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    Clinical Trial Results:
    A Phase 2, Multicenter, Double-Blind, Parallel Dosing, Randomized Study of Fresolimumab or Placebo in Patients with Steroid-Resistant Primary Focal Segmental Glomerulosclerosis

    Summary
    EudraCT number
    		 2012-002365-35
    Trial protocol
    		 DE   IT   ES  
    Global end of trial date
    11 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 May 2016
    First version publication date
    01 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DRI12792/ GC1008FSGS03110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01665391
    WHO universal trial number (UTN)
    		 U1111-1139-9082
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    500 Kendall Street, Cambridge, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    17 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the achievement of partial remission (PR) or complete remission (CR) in urinary protein:creatinine ratio (Up/c ratio) and to compare the safety profile of subjects treated with fresolimumab versus placebo.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    36
    EEA total number of subjects
    10
    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)
    33
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 32 sites in 5 countries. A total of 82 subjects were screened between 29 March 2013 and 23 April 2014, 4 of whom were re-screened and 46 were screen failures. Screen failures were mainly due to violation of inclusion/exclusion criteria.

    Pre-assignment
    Screening details
    		 Subjects were stratified by race (Black vs non-Black) and prior calcineurin inhibitor (CNI) therapy (yes, no) at a ratio of 3:3:2 (fresolimumab 1 mg/kg: fresolimumab 4 mg/kg: placebo) using an Interactive Response Technology system.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fresolimumab 1 mg/kg
    Arm description
    		 Fresolimumab 1 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fresolimumab
    Investigational medicinal product code
    FSGS03110 / GZ402669
    Other name
    GC1008
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fresolimumab 1 mg/kg infusion, administered over approximately 30 minutes.

    Arm title
    		 Fresolimumab 4 mg/kg
    Arm description
    		 Fresolimumab 4 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fresolimumab
    Investigational medicinal product code
    FSGS03110 / GZ402669
    Other name
    GC1008
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fresolimumab 4 mg/kg infusion, administered over approximately 30 minutes.

    Arm title
    		 Placebo
    Arm description
    		 Placebo (for fresolimumab) administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (for fresolimumab) infusion, administered over approximately 30 minutes.

    Number of subjects in period 1
    		Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Started
    14
    12
    10
    Completed
    14
    12
    10
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fresolimumab 1 mg/kg
    Arm description
    		 Fresolimumab 1 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Fresolimumab 4 mg/kg
    Arm description
    		 Fresolimumab 4 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo
    Arm description
    		 Placebo (for fresolimumab) administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Started
    14
    12
    10
    Completed
    14
    11
    10
    Not completed
    0
    1
    0
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fresolimumab 1 mg/kg
    Reporting group description
    		 Fresolimumab 1 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Fresolimumab 4 mg/kg
    Reporting group description
    		 Fresolimumab 4 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (for fresolimumab) administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo Total
    Number of subjects
    		 14 12 10 36
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.08 ± 17.653 41.03 ± 12.311 46.77 ± 19.285 -
    Gender categorical
    Units: Subjects
        Female
    		 7 6 4 17
        Male
    		 7 6 6 19

    End points

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    End points reporting groups
    Reporting group title
    Fresolimumab 1 mg/kg
    Reporting group description
    		 Fresolimumab 1 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Fresolimumab 4 mg/kg
    Reporting group description
    		 Fresolimumab 4 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (for fresolimumab) administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).
    Reporting group title
    Fresolimumab 1 mg/kg
    Reporting group description
    		 Fresolimumab 1 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Fresolimumab 4 mg/kg
    Reporting group description
    		 Fresolimumab 4 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (for fresolimumab) administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Primary: Percentage of Subjects Achieving Partial Remission (PR) or Complete Remission (CR) in Urinary Protein: Creatinine Ratio (Up/c ratio) at Day 112

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    End point title
    		 Percentage of Subjects Achieving Partial Remission (PR) or Complete Remission (CR) in Urinary Protein: Creatinine Ratio (Up/c ratio) at Day 112
    End point description
    PR was defined as a 50% or greater decline in Up/c ratio from baseline to a level between ≥ 0.3 and ≤ 3.0 mg protein/mg creatinine. CR was defined as a decline in Up/c ratio to a level <0.3 mg protein/mg creatinine. Full Analysis Set (FAS) included all randomized subjects who received at least 1 dose of study drug with at least 1 post-baseline Up/c assessment. Missing data was imputed using last observation carried forward (LOCF).
    End point type
    Primary
    End point timeframe
    At Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: Percentage of subjects
        number (not applicable)
    14.3
    0
    0
    Statistical analysis title
    		 Fresolimumab 1 mg/kg vs Placebo
    Comparison groups
    Fresolimumab 1 mg/kg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.833
    Method
    		 Fisher's exact test
    Parameter type
    		 Treatment Difference
    Point estimate
    14.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.7
         upper limit
    		 52.34

    Primary: Overview of Adverse Events

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    End point title
    		 Overview of Adverse Events [1]
    End point description
    An AE was any unfavorable and unintended symptom, sign, disease or condition, or test abnormality whether or not considered related to the study drug. Serious adverse event (SAE) was defined as any of following outcomes: Death, life-threatening event, required prolonged in-patient hospitalization, persistent/significant disability, congenital anomaly, or considered as important medical events. Medical events of interest (MEOIs) included herpes zoster, treatment-emergent skin lesions, bleeding events, cancers and other events deemed of interest by sponsor. Safety set included all randomized subjects who received at least 1 dose of study drug. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during the TEAE period. TEAE period was defined as the time form first infusion of study drug upto 252 days.
    End point type
    Primary
    End point timeframe
    Up to Day 252
    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: Due to descriptive nature of endpoint, statistical analysis was not planned.
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: percentage of subjects
    number (not applicable)
        Any TEAE
    64.3
    91.7
    70
        Serious TEAEs
    0
    25
    10
        MEOIs
    28.6
    33.3
    20
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving CR in Up/c ratio at Day 112

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    End point title
    		 Percentage of Subjects Achieving CR in Up/c ratio at Day 112
    End point description
    CR was defined as a decline in Up/c ratio to a level < 0.3 mg protein/mg creatinine. Analysis was performed on FAS. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: Percentage of subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving PR in Up/c ratio at Day 112

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    End point title
    		 Percentage of Subjects Achieving PR in Up/c ratio at Day 112
    End point description
    PR was defined as a 50% or greater decline in Up/c ratio from baseline to a level between ≥ 0.3 and ≤ 3.0 mg protein/mg creatinine. Analysis was performed on FAS. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: Percentage of subjects
        number (not applicable)
    14.3
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Up/c Ratio at Day 112

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    End point title
    		 Change From Baseline in Up/c Ratio at Day 112
    End point description
    Analysis was performed on full analysis set. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: mg protein/mg creatinine
        arithmetic mean (standard deviation)
    -1.9 ± 2.27
    1 ± 5.39
    -0.1 ± 2.93
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urinary Protein Excretion Rate at Day 112

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    End point title
    		 Change From Baseline in Urinary Protein Excretion Rate at Day 112
    End point description
    Analysis was performed on full analysis set. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    9
    11
    8
    Units: mg per 24hr
        arithmetic mean (standard deviation)
    -1637.9 ± 4270.65
    -1716.5 ± 4455.31
    -669.4 ± 10833.69
    No statistical analyses for this end point

    Secondary: Time to First Achievement of PR or CR in Up/c Ratio

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    End point title
    		 Time to First Achievement of PR or CR in Up/c Ratio
    End point description
    Time from the first infusion of the study drug to PR or CR, whichever occurred first. PR was defined as a 50% or greater decline in Up/c ratio from baseline to a level between ≥ 0.3 and ≤ 3.0 mg protein/mg creatinine. CR was defined as a decline in Up/c ratio to a level <0.3 mg protein/mg creatinine. Analysis was performed on full analysis set. In this section, 99999 represents that data not available for median and full range (min-max) in respective arms.
    End point type
    Secondary
    End point timeframe
    From the first infusion of the study drug up to Day 112
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: days
        median (full range (min-max))
    78 (21 to 115)
    99999 (99999 to 99999)
    53 (53 to 53)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Day 112

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    End point title
    		 Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Day 112
    End point description
    GFR is a measure of the rate at which blood filtered by the kidney. Analysis was performed on full analysis set. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: mL/min per 1.73 m^2
        arithmetic mean (standard deviation)
    -2.8 ± 15.05
    -6.1 ± 18.31
    -9.9 ± 18.07
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving PR or CR with stable eGFR at Day 112

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    End point title
    		 Percentage of subjects achieving PR or CR with stable eGFR at Day 112
    End point description
    Stable eGFR was defined as <35% reduction in eGFR. GFR was measured for the rate at which blood filtered by the kidney. Analysis was performed on full analysis set. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Day 112 (LOCF)
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg Placebo
    Number of subjects analysed
    14
    12
    10
    Units: Percentage of subjects
        number (not applicable)
    7.1
    0
    0
    No statistical analyses for this end point

    Secondary: Fresolimumab Serum Concentration

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    End point title
    		 Fresolimumab Serum Concentration
    End point description
    Analysis was performed on pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of study drug with at least 1 PK sample taken and analysed. In this section, 99999 represents that data not available for mean and standard deviation in respective arms. Here n= number of subjects for each arm.
    End point type
    Secondary
    End point timeframe
    Days 01, 28, 56, 84 (Pre and post infusion); Days 112, 140, 168 and 252
    End point values
    		 Fresolimumab 1 mg/kg Fresolimumab 4 mg/kg
    Number of subjects analysed
    14
    12
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-infusion day 01 (n=1, n=0)
    14.3 ± 99999
    99999 ± 99999
        Post-infusion day 01 (n=12, n=12)
    26034.75 ± 11066.01
    126412.2 ± 49814.84
        Pre-infusion day 28 (n=14, n=12)
    4173.07 ± 6121.266
    5206.67 ± 5382.262
        Post-infusion day 28 (n=14, n=12)
    31209.36 ± 16992.5
    159302.5 ± 38913.64
        Pre-infusion day 56 (n=14, n=12)
    7313.5 ± 12330.26
    7617.58 ± 8217.674
        Post-infusion day 56 (n=14, n=11)
    29591.93 ± 22113.08
    141026.5 ± 24028.76
        Pre-infusion day 84 (n=14, n=12)
    3717 ± 2571.526
    7822.66 ± 7831.148
        Post-infusion day 84 (n=12, n=09)
    34622.42 ± 15074.99
    149286 ± 38668.79
        Day 112 (n=14, n=11)
    2573.48 ± 2520.555
    8530.31 ± 15371.46
        Day 140 (n=13, n=08)
    877.24 ± 1064.762
    1776.49 ± 2256.125
        Day 168 (n=11, n=07)
    354.35 ± 509.894
    871.99 ± 814.182
        Day 252 (n=05, n=04)
    34.84 ± 21.88
    23.19 ± 11.923
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Day 252) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (from first infusion of study drug upto 252 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Fresolimumab 1 mg/kg
    Reporting group description
    		 Fresolimumab 1 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (for Fresolimumab) administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Reporting group title
    Fresolimumab 4 mg/kg
    Reporting group description
    		 Fresolimumab 4 mg/kg administered every 28 days up to 112 days (treatment period). Subjects were then followed up to Day 252 (follow up period).

    Serious adverse events
    		 Fresolimumab 1 mg/kg Placebo Fresolimumab 4 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    3 / 12 (25.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Anastomotic Complication
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (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
    General disorders and administration site conditions
    Generalised Oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large Intestine Perforation
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (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
    Rectal Prolapse
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (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
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure Acute
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (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
    Pelvic Abscess
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (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
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fresolimumab 1 mg/kg Placebo Fresolimumab 4 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 14 (64.29%)
    7 / 10 (70.00%)
    11 / 12 (91.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Keratoacanthoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Catheter Site Erythema
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter Site Oedema
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Chest Discomfort
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Generalised Oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Oedema Peripheral
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Breast Pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Penile Oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Scrotal Oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthmatic Crisis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Dysphonia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Nasal Congestion
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Productive Cough
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Respiratory Distress
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Transaminases Increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Ligament Sprain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Muscle Strain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Tongue Injury
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Ventricular Extrasystoles
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
         occurrences all number
    3
    1
    2
    Dizziness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Frequent Bowel Movements
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Gingival Bleeding
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    0
    4
    Haemorrhoids Thrombosed
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth Ulceration
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Nausea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Actinic Keratosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Alopecia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 10 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    Rash
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    2
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Pollakiuria
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Renal Failure Chronic
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Urine Odour Abnormal
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Back Pain
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    3
    Muscle Contracture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Muscle Spasms
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes Simplex
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    Oral Herpes
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Pneumonia Mycoplasmal
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Viral Infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Hypervolaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Vitamin D Deficiency
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2012
    - Study Follow-up period was extended to Day 252. - Pharmacokinetic parameters to be calculated for this study was expanded. - clarified that the efficacy endpoints will be evaluated at Day 112/ET. - use of immunosuppressive medications including steroids during the Follow-up period. - clarified the blinding procedures. - assessment of height was added. - was to clarify 24-hour urine collections. - was to add the assessment of international normalized ratio. - updated the definition of MEOI - was to specify that only drug-related and protocol-related SAEs and all MEOIs will be collected during the Follow-up - was to reflect changes in company ownership and department name changes
    07 Aug 2013
    - That amendment was only for Germany. - Extension of the follow-up observation period following an infusion to 6 hours and to added a follow-up clinic assessment between hours 16 to 24 following the infusion. - Medical instructions for the treatment of allergic reactions was included. - Subjects with non-melanomatous skin cancer within 5 years prior to Visit 1 was excluded. - Contact information was revised of study team to reflect changes in study personnel and corporate organization.

    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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    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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