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    Clinical Trial Results:
    A randomized, double blind, placebo controlled, multi-center study to assess the pharmacodynamics, pharmacokinetics, safety and tolerability of BYM338 in chronic obstructive pulmonary disease patients with cachexia

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2011-000461-12
    Trial protocol
    GB   NL  
    Global end of trial date
    13 Dec 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CBYM338X2204
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01669174
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    03 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assess the effect of BYM338 on muscle volume of the thigh (assessed by Magnetic Resonance Imaging (MRI)) at 4, 8, 16 and 24 weeks, compared to placebo, in chronic obstructive pulmonary disease (COPD) patients with pulmonary cachexia.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Jun 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
    United Kingdom: 24
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    United States: 37
    Worldwide total number of subjects
    67
    EEA total number of subjects
    30
    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)
    37
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Sixty-seven (33 in BYM338 and 34 in placebo groups) patients with COPD GOLD stage II to IV with associated cachexia were randomized into the study, with the aim of a minimum of 50 patients completing all study visits. Seven patients were added to the original 60 planned for enrollment due to unexpected attrition

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BYM338
    Arm description
    30 mg/kg
    Arm type
    Experimental

    Investigational medicinal product name
    Bimagrumab
    Investigational medicinal product code
    BYM338
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    lyophilized powder

    Arm title
    Placebo
    Arm description
    Placebo to BYM338 30mg/kg
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    lyophilized powder

    Number of subjects in period 1
    BYM338 Placebo
    Started
    33
    34
    Completed
    27
    28
    Not completed
    6
    6
         Subject withdrew consent
    2
    2
         Administrative problems
    1
    2
         Adverse event, non-fatal
    2
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BYM338
    Reporting group description
    30 mg/kg

    Reporting group title
    Placebo
    Reporting group description
    Placebo to BYM338 30mg/kg

    Reporting group values
    BYM338 Placebo Total
    Number of subjects
    33 34 67
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    17 20 37
        From 65-84 years
    16 14 30
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    64.5 ± 5.93 63.1 ± 7.51 -
    Gender, Male/Female
    Units: Participants
        Female
    16 18 34
        Male
    17 16 33

    End points

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    End points reporting groups
    Reporting group title
    BYM338
    Reporting group description
    30 mg/kg

    Reporting group title
    Placebo
    Reporting group description
    Placebo to BYM338 30mg/kg

    Primary: Percentage Change from Baseline of Thigh Muscle Volume (TMV) by MRI Scan at week 4, 8, 16, and 24

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    End point title
    Percentage Change from Baseline of Thigh Muscle Volume (TMV) by MRI Scan at week 4, 8, 16, and 24
    End point description
    Thigh Muscle Volume (TMV) change was evaluated by a responder analysis. Patients whose loss of muscle TMV by MRI was no more than or equal to 2% at Week 4,8,16 and 24 was considered responders.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 24
    End point values
    BYM338 Placebo
    Number of subjects analysed
    33
    34
    Units: Percentage Change of TMV
    arithmetic mean (standard deviation)
        Week 4 Day 29 (n=30,31)
    5.87 ± 3.413
    0.02 ± 3.261
        Week 8 Day 57 (n=27,27)
    7.01 ± 3.707
    -0.65 ± 2.752
        Week 16 Day 113 (27,28)
    7.84 ± 5.052
    -0.88 ± 4.471
        End of Study, week 24 (n=27,28)
    5.04 ± 4.872
    -1.31 ± 4.282
    Statistical analysis title
    Thigh Muscle Volume
    Statistical analysis description
    Week 4
    Comparison groups
    BYM338 v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    106.1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    104.64
         upper limit
    107.58
    Statistical analysis title
    Thigh Muscle Volume
    Statistical analysis description
    Week 8
    Comparison groups
    BYM338 v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    107.75
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    106.18
         upper limit
    109.35
    Statistical analysis title
    Thigh Muscle Volume
    Statistical analysis description
    Week 16
    Comparison groups
    BYM338 v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    108.63
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    106.31
         upper limit
    111
    Statistical analysis title
    Thigh Muscle Volume
    Statistical analysis description
    Week 24
    Comparison groups
    BYM338 v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Median difference (net)
    Point estimate
    106.63
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    104.39
         upper limit
    108.93

    Secondary: Change in 6 minute walk distance compared to placebo

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    End point title
    Change in 6 minute walk distance compared to placebo
    End point description
    Practical simple test that requires a 100-ft hallway but no exercise quipment or advanced training for technicians. Walking is an activity performed daily by all but the most severely impaired patients. This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD)
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 24
    End point values
    BYM338 Placebo
    Number of subjects analysed
    33
    34
    Units: meter
    arithmetic mean (standard deviation)
        Week 4 Day 29 (n=30,32)
    364.6 ± 85.45
    388.5 ± 100.22
        Week 8 Day 57 (n=27,29)
    373.9 ± 101.42
    387.4 ± 99.73
        Week 12 Day 85 (n=27,28)
    383 ± 84.63
    385.6 ± 107.62
        Week 16 Day 113 (n=25,28)
    379.7 ± 83.78
    352.9 ± 104.01
        End of Study week 24 (n=27, 28)
    374.9 ± 98.29
    378.8 ± 81.5
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax)

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    End point title
    Maximum Observed Serum Concentration (Cmax) [1]
    End point description
    The observed maximum plasma concentration following drug administration
    End point type
    Secondary
    End point timeframe
    0 hour, 2 hour, Day 8, 15, 29, 57, 71, 85, 99, 113, 127, 168 post dose
    Notes
    [1] - 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: No statistical analysis for this secondary outcome
    End point values
    BYM338
    Number of subjects analysed
    33
    Units: ug/mL
    arithmetic mean (standard deviation)
        Cmax dose 1 (n=31)
    614 ± 143
        Cmax dose 2 (n=26)
    580 ± 121
    No statistical analyses for this end point

    Secondary: Time to Reach the Maximum Concentration After Drug Administration (Tmax)

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    End point title
    Time to Reach the Maximum Concentration After Drug Administration (Tmax) [2]
    End point description
    The time to reach the maximum concentration after drug administration
    End point type
    Secondary
    End point timeframe
    24 weeks
    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: No statistical analysis for this secondary outcome
    End point values
    BYM338
    Number of subjects analysed
    33
    Units: hr
    median (full range (min-max))
        Tmax dose 1 (n=31)
    2.22 (2.02 to 3.17)
        Tmax dose 2 (n=26)
    2.23 (1.97 to 3.2)
    No statistical analyses for this end point

    Secondary: AUC0-56 and AUClast

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    End point title
    AUC0-56 and AUClast [3]
    End point description
    AUC0-56, the area under the serum concentration-time curve from the time zero to the end of the dosing interval, day 56. AUC0-56 was analyzed for dose 1 and 2. AUClast is from time zero to the last quantifiable concentration. AUClast was analyzed for dose 2 only.
    End point type
    Secondary
    End point timeframe
    0 hour, 2 hour, Day 8, 15, 29, 57, 71, 85, 99, 113, 127, 168 post dose
    Notes
    [3] - 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: No statistical analysis for this secondary outcome
    End point values
    BYM338
    Number of subjects analysed
    33
    Units: day*ug/mL
    arithmetic mean (standard deviation)
        AUC0-56 dose 1 (n=26)
    4540 ± 897
        AUC0-56 dose 2 (n=25)
    5790 ± 1300
        AUClast dose 2 (n=25)
    7480 ± 2080
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group title
    BYM338 30mg/kg
    Reporting group description
    BYM338 30mg/kg

    Serious adverse events
    Placebo BYM338 30mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 33 (12.12%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Throat cancer
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo BYM338 30mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 34 (88.24%)
    31 / 33 (93.94%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 33 (6.06%)
         occurrences all number
    2
    3
    Fall
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Skin abrasion
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Blood glucose increased
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 33 (6.06%)
         occurrences all number
    1
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Haemoglobin urine present
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 33 (6.06%)
         occurrences all number
    3
    2
    Urine leukocyte esterase positive
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    12 / 34 (35.29%)
    16 / 33 (48.48%)
         occurrences all number
    20
    25
    Cough
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 33 (12.12%)
         occurrences all number
    9
    4
    Dyspnoea
         subjects affected / exposed
    5 / 34 (14.71%)
    5 / 33 (15.15%)
         occurrences all number
    6
    6
    Dyspnoea exertional
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Headache
         subjects affected / exposed
    8 / 34 (23.53%)
    3 / 33 (9.09%)
         occurrences all number
    15
    6
    Paraesthesia
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 33 (9.09%)
         occurrences all number
    1
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 33 (6.06%)
         occurrences all number
    5
    2
    Feeling abnormal
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 33 (12.12%)
         occurrences all number
    4
    4
    Feeling cold
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Depression
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    3 / 34 (8.82%)
    7 / 33 (21.21%)
         occurrences all number
    4
    9
    Dyspepsia
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 33 (6.06%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Blister
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Dermatitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Ecchymosis
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Erythema
         subjects affected / exposed
    4 / 34 (11.76%)
    4 / 33 (12.12%)
         occurrences all number
    4
    8
    Papule
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Petechiae
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    7 / 34 (20.59%)
    5 / 33 (15.15%)
         occurrences all number
    26
    7
    Skin exfoliation
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Rash
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Back pain
         subjects affected / exposed
    4 / 34 (11.76%)
    4 / 33 (12.12%)
         occurrences all number
    7
    4
    Muscle spasms
         subjects affected / exposed
    16 / 34 (47.06%)
    26 / 33 (78.79%)
         occurrences all number
    120
    370
    Joint lock
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    14
    Muscle tightness
         subjects affected / exposed
    5 / 34 (14.71%)
    18 / 33 (54.55%)
         occurrences all number
    31
    122
    Muscle twitching
         subjects affected / exposed
    9 / 34 (26.47%)
    15 / 33 (45.45%)
         occurrences all number
    65
    48
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 33 (9.09%)
         occurrences all number
    1
    7
    Myalgia
         subjects affected / exposed
    6 / 34 (17.65%)
    7 / 33 (21.21%)
         occurrences all number
    7
    15
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Neck pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    7 / 34 (20.59%)
    8 / 33 (24.24%)
         occurrences all number
    15
    11
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    4
    Pneumonia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Rash pustular
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 33 (9.09%)
         occurrences all number
    2
    5
    Sinusitis
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2012
    The primary purpose of this amendment was to eliminate unnecessary delays in qualifying patients caused by the use of a single instrument. The exclusion criterion for minimum protein/calorie intake was revised to provide a choice of well accepted, valid methods for diet evaluation. In addition, the exclusion criteria were amended to identify a minimum body weight. Both of these changes could assist Investigators in identifying potential study patients and reduced the burden on patients who could not be enrolled. Because this amendment was necessary, an opportunity was taken to improve the clarity of certain text, correct a typographical error and update the risks section from data that became available after submission of the original protocol. These data were included in the the Investigator’s Brochure (Edition 3). In addition, two lab parameters were added, but this did not require extra blood sampling. No patients was screened or enrolled in this study at the time of this amendment
    16 Jul 2012
    The primary purpose of this amendment was to address comments from the IRB, requesting additional exclusion criteria added relating to the optional muscle biopsies. The additional text clarified patient eligibility for this procedure to assist in patient safety and recruitment. A muscle symptoms log was added, to allow patients to record any symptoms related to their muscle throughout the study. To try to clarify and detail adverse events, a detailed dermatology assessment was added to the physical examination
    03 Sep 2012
    The purpose of this amendment was to update the blood log to adjust the blood volumes taken for safety and PK assessments. Some assessments listed in the biomarkers sections of the protocol, after this amendment, were done together with the safety lab samples, and other volumes adjusted to ensure a sufficient volume for the assay used. There were no changes to the safety, PK, or biomarker parameters being assessed
    28 Nov 2012
    The purpose of this amendment was to include the addition of an internal DMC separate from the BYM338 project team, which was being implemented in all new and ongoing phase I and IIa studies with BYM338. This DMC was introduced at the request of the US Food and Drug Administration (FDA) because of the new mode of action of BYM338, for which the safety profile was not fully characterized and because of safety concerns observed by FDA with a non-Novartis molecule with a similar mode of action. This amendment also added a second 30 mg/kg iv dose of BYM338 at Week 8 to the study design. Therefore, patients received two doses of BYM338 (Days 1 and 57) during the study period. This additional dosing was to provide drug exposure at a certain serum level over 16 continuous weeks rather than 8 weeks seen with a single dose. This additional exposure extended the treatment time to cover the estimated 16 weeks needed to see a measurable change in physical function, i.e., 6-MWD. Text was modified to clarify the NIRS assessment.
    29 Jan 2013
    Following a review of the protocol by Health Authorities and ECs, it was requested that an additional exclusion criteria be added, to specifically exclude immunocompromised patients. While most immunodeficient patients were excluded by their primary pathology or medication, i.e. rheumatoid arthritis, it was specified their exclusion to eliminate the possible risk of acquiring from or transmitting infections to other study patients. It was also requested that text included in the ICF section of the protocol regarding pregnancy was removed, as this study excluded women of child bearing potential
    17 Mar 2014
    The primary purpose of this amendment was to change the number of patients required for the second interim analysis. Following the first interim analysis, the protocol was updated to reflect the need for 50 patients at Week 16 for the second planned interim analysis. This was supported by simulations that showed that this sample size would provide sufficient power to declare that BYM338 significantly improves TMV at Week 8 compared to placebo. Minor administrative changes to the protocol were also included in this amendment.

    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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