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    Clinical Trial Results:
    A Phase IIa, Open-Label, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of Vamorolone in Boys with Duchenne Muscular Dystrophy (DMD)

    Summary
    EudraCT number
    		 2016-004262-26
    Trial protocol
    		 SE   GB  
    Global end of trial date
    01 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2018
    First version publication date
    19 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VBP15-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02760264
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ReveraGen BioPharma Inc.
    Sponsor organisation address
    155 Gibbs Street Suite 433, Rockville, United States, 20850
    Public contact
    Vice President, Operations, ReveraGen BioPharma Inc., +1 215 680 8286, jesse.damsker@reveragen.com
    Scientific contact
    Vice President, Operations, ReveraGen BioPharma Inc., +1 215 680 8286, jesse.damsker@reveragen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001794-PIP02-16
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of multiple ascending oral doses of vamorolone in ambulant boys ages 4-< 7 years with DMD.
    Protection of trial subjects
    This study was conducted in accordance with the principles of the 18th World Medical Assembly (Helsinki, June 1964), and amendments of the 29th (Tokyo, 1975), 35th (Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, 1996), 52nd (Edinburgh, 2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), 59th (Seoul, 2008), and 64th (Fortaleza, 2013) World Medical Assemblies. Further, the trial was conducted in accordance with: -International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) -The United States (US) Food and Drug Administration (FDA) Code of Federal Regulations, Title 21 CFR Part 312 - IND Application, Part 50 - Protection of Human Patients with particular focus in SubPart D, and/or Part 56 - Institutional Review Boards -US Health Insurance Portability and Accountability Act of 1996 (HIPAA)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Israel: 5
    Worldwide total number of subjects
    48
    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)
    48
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were screened based on inclusion and exclusion criteria specified in the VBP15-002 protocol

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose level group 1
    Arm description
    		 0.25 mg/kg/day for 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vamorolone 4% oral suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug was administered by mouth using a volumetric syringe. Following administration of the dose of study drug, the syringe was filled once with water and the water was administered by mouth using the volumetric syringe. The subject then drank approximately 50 mL (approximately 2 ounces) of water to ensure the full dose had been ingested.

    Arm title
    		 Dose level group 2
    Arm description
    		 0.75 mg/kg/day for 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vamorolone 4% oral suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug was administered by mouth using a volumetric syringe. Following administration of the dose of study drug, the syringe was filled once with water and the water was administered by mouth using the volumetric syringe. The subject then drank approximately 50 mL (approximately 2 ounces) of water to ensure the full dose had been ingested.

    Arm title
    		 Dose level group 3
    Arm description
    		 2.0 mg/kg/day for 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vamorolone 4% oral suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug was administered by mouth using a volumetric syringe. Following administration of the dose of study drug, the syringe was filled once with water and the water was administered by mouth using the volumetric syringe. The subject then drank approximately 50 mL (approximately 2 ounces) of water to ensure the full dose had been ingested.

    Arm title
    		 Dose level group 4
    Arm description
    		 6.0 mg/kg/day for 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vamorolone 4% oral suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug was administered by mouth using a volumetric syringe. Following administration of the dose of study drug, the syringe was filled once with water and the water was administered by mouth using the volumetric syringe. The subject then drank approximately 50 mL (approximately 2 ounces) of water to ensure the full dose had been ingested.

    Number of subjects in period 1
    		Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Started
    12
    12
    12
    12
    Completed
    12
    12
    12
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose level group 1
    Reporting group description
    		 0.25 mg/kg/day for 14 days

    Reporting group title
    Dose level group 2
    Reporting group description
    		 0.75 mg/kg/day for 14 days

    Reporting group title
    Dose level group 3
    Reporting group description
    		 2.0 mg/kg/day for 14 days

    Reporting group title
    Dose level group 4
    Reporting group description
    		 6.0 mg/kg/day for 14 days

    Reporting group values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4 Total
    Number of subjects
    		 12 12 12 12 48
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 12 12 12 12 48
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0
        Male
    		 12 12 12 12 48

    End points

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    End points reporting groups
    Reporting group title
    Dose level group 1
    Reporting group description
    		 0.25 mg/kg/day for 14 days

    Reporting group title
    Dose level group 2
    Reporting group description
    		 0.75 mg/kg/day for 14 days

    Reporting group title
    Dose level group 3
    Reporting group description
    		 2.0 mg/kg/day for 14 days

    Reporting group title
    Dose level group 4
    Reporting group description
    		 6.0 mg/kg/day for 14 days

    Primary: Overall Summary of Adverse Events as Assessed by CTCAE Version 4.03

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    End point title
    		 Overall Summary of Adverse Events as Assessed by CTCAE Version 4.03 [1]
    End point description
    Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening of an existing conditions after initiation of the investigational product and through the subject's last study visit (study completion or early termination). Serious adverse events were recorded for up to 30 days after the final administration of study drug. Related TEAEs include those considered possibly, probably, and definitely related.
    End point type
    Primary
    End point timeframe
    Adverse events will be recorded from the date of informed consent and through the time of the subject’s last study visit. Serious adverse events will be recorded from the date of informed consent and for up to 30 days after final drug administration.
    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: Safety analyses will be performed using the Safety Population and were completed using the actual treatment a subject received and will address the primary objective of the study. Treatment levels were not compared.
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    12
    12
    12
    12
    Units: Number of Participants
        Total Number of Adverse Events
    16
    18
    13
    11
        Total Number of Treatment Emergent Adverse Events
    13
    13
    11
    9
        Any TEAE
    7
    6
    8
    7
        Any Drug Related TEAE
    1
    2
    2
    3
        Any CTCAE Grade 3 or higher
    0
    0
    0
    0
        Discontinuation of Study Drug due to a TEAE
    0
    0
    0
    0
        Any Serious TEAE
    0
    0
    0
    0
        Death
    0
    0
    0
    0
    Attachments
    		 Untitled (Filename: Summary of Adverse Events Overall.pdf)
    No statistical analyses for this end point

    Secondary: Serum Pharmacodynamic Biomarkers (Bone Turnover) Osteocalcin

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    End point title
    		 Serum Pharmacodynamic Biomarkers (Bone Turnover) Osteocalcin
    End point description
    Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
    End point type
    Secondary
    End point timeframe
    Baseline Day 1 Week 2 Week 4
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    12
    12
    12
    12
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline
    37.94 ± 11.622
    35.66 ± 6.800
    41.17 ± 5.617
    44.36 ± 5.979
        Day 1
    39.37 ± 14.189
    35.89 ± 7.526
    34.93 ± 6.881
    33.52 ± 9.135
        Day 1 Change from Baseline
    1.43 ± 8.197
    0.23 ± 5.304
    -6.23 ± 10.930
    -11.37 ± 9.137
        Day 1 Percent Change from Baseline
    3.95 ± 22.015
    1.41 ± 15.449
    -12.63 ± 25.020
    -25.05 ± 20.228
        Week 2
    38.53 ± 12.025
    35.10 ± 8.238
    37.51 ± 8.624
    29.04 ± 4.853
        Week 2 Change from Baseline
    0.58 ± 5.986
    -0.56 ± 7.934
    -3.66 ± 9.818
    -15.32 ± 6.450
        Week 2 Percent change from Baseline
    2.48 ± 16.756
    -0.07 ± 22.408
    -7.81 ± 23.644
    -33.87 ± 12.548
        Week 4
    39.20 ± 14.136
    42.24 ± 8.426
    47.91 ± 6.648
    42.81 ± 10.851
        Week 4 Change from Baseline
    1.26 ± 5.650
    6.58 ± 9.341
    6.74 ± 9.747
    -1.55 ± 11.176
        Week 4 Percent Change from Baseline
    2.72 ± 14.063
    20.91 ± 28.644
    18.74 ± 25.095
    -2.43 ± 25.932
    Attachments
    		 Untitled (Filename: Osteocalcin.pdf)
    No statistical analyses for this end point

    Secondary: Serum Pharmacodynamic Biomarkers (Bone Turnover) Procollagen 1 N-Terminal Propeptide

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    End point title
    		 Serum Pharmacodynamic Biomarkers (Bone Turnover) Procollagen 1 N-Terminal Propeptide
    End point description
    Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
    End point type
    Secondary
    End point timeframe
    Baseline Day 1 Week 2 Week 4
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    12
    12
    12
    12
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline
    555.8 ± 184.72
    480.7 ± 118.20
    508.2 ± 94.36
    511.5 ± 106.50
        Day 1
    474.0 ± 116.45
    443.7 ± 112.38
    417.1 ± 87.35
    475.2 ± 147.10
        Day 1 Change from Baseline
    -81.8 ± 124.24
    -34.5 ± 101.97
    -91.1 ± 64.64
    -36.5 ± 144.04
        Day 1 Percent Change from Baseline
    -12.2 ± 17.07
    -5.4 ± 24.58
    -17.4 ± 12.59
    -5.7 ± 30.76
        Week 2
    443.8 ± 93.86
    407.8 ± 96.54
    346.6 ± 68.59
    303.7 ± 56.38
        Week 2 Change from Baseline
    -112.0 ± 125.08
    -70.6 ± 123.69
    -161.6 ± 73.52
    -207.8 ± 78.16
        Week 2 Percent Change from Baseline
    -17.5 ± 14.65
    -11.2 ± 29.19
    -30.9 ± 11.80
    -39.9 ± 9.22
        Week 4
    573.8 ± 251.02
    496.7 ± 117.57
    492.0 ± 81.92
    566.3 ± 149.32
        Week 4 Change from Baseline
    18.1 ± 153.10
    21.3 ± 122.87
    -16.2 ± 79.64
    54.8 ± 118.09
        Week 4 Percent Change from Baseline
    2.8 ± 25.57
    7.8 ± 30.86
    -1.4 ± 17.47
    11.8 ± 28.24
    Attachments
    		 Untitled (Filename: Procollagen 1 N-Terminal Propeptide.pdf)
    No statistical analyses for this end point

    Secondary: Serum Pharmacodynamic Biomarkers (Bone Turnover) Type I Collagen C-Telopeptides

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    End point title
    		 Serum Pharmacodynamic Biomarkers (Bone Turnover) Type I Collagen C-Telopeptides
    End point description
    Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1, Week 4
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    12
    12
    12
    12
    Units: pg/mL
    arithmetic mean (standard deviation)
        Baseline
    871.0 ± 160.85
    935.8 ± 286.50
    936.8 ± 256.25
    889.3 ± 186.68
        Day 1
    974.8 ± 252.77
    940.8 ± 227.60
    838.3 ± 233.30
    786.8 ± 331.68
        Day 1 Change from Baseline
    72.4 ± 241.87
    -12.9 ± 233.44
    -98.5 ± 237.69
    -115.7 ± 421.04
        Day 1 Percent change from Baseline
    9.9 ± 25.38
    2.7 ± 23.76
    -8.0 ± 23.93
    -6.7 ± 53.72
        Week 2
    963.7 ± 157.68
    903.3 ± 251.01
    710.4 ± 180.03
    625.7 ± 203.19
        Week 2 Change from Baseline
    85.0 ± 185.90
    -19.9 ± 266.99
    -226.4 ± 185.99
    -263.7 ± 229.69
        Week 2 Percent Change from Baseline
    11.9 ± 20.52
    2.2 ± 26.44
    -22.5 ± 15.27
    -27.7 ± 26.50
        Week 4
    915.9 ± 263.13
    983.5 ± 298.47
    949.8 ± 303.76
    989.2 ± 216.29
        Week 4 Change from Baseline
    17.4 ± 267.45
    34.8 ± 271.50
    12.9 ± 181.45
    99.8 ± 211.90
        Week 4 Percent Change from Baseline
    3.6 ± 28.96
    6.8 ± 34.06
    2.7 ± 19.03
    14.5 ± 32.98
    Attachments
    		 Untitled (Filename: Type I Collagen C-Telopeptides.pdf)
    No statistical analyses for this end point

    Secondary: Serum Pharmacodynamic Biomarkers (Insulin Resistance) Fasting Glucose

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    End point title
    		 Serum Pharmacodynamic Biomarkers (Insulin Resistance) Fasting Glucose
    End point description
    Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    12
    12
    12
    12
    Units: mg/ dL
    arithmetic mean (standard deviation)
        Baseline
    87.5 ± 9.44
    88.9 ± 18.71
    89.3 ± 7.91
    92.3 ± 8.19
        Week 2
    85.3 ± 9.29
    83.1 ± 6.69
    89.5 ± 5.20
    89.2 ± 11.12
        Week 2 Change from Baseline
    -2.2 ± 10.46
    -5.8 ± 18.92
    0.2 ± 8.79
    -1.3 ± 9.41
        Week 2 Percent Change from Baseline
    -1.8 ± 13.07
    -4.2 ± 13.98
    0.8 ± 9.76
    -1.2 ± 9.80
    Attachments
    		 Untitled (Filename: Fasting Glucose.pdf)
    No statistical analyses for this end point

    Secondary: Serum Pharmacodynamic Biomarkers (Insulin Resistance) Insulin

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    End point title
    		 Serum Pharmacodynamic Biomarkers (Insulin Resistance) Insulin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline , Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    12
    12
    12
    12
    Units: µIU/mL
    arithmetic mean (standard deviation)
        Baseline
    5.54 ± 3.651
    3.09 ± 2.033
    3.40 ± 1.548
    3.96 ± 2.027
        Week 2
    5.29 ± 2.671
    3.22 ± 1.924
    3.87 ± 2.118
    6.73 ± 4.599
        Week 2 Change from Baseline
    -0.65 ± 2.913
    0.34 ± 1.289
    0.47 ± 2.777
    2.78 ± 4.651
        Week 2 Percent Change from Baseline
    -5.54 ± 32.622
    26.07 ± 76.483
    42.85 ± 107.337
    83.55 ± 117.064
    Attachments
    		 Untitled (Filename: Insulin.pdf)
    No statistical analyses for this end point

    Secondary: Serum Pharmacodynamic Biomarkers (Adrenal Axis Suppression) First in Morning Cortisol

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    End point title
    		 Serum Pharmacodynamic Biomarkers (Adrenal Axis Suppression) First in Morning Cortisol
    End point description
    Pharmacodynamic biomarkers were measured to investigate the effects of single and multiple oral doses of vamorolone on serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD.
    End point type
    Secondary
    End point timeframe
    Week 2 (pre-dose)
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    11
    11
    11
    10
    Units: mcg/dL
    arithmetic mean (standard deviation)
        Week 2 (pre-dose)
    10.425 ± 1.7358
    9.755 ± 2.7614
    7.321 ± 3.0322
    3.010 ± 1.0141
    Attachments
    		 Untitled (Filename: First in Morning Cortisol.pdf)
    No statistical analyses for this end point

    Secondary: Metabolites in Safety Testing (MIST)

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    End point title
    		 Metabolites in Safety Testing (MIST) [2]
    End point description
    A portion of each blood sample collected for PK testing at each of the Week 2 (Day 14) assessment time points will be used for analysis of vamorolone metabolites. The relative exposures of the metabolites observed in human plasma were obtained to determine if any metabolite exceeded the 10% total drug related exposure (TDRE) threshold specified by the FDA and ICH guidance documents.
    End point type
    Secondary
    End point timeframe
    Week 2 (Day 14)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Percent total drug related exposures for each metabolite in each sample were calculated by dividing the average area ratio for each metabolite by the sum of the average area ratios for all metabolites and Vamorolone in that sample. Treatment levels were not compared.
    End point values
    		 Dose level group 3
    Number of subjects analysed
    12
    Units: Average % of total drug related exposure
    arithmetic mean (standard deviation)
        M1
    34.42 ± 2.79
        M2
    1.16 ± 0.06
        M3
    1.21 ± 0.07
        M4
    37.84 ± 3.78
        M5
    2.73 ± 0.17
        Vamorolone
    22.64 ± 0.69
    Attachments
    		 Untitled (Filename: MIST Average % of total drug related exposure.pdf)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Assessments (Cmax)

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    End point title
    		 Pharmacokinetic (PK) Assessments (Cmax)
    End point description
    Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. Cmax= maximum concentration.
    End point type
    Secondary
    End point timeframe
    Day 1, Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    11
    12
    12
    12
    Units: Cmax (ng/mL)
    arithmetic mean (standard deviation)
        Day 1
    22.9 ± 13.4
    75.9 ± 25.9
    199 ± 111
    855.6 ± 471
        Week 2
    32.2 ± 15.2
    124.7 ± 42.5
    252.5 ± 96
    970 ± 270
    Attachments
    		 Untitled (Filename: PK Vamorolone.pdf)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Assessments (tmax)

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    End point title
    		 Pharmacokinetic (PK) Assessments (tmax)
    End point description
    Plasma concentrations of vamorolone were measured using a specifc and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. tmax= time when plasma concentration is at maximum.
    End point type
    Secondary
    End point timeframe
    Day 1, Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    11
    12
    12
    12
    Units: hour
    arithmetic mean (standard deviation)
        Day 1
    3.6 ± 1.2
    4.6 ± 2.1
    2.5 ± 1.3
    2.7 ± 1.3
        Week 2
    3.8 ± 1.80
    3.8 ± 2.2
    2.8 ± 1
    2.3 ± 0.86
    Attachments
    		 Untitled (Filename: PK Vamorolone.pdf)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Assessments (AUC inf)

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    End point title
    		 Pharmacokinetic (PK) Assessments (AUC inf)
    End point description
    Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. AUC inf= Area under the concentration vs. time curve to time infinity.
    End point type
    Secondary
    End point timeframe
    Day 1, Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    11
    12
    12
    12
    Units: [(hr)(ng)/mL]
    arithmetic mean (standard deviation)
        Day 1
    118 ± 48
    379 ± 117
    761 ± 352
    3279 ± 1693
        Week 2
    164 ± 61
    544 ± 155
    1138 ± 467
    3606 ± 897
    Attachments
    		 Untitled (Filename: PK Vamorolone.pdf)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Assessments t(1/2)

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    End point title
    		 Pharmacokinetic (PK) Assessments t(1/2)
    End point description
    Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. t1/2= elimination half life
    End point type
    Secondary
    End point timeframe
    Day 1, Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    11
    12
    12
    12
    Units: hour
    arithmetic mean (standard deviation)
        Day 1
    2.1 ± 0.85
    1.8 ± 0.43
    1.9 ± 0.79
    1.9 ± 0.95
        Week 2
    1.9 ± 0.96
    2.1 ± 0.8
    1.9 ± 1.02
    1.4 ± 0.35
    Attachments
    		 Untitled (Filename: PK Vamorolone.pdf)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Assessments CL (ml/hr/kg)

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    End point title
    		 Pharmacokinetic (PK) Assessments CL (ml/hr/kg)
    End point description
    Plasma concentrations of vamorolone were measured using a specific and validated liquid chromatography tandem mass spectrometry (LC-MS) assay. CL= clearance
    End point type
    Secondary
    End point timeframe
    Day 1, Week 2
    End point values
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Number of subjects analysed
    11
    12
    12
    12
    Units: ml/hr/kg
    arithmetic mean (standard deviation)
        Day 1
    2459 ± 897
    2285 ± 1103
    2697 ± 1285
    2320 ± 1375
        Week 2
    1828 ± 919
    1509 ± 482
    2047 ± 771
    1777 ± 476
    Attachments
    		 Untitled (Filename: PK Vamorolone.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events will be recorded from the date of informed consent and through the time of the subject’s last study visit. Serious adverse events will be recorded from the date of informed consent and for up to 30 days after final drug administration.
    Adverse event reporting additional description
    The incidence of TEAEs will be summarized by dose level, SOC and preferred term; dose level, SOC, and intensity (CTCAE grade; CTCAE version 4.03); dose level, SOC, and outcome; and dose level, SOC and relationship to study drug. No serious treatment emergent adverse events No subjects with all-cause mortality.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Dose level group 1
    Reporting group description
    		 -

    Reporting group title
    Dose level group 2
    Reporting group description
    		 -

    Reporting group title
    Dose level group 3
    Reporting group description
    		 -

    Reporting group title
    Dose level group 4
    Reporting group description
    		 -

    Serious adverse events
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose level group 1 Dose level group 2 Dose level group 3 Dose level group 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    6 / 12 (50.00%)
    8 / 12 (66.67%)
    7 / 12 (58.33%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    1
    2
    Faeces discoloured
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip swelling
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash macular
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Emotional Disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Irritability
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 12 (25.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Infections and infestations
    Enterobiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lice infestation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 12 (16.67%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    1
    0

    More information

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

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30219580
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