        >=1 Grade 5 TEAE related to DURVA
    0
    0
    1
        >=1 Grade 5 TEAE related to LEN
    0
    0
    0
        >=1 Grade 5 TEAE related to dex
    0
    0
    99999
        >=1 Serious TEAE
    12
    6
    4
        >=1 Serious TEAE related to study drug
    8
    4
    4
        >=1 Serious TEAE related to DURVA
    5
    1
    4
        >=1 Serious TEAE related to LEN
    6
    3
    2
        >=1 Serious TEAE related to dex
    5
    1
    99999
        >=1 TEAE leading to discontinuation of study drug
    3
    0
    1
        >= TEAE leading to discontinuation of DURVA
    2
    0
    1
        >= TEAE leading to discontinuation of LEN
    3
    0
    0
        >= TEAE leading to discontinuation of dex
    2
    0
    99999
        >=1 leading to delay/reduction/interruption drug
    14
    7
    6
        >=1 leading to dose delay of DURVA
    10
    3
    4
        >=1 leading to infusion interruption of DURVA
    0
    0
    1
        >=1 leading to dose reduction of LEN
    2
    2
    3
        >=1 leading to interruption of LEN
    13
    5
    5
        >=1 leading to dose reduction of dex
    1
    3
    99999
        >=1 leading to interruption of dex
    9
    3
    99999
    No statistical analyses for this end point

    Secondary: Response Improvement Rate (RIR) for Cohort C: Percentage of Participants Achieving a Response Improved from Cycle 1 Day 1 as Assessed by the Investigators Using the International Myeloma Working Group (IMWG) Uniform Response Criteria

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    End point title
    		 Response Improvement Rate (RIR) for Cohort C: Percentage of Participants Achieving a Response Improved from Cycle 1 Day 1 as Assessed by the Investigators Using the International Myeloma Working Group (IMWG) Uniform Response Criteria
    End point description
    Response Improvement Rate is defined as the percentage of participants who achieved a response from treatment as compared to the pre-autologous stem cell transplantation [ASCT] diseases measurement used as baseline for response assessment. IMWG response categories could be stable disease (SD), partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), as long as it represented an improvement compared to prior to transplant. 99999=NA
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1); Treatment: Day 1 of each cycle starting with Cycle 2 up to Cycle 15 plus one week for the end of treatment visit (Day 29 up to Week 61)
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    0 [2]
    0 [3]
    21
    Units: percentage of participants
        number (confidence interval 80%)
    ( to )
    ( to )
    0 (-99999 to 99999)
    Notes
    [2] - 0 subjects analyzed
    [3] - 0 subjects analyzed
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) for Cohorts A and B: Percentage of Participants Who Achieved a Partial Response or Better According to the International Myeloma Working Group (IMWG) Uniform Response Criteria

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    End point title
    		 Overall Response Rate (ORR) for Cohorts A and B: Percentage of Participants Who Achieved a Partial Response or Better According to the International Myeloma Working Group (IMWG) Uniform Response Criteria
    End point description
    Tumor response, including progressive disease, was assessed by the investigators and captured the best assessment of response during the treatment period. ORR was defined as partial response (PR) or better which includes PR, very good partial response (VGPR), complete response (CR), or stringent complete response (sCR). A PR required ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg per 24 hours. If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas was also required. sCR required - a negative immunofixation of serum and urine and - disappearance of any soft tissue plasmacytomas and - ≤ 5% plasma cells in bone marrow and normal free light-chain (FLC) ratio and - absence of clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometry.
    End point type
    Secondary
    End point timeframe
    Day 1 of each cycle starting with Cycle 2 up to Cycle 17 plus one week for the end of treatment visit (Day 29 up to Week 73)
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    24
    10
    0 [4]
    Units: percentage of participants
        number (confidence interval 80%)
    66.7 (51.6 to 79.5)
    50.0 (26.7 to 73.3)
    ( to )
    Notes
    [4] - 0 subjects analyzed.
    No statistical analyses for this end point

    Secondary: Time to Response (for Cohorts A and B)

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    End point title
    		 Time to Response (for Cohorts A and B)
    End point description
    Time to response (for responders only, per IMWG Uniform Response Criteria) is calculated as the time from the first date of dosing of study medication to the first date of documented response (PR or better).
    End point type
    Secondary
    End point timeframe
    Day 1 of each cycle starting with Cycle 2 up to Cycle 17 plus one week for the end of treatment visit (Day 29 up to Week 73)
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    16
    5
    0 [5]
    Units: weeks
        median (full range (min-max))
    4.20 (3.9 to 23.1)
    4.10 (4.0 to 13.0)
    ( to )
    Notes
    [5] - 0 subjects analyzed
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates for Duration of Response (for Cohort A and B)

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    End point title
    		 Kaplan-Meier Estimates for Duration of Response (for Cohort A and B)
    End point description
    Duration of response (for responders only) was defined as the time from earliest date of documented response (PR or better) to the earliest date of disease progression (DP) as determined by the investigator per IMWG Uniform Response criteria or death during study treatment, whichever occurred first. 99999=NA
    End point type
    Secondary
    End point timeframe
    Day 1 of each cycle starting with Cycle 2 up to Cycle 17 plus one week for the end of treatment visit (Day 29 up to Week 73)
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    16
    5
    0 [6]
    Units: months
        median (confidence interval 80%)
    10.3 (7.2 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [6] - 0 subjects analyzed
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum Pharmacokinetic (PK) Parameters in Cycle 1: Area Under the Concentration-time Curve from Time Zero to the Last Measured Time Point (AUC0-last)

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    End point title
    		 Durvalumab (DURVA) Serum Pharmacokinetic (PK) Parameters in Cycle 1: Area Under the Concentration-time Curve from Time Zero to the Last Measured Time Point (AUC0-last)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    10
    20
    Units: day*µg/L
        geometric mean (geometric coefficient of variation)
    3535033.014 ( 39.8 )
    3582905.960 ( 21.0 )
    4026520.655 ( 39.1 )
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC0-inf)

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    End point title
    		 Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC0-inf)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    9
    19
    Units: day*µg/L
        geometric mean (geometric coefficient of variation)
    4944601.671 ( 60.9 )
    5532568.144 ( 62.5 )
    6531541.670 ( 36.4 )
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Maximum Observed Concentration (Cmax)

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    End point title
    		 Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Maximum Observed Concentration (Cmax)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    10
    20
    Units: µg/L
        geometric mean (geometric coefficient of variation)
    449280.231 ( 36.7 )
    452827.419 ( 25.5 )
    482602.748 ( 39.9 )
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Time to Maximum Observed Concentration (Tmax)

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    End point title
    		 Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Time to Maximum Observed Concentration (Tmax)
    End point description
    Time to maximum observed concentration of Durvalumab (DURVA) after multiple doses on day 1 obtained from the observed concentration versus time data
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    10
    20
    Units: day
        median (full range (min-max))
    0.051 (0.04 to 0.22)
    0.106 (0.04 to 0.22)
    0.180 (0.04 to 0.22)
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Clearance (CL)

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    End point title
    		 Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Clearance (CL)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    9
    19
    Units: L/day
        geometric mean (geometric coefficient of variation)
    0.303 ( 60.9 )
    0.271 ( 62.5 )
    0.230 ( 36.4 )
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Terminal Elimination Half-life (t1/2)

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    End point title
    		 Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Terminal Elimination Half-life (t1/2)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    9
    19
    Units: day
        geometric mean (geometric coefficient of variation)
    10.984 ( 52.1 )
    13.376 ( 90.9 )
    15.844 ( 29.8 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Maximum Observed Concentration (Cmax)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Maximum Observed Concentration (Cmax)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    24
    10
    21
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    395.774 ( 56.2 )
    354.018 ( 34.7 )
    161.372 ( 33.9 )
    No statistical analyses for this end point

    Secondary: Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Volume of Distribution (Vz)

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    End point title
    		 Durvalumab (DURVA) Serum PK Parameters in Cycle 1: Volume of Distribution (Vz)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    23
    9
    19
    Units: liters
        geometric mean (geometric coefficient of variation)
    4.244 ( 33.5 )
    4.582 ( 33.3 )
    4.563 ( 42.9 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Area Under the Concentration-time Curve from Time Zero to the Last Measured Time Point (AUC0-last)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Area Under the Concentration-time Curve from Time Zero to the Last Measured Time Point (AUC0-last)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    24
    10
    21
    Units: hour*ng/mL
        geometric mean (geometric coefficient of variation)
    1468.102 ( 78.6 )
    1442.549 ( 29.9 )
    591.085 ( 22.3 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC0-inf)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC0-inf)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    13
    3
    12
    Units: hour*ng/mL
        geometric mean (geometric coefficient of variation)
    2534.684 ( 48.6 )
    2011.889 ( 26.8 )
    768.104 ( 33.5 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Apparent Clearance (CL/F)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Apparent Clearance (CL/F)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    13
    3
    12
    Units: L/hour
        geometric mean (geometric coefficient of variation)
    8.838 ( 52.7 )
    12.426 ( 26.8 )
    13.019 ( 33.5 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Time to Maximum Observed Concentration (Tmax)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Time to Maximum Observed Concentration (Tmax)
    End point description
    Time to maximum observed concentration of Lenalidomide (LEN) after multiple doses on day 1 obtained from the observed concentration versus time data
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    24
    10
    21
    Units: hour
        median (full range (min-max))
    1.050 (0.42 to 4.08)
    1.925 (0.50 to 4.00)
    1.150 (0.43 to 4.17)
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Terminal Elimination Half-life (t1/2)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Terminal Elimination Half-life (t1/2)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    13
    3
    12
    Units: hour
        geometric mean (geometric coefficient of variation)
    3.477 ( 61.3 )
    3.051 ( 16.8 )
    2.883 ( 29.2 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Apparent Volume of Distribution (Vz/F)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 1: Apparent Volume of Distribution (Vz/F)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    13
    3
    12
    Units: liters
        geometric mean (geometric coefficient of variation)
    44.329 ( 25.4 )
    54.689 ( 29.7 )
    54.157 ( 22.3 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma PK parameters in Cycle 1 Day 15: Area Under the Concentration-time Curve from Time Zero to the Last Measured Time Point (AUC0-last)

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    End point title
    		 Lenalidomide (LEN) Plasma PK parameters in Cycle 1 Day 15: Area Under the Concentration-time Curve from Time Zero to the Last Measured Time Point (AUC0-last)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    18
    9
    16
    Units: hour*ng/mL
        geometric mean (geometric coefficient of variation)
    1911.739 ( 65.5 )
    1754.349 ( 34.3 )
    629.151 ( 16.8 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 15: Maximum Observed Concentration (Cmax)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 15: Maximum Observed Concentration (Cmax)
    End point description
    Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    18
    9
    16
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    409.764 ( 66.0 )
    452.850 ( 31.7 )
    171.235 ( 33.6 )
    No statistical analyses for this end point

    Secondary: Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 15: Time to Maximum Observed Concentration (Tmax)

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    End point title
    		 Lenalidomide (LEN) Plasma Pharmacokinetic (PK) Parameters in Cycle 1 Day 15: Time to Maximum Observed Concentration (Tmax)
    End point description
    Time to maximum observed concentration of Lenalidomide (LEN) after multiple doses on day 15 obtained from the observed concentration versus time data
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    18
    9
    16
    Units: hour
        median (full range (min-max))
    2.000 (1.00 to 8.00)
    1.000 (0.55 to 2.00)
    1.042 (0.47 to 4.00)
    No statistical analyses for this end point

    Secondary: Participants Who Had Either Disease Progression or Death

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    End point title
    		 Participants Who Had Either Disease Progression or Death
    End point description
    This outcome was originally defined as a Kaplan-Meier estimate of progression-free survival (PFS) which estimated the time between first date of dosing of study medication and disease progression, as determined by the investigator using the IMWG Uniform Response Criteria, or death during study treatment, whichever occurred earlier. However due to the early study termination and limited follow-up time, the majority of participants were censored for PFS analysis. Data reported instead represent the number of participants who died during study treatment or had disease progression within 90 days of the last dose of durvalumab.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 84
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    25
    10
    21
    Units: Count of participants
    4
    1
    3
    No statistical analyses for this end point

    Secondary: Participants Who Developed Anti-drug Antibody Against Durvalumab

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    End point title
    		 Participants Who Developed Anti-drug Antibody Against Durvalumab
    End point description
    The number of participants who develop antidrug antibody against durvalumab at any of the sampling timepoints during the study.
    End point type
    Secondary
    End point timeframe
    Pre-dose samples on Day 1 of cycles 1, 2, 4, 6, 10, and 14 (study days 1, 29, 85, 141, 253, 393)
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    25
    10
    21
    Units: Count of participants
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Participants Who Died Up To Data Cut-off Date (15 December 2017)

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    End point title
    		 Participants Who Died Up To Data Cut-off Date (15 December 2017)
    End point description
    This outcome was originally defined as a Kaplan-Meier estimate of overall survival (OS) and was defined as the time between first date of dosing of study medication and death due to any cause. However due to the early study termination and limited follow-up time, the majority of participants were censored for OS analysis. Data reported instead represent the number of participants who died due to any cause from Day 1 up to data cut-off.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 87
    End point values
    		 Cohort A: High risk, TNE Cohort B: >=65 years old, TNE Cohort C: High risk, Post-transplant
    Number of subjects analysed
    25
    10
    21
    Units: Count of participants
    2
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs assessed from first dose up to week 84 (the longer of 90 days after d/c treatment with DURVA, or 28 days after the last dose of LEN or DEX). Deaths (all-causes) assessed from first dose to study completion (Up to approximately 88 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Cohort A: High Risk, TNE
    Reporting group description
    		 High risk, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle.

    Reporting group title
    Cohort B: >=65 Years Old, TNE
    Reporting group description
    		 >= 65 years old, transplant non-eligible [TNE], newly diagnosed multiple myeloma (NDMM) participants who were not high risk were administered • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 25 mg/day (adjust per the creatinine clearance [CrCl] value) on Days 1 to 21 of each 28-day treatment cycle • Oral dexamethasone (dex) 40 mg/day (≤ 75 years old) or 20 mg/day (> 75 years old) on Days 1, 8, 15, and 22 of each 28-day cycle, up to 12 cycles.

    Reporting group title
    Cohort C: High Risk, Post-transplant
    Reporting group description
    		 High risk, post-transplant NDMM participants were administered the following as maintenance therapy: • Intravenous (IV) durvalumab at 1500 mg on Day 1 of each 28-day cycle • Oral lenalidomide (LEN) 10 mg/day on Days 1 to 21 of each 28-day treatment cycle.

    Serious adverse events
    		 Cohort A: High Risk, TNE Cohort B: >=65 Years Old, TNE Cohort C: High Risk, Post-transplant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 25 (48.00%)
    6 / 10 (60.00%)
    4 / 21 (19.05%)
         number of deaths (all causes)
    9
    3
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to lung
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pubis fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis klebsiella
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (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
    Sepsis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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: High Risk, TNE Cohort B: >=65 Years Old, TNE Cohort C: High Risk, Post-transplant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 25 (96.00%)
    9 / 10 (90.00%)
    18 / 21 (85.71%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotension
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 10 (30.00%)
    7 / 21 (33.33%)
         occurrences all number
    4
    3
    8
    Chills
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Asthenia
         subjects affected / exposed
    7 / 25 (28.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    7
    2
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 10 (40.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    5
    3
    Peripheral swelling
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Oedema peripheral
         subjects affected / exposed
    8 / 25 (32.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    8
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 10 (20.00%)
    5 / 21 (23.81%)
         occurrences all number
    3
    2
    5
    Dysphonia
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 10 (20.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 10 (30.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    3
    0
    Epistaxis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    3
    Productive cough
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    1
    Respiratory tract congestion
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    0
    2
    Insomnia
         subjects affected / exposed
    2 / 25 (8.00%)
    4 / 10 (40.00%)
    3 / 21 (14.29%)
         occurrences all number
    2
    4
    3
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Amylase increased
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Lipase increased
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    0
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    5 / 25 (20.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    5
    1
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Fall
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Infusion related reaction
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Atrial flutter
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 10 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    1
    4
    Dysgeusia
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    1
    2
    Headache
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 10 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    1
    Paraesthesia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Tremor
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 25 (52.00%)
    2 / 10 (20.00%)
    3 / 21 (14.29%)
         occurrences all number
    20
    2
    3
    Leukopenia
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    8 / 25 (32.00%)
    2 / 10 (20.00%)
    4 / 21 (19.05%)
         occurrences all number
    16
    3
    6
    Neutropenia
         subjects affected / exposed
    11 / 25 (44.00%)
    5 / 10 (50.00%)
    3 / 21 (14.29%)
         occurrences all number
    21
    11
    6
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Vomiting
         subjects affected / exposed
    5 / 25 (20.00%)
    2 / 10 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    6
    2
    2
    Nausea
         subjects affected / exposed
    7 / 25 (28.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    11
    0
    3
    Haemorrhoids
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Diarrhoea
         subjects affected / exposed
    13 / 25 (52.00%)
    2 / 10 (20.00%)
    5 / 21 (23.81%)
         occurrences all number
    19
    3
    5
    Constipation
         subjects affected / exposed
    9 / 25 (36.00%)
    4 / 10 (40.00%)
    4 / 21 (19.05%)
         occurrences all number
    12
    5
    4
    Anal fissure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    1
    0
    Hepatobiliary disorders
    Hepatobiliary disease
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    1
    0
    7
    Erythema
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    3
    0
    Night sweats
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    Pruritus
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    1
    3
    Rash
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    2
    Rash erythematous
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Rash generalised
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Solar dermatitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Haematuria
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Nocturia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Polyuria
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Urethral stenosis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    2
    0
    4
    Hyperthyroidism
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    6 / 21 (28.57%)
         occurrences all number
    2
    0
    6
    Adrenal insufficiency
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 10 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    3
    0
    4
    Back pain
         subjects affected / exposed
    6 / 25 (24.00%)
    2 / 10 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    6
    2
    2
    Bone pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Flank pain
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle contracture
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Pain in extremity
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    1
    Pathological fracture
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Herpes simplex
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    0
    7
    Oral candidiasis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    2
    Pneumonia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    0
    4
    Urinary tract infection
         subjects affected / exposed
    5 / 25 (20.00%)
    0 / 10 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    9
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 10 (30.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    3
    2
    Dehydration
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 10 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    7
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2016
    Table of Events Update
    06 Apr 2017
    Inclusion Criteria Update
    05 Dec 2019
    Clinical Hold on the Study Update

    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.
    Study was placed on full clinical hold by the US FDA on 05 Sep 2017. Study was closed for further enrollment and subjects were discontinued from all treatments. Subjects were followed for SPMs for 5 years after last subject was enrolled per protocol.
    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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