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    Clinical Trial Results:
    PhaseOut DMD: A Phase 2 Clinical Study to Assess the Activity and Safety of Utrophin Modulation with SMT C1100 in Ambulatory Paediatric Male Subjects with Duchenne Muscular Dystrophy (C11005)

    Summary
    EudraCT number
    2015-004333-27
    Trial protocol
    GB  
    Global end of trial date
    11 Sep 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Jun 2019
    First version publication date
    25 Oct 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    SMT C11005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02858362
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Summit (Oxford) Limited
    Sponsor organisation address
    136a Eastern Avenue, Milton Park, Abingdon, United Kingdom,
    Public contact
    Clinical Trial Information, Summit (Oxford) Limited, clinicaltrials@summitplc.com
    Scientific contact
    Clinical Trial Information, Summit (Oxford) Limited, clinicaltrials@summitplc.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate changes in leg magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) in paediatric patients with Duchenne Muscular Dystrophy (DMD), following treatment with SMT C1100 (Cohorts 1 and 2). To investigate the relationships between changes in leg MRI/MRS with plasma concentrations of SMT C1100 and its metabolites in paediatric patients with DMD, following treatment with SMT C1100 (Cohorts 1 and 2). To assess the safety and tolerability of SMT C1100 and its metabolites in paediatric patients with DMD.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, The International Council on Harmonisation of technical requirements for pharmaceuticals for human use (ICH) harmonized tripartite guideline regarding Good Clinical Practice (ICH-GCP E6 (R2) Consolidated Guidance, November 2016), all applicable subject privacy requirements and the ethical principles that are outlined in the Declaration of Helsinki (revised version of Fortaleza, Brazil, 2013). This includes but is not limited to: Independent IRB/EC review and approval of study protocol and any subsequent amendments, subject informed consent, and investigator reporting requirements. Prior to initiation of a study site, the Sponsor obtained approval from the appropriate regulatory agency to conduct the study in accordance with the ICH GCP and applicable country specific regulatory requirements. The study was conducted in accordance with all applicable regulatory requirements. The Investigator was to ensure that this protocol was conducted in full conformance with these principles or with the laws and regulations of the locality in which the research was conducted, whichever afforded the greater protection of the individual. Written informed consent and assent was obtained from each patient (and their parents/guardian) prior to participation in the study. Written informed consent was collected following a review of the patient information leaflet by the potential patient and their parents/guardian and a discussion between the subject and their parents/guardian and the Investigator or suitably qualified designee.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Jun 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    43
    EEA total number of subjects
    21
    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)
    41
    Adolescents (12-17 years)
    2
    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
    Cohort 1 was conducted in the United Kingdom (UK) and the United States (US). Cohort 2 was conducted in the US. Cohort 3 was conducted in the UK.

    Pre-assignment
    Screening details
    40 male patients aged between 5 and 10 years, with a diagnosis of Duchenne Muscular Dystrophy (confirmed by phenotypic and genetic evidence) were enrolled in either Cohort 1 or Cohort 2. An additional 3 patients were enrolled to Cohort 3 who had previously received SMT C1100 in other studies, but were not eligible for Cohorts 1 or 2 in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Microfluidised Oral Suspension F3
    Arm description
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous oral suspension formulation (F3) twice-daily (BID) for at least 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    SMT C1100
    Investigational medicinal product code
    Ezutromid
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous suspension formulation (F3) BID for at least 48 weeks.

    Arm title
    Cohort 2: Powder for Oral Suspension F6
    Arm description
    Patients were to receive 1 g of SMT C1100 as a powder for oral suspension (F6) BID for at least 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    SMT C1100
    Investigational medicinal product code
    Ezutromid
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive 1 g of SMT C1100 as a powder for oral suspension (F6) BID for at least 48 weeks.

    Arm title
    Cohort 3: Microfluidised Oral Suspension F3
    Arm description
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous oral suspension formulation (F3) twice-daily (BID) for at least 48 weeks. All 3 patients in Cohort 3 discontinued from the study prior to Week 24 due to premature study termination.
    Arm type
    Experimental

    Investigational medicinal product name
    SMT C1100
    Investigational medicinal product code
    Ezutromid
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous suspension formulation (F3) BID for at least 48 weeks.

    Number of subjects in period 1
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6 Cohort 3: Microfluidised Oral Suspension F3
    Started
    30
    10
    3
    Completed
    29
    9
    0
    Not completed
    1
    1
    3
         Discontinued due to study termination
    -
    -
    3
         Protocol deviation
    -
    1
    -
         Consent withdrawn by subject
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Microfluidised Oral Suspension F3
    Reporting group description
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous oral suspension formulation (F3) twice-daily (BID) for at least 48 weeks.

    Reporting group title
    Cohort 2: Powder for Oral Suspension F6
    Reporting group description
    Patients were to receive 1 g of SMT C1100 as a powder for oral suspension (F6) BID for at least 48 weeks.

    Reporting group title
    Cohort 3: Microfluidised Oral Suspension F3
    Reporting group description
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous oral suspension formulation (F3) twice-daily (BID) for at least 48 weeks. All 3 patients in Cohort 3 discontinued from the study prior to Week 24 due to premature study termination.

    Reporting group values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6 Cohort 3: Microfluidised Oral Suspension F3 Total
    Number of subjects
    30 10 3 43
    Age categorical
    Units: Subjects
        Children (2-11 years)
    30 10 1 41
        Adolescents (12-17 years)
    0 0 2 2
    Age continuous
    Units: years
        median (full range (min-max))
    8.820 (5.22 to 10.02) 8.835 (6.82 to 10.10) 12.21 (11.27 to 12.56) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0 0
        Male
    30 10 3 43
    Race
    Units: Subjects
        White
    26 9 3 38
        Asian
    1 1 0 2
        Other
    3 0 0 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 2 0 3
        Not Hispanic or Latino
    29 8 3 40

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Microfluidised Oral Suspension F3
    Reporting group description
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous oral suspension formulation (F3) twice-daily (BID) for at least 48 weeks.

    Reporting group title
    Cohort 2: Powder for Oral Suspension F6
    Reporting group description
    Patients were to receive 1 g of SMT C1100 as a powder for oral suspension (F6) BID for at least 48 weeks.

    Reporting group title
    Cohort 3: Microfluidised Oral Suspension F3
    Reporting group description
    Patients were to receive 2.5 g of SMT C1100 microfluidised aqueous oral suspension formulation (F3) twice-daily (BID) for at least 48 weeks. All 3 patients in Cohort 3 discontinued from the study prior to Week 24 due to premature study termination.

    Subject analysis set title
    All Patients
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1, Cohort 2 and Cohort 3.

    Subject analysis set title
    Baseline (MRS FF Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for MRS FF vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 12 Change from Baseline (MRS FF Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for MRS FF vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 24 Change from Baseline (MRS FF Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for MRS FF vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 36 Change from Baseline (MRS FF Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for MRS FF vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 48 Change from Baseline (MRS FF Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for MRS FF vastus lateralis leg muscle parameter.

    Subject analysis set title
    Baseline (MRS FF Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for MRS FF soleus leg muscle parameter.

    Subject analysis set title
    Week 12 Change from Baseline (MRS FF Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for MRS FF soleus leg muscle parameter.

    Subject analysis set title
    Week 24 Change from Baseline (MRS FF Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for MRS FF soleus leg muscle parameter.

    Subject analysis set title
    Week 36 Change from Baseline (MRS FF Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for MRS FF soleus leg muscle parameter.

    Subject analysis set title
    Week 48 Change from Baseline (MRS FF Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for MRS FF soleus leg muscle parameter.

    Subject analysis set title
    Baseline (MRS WTRT Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for MRS WTRT vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 12 Change from Baseline (MRS WTRT Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for MRS WTRT vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 24 Change from Baseline (MRS WTRT Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to week 24 for MRS WTRT vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 36 Change from Baseline (MRS WTRT Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for MRS WTRT vastus lateralis leg muscle parameter.

    Subject analysis set title
    Week 48 Change from Baseline (MRS WTRT Vastus Lateralis)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for MRS WTRT vastus lateralis leg muscle parameter.

    Subject analysis set title
    Baseline (MRS WTRT Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for MRS WTRT soleus leg muscle parameter.

    Subject analysis set title
    Week 12 Change from Baseline (MRS WTRT Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for MRS WTRT soleus leg muscle parameter.

    Subject analysis set title
    Week 24 Change from Baseline (MRS WTRT Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for MRS WTRT soleus leg muscle parameter.

    Subject analysis set title
    Week 36 Change from Baseline (MRS WTRT Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for MRS WTRT soleus leg muscle parameter.

    Subject analysis set title
    Week 48 Change from Baseline (MRS WTRT Soleus)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for MRS WTRT soleus leg muscle parameter.

    Subject analysis set title
    Week 24 Baseline (Utrophin Intensity)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for Week 24 utrophin intensity. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 24 Observed Values (Utrophin Intensity)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Observed values for subjects at Week 24 visit. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 48 Baseline (Utrophin Intensity)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for Week 48 utrophin intensity. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 48 Observed Values (Utrophin Intensity)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Observed values for subjects at Week 48 visit. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 24 Baseline (Percentage Developmental Myosin)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for Week 24 percentage developmental myosin. Data from Week 24 and Week 48 are from different subjects.

    Subject analysis set title
    Week 24 Observed Values (Percentage Developmental Myosin)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Observed values for subjects at Week 24 visit. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 48 Baseline (Percentage Developmental Myosin)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for Week 48 percentage developmental myosin. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 48 Observed Values (Percentage Developmental Myosin)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Observed values for subjects at Week 48 visit. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 24 Baseline (Fibre Diameter)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for Week 24 fibre diameter. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 24 Observed Value (Fibre Diameter)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Observed values for subjects at Week 24 visit. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 48 Baseline (Fibre Diameter)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for Week 48 fibre diameter. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Week 48 Observed Values (Fibre Diameter)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Observed values for subjects at Week 48 visit. Data from Week 24 and Week 48 are from different patients.

    Subject analysis set title
    Baseline (Forced Expiratory Volume in 1 Second [FEV1])
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for FEV1.

    Subject analysis set title
    Week 12 Change from Baseline (FEV1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for FEV1.

    Subject analysis set title
    Week 24 Change from Baseline (FEV1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for FEV1.

    Subject analysis set title
    Week 36 Change from Baseline (FEV1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for FEV1.

    Subject analysis set title
    Week 48 Change from Baseline (FEV1)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for FEV1.

    Subject analysis set title
    Baseline (Forced Vital Capacity [FVC])
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for FVC.

    Subject analysis set title
    Week 12 Change from Baseline (FVC)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for FVC.

    Subject analysis set title
    Week 24 Change from Baseline (FVC)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for FVC.

    Subject analysis set title
    Week 36 Change from Baseline (FVC)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for FVC.

    Subject analysis set title
    Week 48 Change from Baseline (FVC)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for FVC.

    Subject analysis set title
    Baseline (Maximum Inspiratory Pressure [MIP])
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for MIP.

    Subject analysis set title
    Week 12 Change from Baseline (MIP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for MIP.

    Subject analysis set title
    Week 24 Change from Baseline (MIP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for MIP.

    Subject analysis set title
    Week 36 Change from Baseline (MIP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for MIP.

    Subject analysis set title
    Week 48 Change from Baseline (MIP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for MIP.

    Subject analysis set title
    Baseline (Maximum Expiratory Pressure [MEP])
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for MEP.

    Subject analysis set title
    Week 12 Change from Baseline (MEP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for MEP.

    Subject analysis set title
    Week 24 Change from Baseline (MEP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for MEP.

    Subject analysis set title
    Week 36 Change from Baseline (MEP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for MEP.

    Subject analysis set title
    Week 48 Change from Baseline (MEP)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for MEP.

    Subject analysis set title
    Baseline (Peak Expiratory Flow [PEF])
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Baseline for PEF.

    Subject analysis set title
    Week 12 Change from Baseline (PEF)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 12 for PEF.

    Subject analysis set title
    Week 24 Change from Baseline (PEF)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 24 for PEF.

    Subject analysis set title
    Week 36 Change from Baseline (PEF)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 36 for PEF.

    Subject analysis set title
    Week 48 Change from Baseline (PEF)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2. Change from baseline to Week 48 for PEF.

    Subject analysis set title
    Cohort 1 and Cohort 2 Total
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Inclusive of Cohort 1 and Cohort 2.

    Primary: MRS Fat Fraction (FF) Vastus Lateralis Leg Muscle Parameter

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    End point title
    MRS Fat Fraction (FF) Vastus Lateralis Leg Muscle Parameter [1]
    End point description
    Value of 99999 has been used as there is no confidence interval data for baseline measure. The standard deviation for the baseline measure is 13.3788.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    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: Descriptive statistics are presented for this endpoint, which include the 95% confidence interval for the mean changes from baseline.
    End point values
    Baseline (MRS FF Vastus Lateralis) Week 12 Change from Baseline (MRS FF Vastus Lateralis) Week 24 Change from Baseline (MRS FF Vastus Lateralis) Week 36 Change from Baseline (MRS FF Vastus Lateralis) Week 48 Change from Baseline (MRS FF Vastus Lateralis)
    Number of subjects analysed
    39
    39
    36
    37
    36
    Units: percent
        arithmetic mean (confidence interval 95%)
    14.954 (-99999 to 99999)
    1.779 (0.939 to 2.620)
    3.914 (2.695 to 5.132)
    5.238 (3.563 to 6.913)
    7.142 (4.866 to 9.417)
    No statistical analyses for this end point

    Primary: MRS FF Soleus Leg Muscle Parameter

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    End point title
    MRS FF Soleus Leg Muscle Parameter [2]
    End point description
    Value of 99999 has been used as there is no confidence interval data for baseline measure. The standard deviation for baseline measure is 8.6310.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented for this endpoint, which include the 95% confidence interval for the mean changes from baseline.
    End point values
    Baseline (MRS FF Soleus) Week 12 Change from Baseline (MRS FF Soleus) Week 24 Change from Baseline (MRS FF Soleus) Week 36 Change from Baseline (MRS FF Soleus) Week 48 Change from Baseline (MRS FF Soleus)
    Number of subjects analysed
    40
    40
    38
    38
    37
    Units: percent
        arithmetic mean (confidence interval 95%)
    9.123 (-99999 to 99999)
    0.615 (0.068 to 1.162)
    1.108 (0.350 to 1.865)
    2.384 (1.287 to 3.481)
    2.584 (1.258 to 3.909)
    No statistical analyses for this end point

    Primary: MRS Water Transverse Relaxation Time (WTRT) Vastus Lateralis Leg Muscle Parameter

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    End point title
    MRS Water Transverse Relaxation Time (WTRT) Vastus Lateralis Leg Muscle Parameter [3]
    End point description
    Value of 99999 has been used as there is no confidence interval data for baseline measure. The standard deviation for the baseline measure is 1.9954.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented for this endpoint, which include the 95% confidence interval for the mean changes from baseline.
    End point values
    Baseline (MRS WTRT Vastus Lateralis) Week 12 Change from Baseline (MRS WTRT Vastus Lateralis) Week 24 Change from Baseline (MRS WTRT Vastus Lateralis) Week 36 Change from Baseline (MRS WTRT Vastus Lateralis) Week 48 Change from Baseline (MRS WTRT Vastus Lateralis)
    Number of subjects analysed
    39
    39
    36
    37
    36
    Units: milliseconds
        arithmetic mean (confidence interval 95%)
    32.226 (-99999 to 99999)
    -0.559 (-1.190 to 0.072)
    -0.486 (-1.193 to 0.221)
    -0.849 (-1.454 to -0.244)
    -0.822 (-1.673 to 0.028)
    No statistical analyses for this end point

    Primary: MRS WTRT Soleus Leg Muscle Parameter

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    End point title
    MRS WTRT Soleus Leg Muscle Parameter [4]
    End point description
    Value of 99999 has been used as there is no confidence interval data for baseline measure. The standard deviation for baseline measure is 1.9235.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented for this endpoint, which include the 95% confidence interval for the mean changes from baseline.
    End point values
    Baseline (MRS WTRT Soleus) Week 12 Change from Baseline (MRS WTRT Soleus) Week 24 Change from Baseline (MRS WTRT Soleus) Week 36 Change from Baseline (MRS WTRT Soleus) Week 48 Change from Baseline (MRS WTRT Soleus)
    Number of subjects analysed
    40
    40
    38
    38
    37
    Units: milliseconds
        arithmetic mean (confidence interval 95%)
    31.878 (-99999 to 99999)
    -0.655 (-1.209 to -0.101)
    -0.861 (-1.440 to -0.281)
    -0.447 (-1.085 to 0.190)
    -0.119 (-0.747 to 0.509)
    No statistical analyses for this end point

    Primary: Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic Parameter

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    End point title
    Trough Concentration (Ctrough) Steady State Plasma Pharmacokinetic Parameter [5] [6]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented for this endpoint.
    [6] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    17 ± 140
    80 ± 83.1
    No statistical analyses for this end point

    Primary: Simulated Maximum Concentration (Cmax) Steady State Plasma Pharmacokinetic Parameter

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    End point title
    Simulated Maximum Concentration (Cmax) Steady State Plasma Pharmacokinetic Parameter [7] [8]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [7] - 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: Descriptive statistics are presented for this endpoint.
    [8] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (full range (min-max))
    135 (97 to 185)
    415 (303 to 640)
    No statistical analyses for this end point

    Primary: Simulated Average Concentration (Cav) Steady State Plasma Pharmacokinetic Parameter

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    End point title
    Simulated Average Concentration (Cav) Steady State Plasma Pharmacokinetic Parameter [9] [10]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [9] - 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: Descriptive statistics are presented for this endpoint.
    [10] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (full range (min-max))
    54 (37 to 82)
    163 (114 to 272)
    No statistical analyses for this end point

    Primary: Ctrough Steady State Plasma Pharmacokinetic Parameter for Dihydrodiol I (DHD I)

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    End point title
    Ctrough Steady State Plasma Pharmacokinetic Parameter for Dihydrodiol I (DHD I) [11] [12]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [11] - 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: Descriptive statistics are presented for this endpoint.
    [12] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    155 ± 61
    365 ± 55
    No statistical analyses for this end point

    Primary: Simulated Cmax Steady State Plasma Pharmacokinetic Parameter for DHD I

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    End point title
    Simulated Cmax Steady State Plasma Pharmacokinetic Parameter for DHD I [13] [14]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [13] - 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: Descriptive statistics are presented for this endpoint.
    [14] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (full range (min-max))
    1897 (1690 to 2158)
    2829 (2597 to 3072)
    No statistical analyses for this end point

    Primary: Simulated Cav Steady State Plasma Pharmacokinetic Parameter for DHD I

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    End point title
    Simulated Cav Steady State Plasma Pharmacokinetic Parameter for DHD I [15] [16]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [15] - 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: Descriptive statistics are presented for this endpoint.
    [16] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (full range (min-max))
    742 (685 to 836)
    1109 (1028 to 1217)
    No statistical analyses for this end point

    Primary: Ctrough Steady State Plasma Pharmacokinetic Parameter for Dihydrodiol III (DHD III)

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    End point title
    Ctrough Steady State Plasma Pharmacokinetic Parameter for Dihydrodiol III (DHD III) [17] [18]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [17] - 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: Descriptive statistics are presented for this endpoint.
    [18] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    484 ± 67
    1206 ± 68
    No statistical analyses for this end point

    Primary: Simulated Cmax Steady State Plasma Pharmacokinetic Parameter for DHD III

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    End point title
    Simulated Cmax Steady State Plasma Pharmacokinetic Parameter for DHD III [19] [20]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [19] - 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: Descriptive statistics are presented for this endpoint.
    [20] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (full range (min-max))
    3162 (2392 to 4053)
    4652 (3802 to 6116)
    No statistical analyses for this end point

    Primary: Simulated Cav Steady State Plasma Pharmacokinetic Parameter for DHD III

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    End point title
    Simulated Cav Steady State Plasma Pharmacokinetic Parameter for DHD III [21] [22]
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point type
    Primary
    End point timeframe
    Week 1 to Week 48
    Notes
    [21] - 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: Descriptive statistics are presented for this endpoint.
    [22] - 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: Summary includes data from Cohorts 1 and 2. Cohort 3 participants were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded.
    End point values
    Cohort 1: Microfluidised Oral Suspension F3 Cohort 2: Powder for Oral Suspension F6
    Number of subjects analysed
    30
    10
    Units: ng/mL
        geometric mean (full range (min-max))
    1359 (972 to 1790)
    2211 (1707 to 3066)
    No statistical analyses for this end point

    Primary: Number of Patients Reporting One or More Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Patients Reporting One or More Treatment-Emergent Adverse Events (TEAEs) [23]
    End point description
    Data provided includes up to the end of the study.
    End point type
    Primary
    End point timeframe
    Baseline to end of study
    Notes
    [23] - 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: There is no statistical analysis associated with this endpoint, as this is a count of participants who experienced TEAEs.
    End point values
    All Patients
    Number of subjects analysed
    43
    Units: Participants
    43
    No statistical analyses for this end point

    Secondary: Utrophin Intensity by Time Point

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    End point title
    Utrophin Intensity by Time Point
    End point description
    Data entered for Weeks 24 and Week 48 are for different subjects.
    End point type
    Secondary
    End point timeframe
    Week 24 Baseline, Week 24, Week 48 Baseline, Week 48
    End point values
    Week 24 Baseline (Utrophin Intensity) Week 24 Observed Values (Utrophin Intensity) Week 48 Baseline (Utrophin Intensity) Week 48 Observed Values (Utrophin Intensity)
    Number of subjects analysed
    22
    22
    15
    15
    Units: Arbitrary Units
        arithmetic mean (standard deviation)
    0.3686 ± 0.0553
    0.3918 ± 0.0536
    0.3520 ± 0.0357
    0.3634 ± 0.0572
    Statistical analysis title
    Week 24 Change from Baseline
    Statistical analysis description
    The number of subjects included in this statistical analysis was 23 and not 44. 22 subjects had evaluable data at both baseline and Week 24, and 1 subject only had evaluable data at baseline. The analysis used a mixed effect model.
    Comparison groups
    Week 24 Observed Values (Utrophin Intensity) v Week 24 Baseline (Utrophin Intensity)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Least Square Mean
    Point estimate
    0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.002
         upper limit
    0.048
    Statistical analysis title
    Week 48 Change from Baseline
    Statistical analysis description
    The number of subjects included in this statistical analysis was 16 and not 30. 15 subjects had evaluable data at both baseline and Week 48, and 1 subject only had evaluable data at baseline. The analysis used a mixed effect model.
    Comparison groups
    Week 48 Baseline (Utrophin Intensity) v Week 48 Observed Values (Utrophin Intensity)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Least Square Mean
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.042

    Secondary: Developmental Myosin by Time Point

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    End point title
    Developmental Myosin by Time Point
    End point description
    Data entered for Weeks 24 and Week 48 are for different subjects.
    End point type
    Secondary
    End point timeframe
    Week 24 Baseline, Week 24, Week 48 Baseline, Week 48
    End point values
    Week 24 Baseline (Percentage Developmental Myosin) Week 24 Observed Values (Percentage Developmental Myosin) Week 48 Baseline (Percentage Developmental Myosin) Week 48 Observed Values (Percentage Developmental Myosin)
    Number of subjects analysed
    22
    22
    16
    16
    Units: Percent (%)
        arithmetic mean (standard deviation)
    11.1392 ± 3.3915
    8.8226 ± 3.1082
    12.7340 ± 3.9410
    13.9588 ± 5.8819
    Statistical analysis title
    Week 24 Change from Baseline
    Statistical analysis description
    The number of subjects included in this statistical analysis was 24 and not 44. 22 subjects had evaluable data at both baseline and Week 24, 1 subject only had evaluable data at baseline, and 1 subject only had evaluable data at Week 24. The analysis used a mixed effect model.
    Comparison groups
    Week 24 Observed Values (Percentage Developmental Myosin) v Week 24 Baseline (Percentage Developmental Myosin)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -2.611
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.324
         upper limit
    -0.898
    Statistical analysis title
    Week 48 Change from Baseline
    Statistical analysis description
    The number of subjects included in this statistical analysis was 16 and not 32. 16 subjects had evaluable data at both baseline and Week 48. The analysis used a mixed effect model.
    Comparison groups
    Week 48 Baseline (Percentage Developmental Myosin) v Week 48 Observed Values (Percentage Developmental Myosin)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Least Square Mean
    Point estimate
    1.166
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.103
         upper limit
    3.435

    Secondary: Fibre Diameter by Time Point

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    End point title
    Fibre Diameter by Time Point
    End point description
    Data for Week 24 and Week 48 are from different subjects.
    End point type
    Secondary
    End point timeframe
    Week 24 Baseline, Week 24, Week 48 Baseline, Week 48
    End point values
    Week 24 Baseline (Fibre Diameter) Week 24 Observed Value (Fibre Diameter) Week 48 Baseline (Fibre Diameter) Week 48 Observed Values (Fibre Diameter)
    Number of subjects analysed
    22
    22
    16
    16
    Units: Micrometers (µm)
        arithmetic mean (standard deviation)
    42.2288 ± 6.0723
    40.3083 ± 6.9697
    44.7365 ± 4.7681
    46.8001 ± 5.1765
    Statistical analysis title
    Week 48 Change from Baseline
    Statistical analysis description
    The number of subjects included in this statistical analysis was 16 and not 32. 16 subjects had evaluable data at both baseline and Week 48. The analysis used a mixed effect model.
    Comparison groups
    Week 48 Baseline (Fibre Diameter) v Week 48 Observed Values (Fibre Diameter)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Least Square Mean
    Point estimate
    2.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.096
         upper limit
    4.324
    Statistical analysis title
    Week 24 Change from Baseline
    Statistical analysis description
    The number of subjects included in this statistical analysis was 24 and not 44. 22 subjects had evaluable data at both baseline and Week 24, 1 subject only had evaluable data at baseline, and 1 subject only had evaluable data at Week 24. The analysis used a mixed effect model.
    Comparison groups
    Week 24 Observed Value (Fibre Diameter) v Week 24 Baseline (Fibre Diameter)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Difference in Least Square Mean
    Point estimate
    -1.837
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.989
         upper limit
    0.315

    Secondary: Forced Expiratory Volume (FEV) in 1 Second by Time Point

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    End point title
    Forced Expiratory Volume (FEV) in 1 Second by Time Point
    End point description
    Summary includes data from Cohorts 1 and 2. No data was available for Cohort 3 from Weeks 12 to 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    End point values
    Baseline (Forced Expiratory Volume in 1 Second [FEV1]) Week 12 Change from Baseline (FEV1) Week 24 Change from Baseline (FEV1) Week 36 Change from Baseline (FEV1) Week 48 Change from Baseline (FEV1)
    Number of subjects analysed
    38
    38
    37
    36
    33
    Units: percent
        arithmetic mean (standard deviation)
    95.0 ± 23.18
    -3.4 ± 20.86
    -2.5 ± 24.88
    -7.3 ± 24.26
    2.0 ± 18.31
    No statistical analyses for this end point

    Secondary: Forced Vital Capacity (FVC) by Time Point

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    End point title
    Forced Vital Capacity (FVC) by Time Point
    End point description
    Summary includes data from Cohorts 1 and 2. No data was available for Cohort 3 from Weeks 12 to 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    End point values
    Baseline (Forced Vital Capacity [FVC]) Week 12 Change from Baseline (FVC) Week 24 Change from Baseline (FVC) Week 36 Change from Baseline (FVC) Week 48 Change from Baseline (FVC)
    Number of subjects analysed
    39
    39
    38
    37
    35
    Units: percent
        arithmetic mean (standard deviation)
    94.3 ± 19.52
    -4.0 ± 16.31
    1.1 ± 16.75
    -3.4 ± 18.39
    1.1 ± 16.29
    No statistical analyses for this end point

    Secondary: Maximum Inspiratory Pressure (MIP) by Time Point

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    End point title
    Maximum Inspiratory Pressure (MIP) by Time Point
    End point description
    Summary includes data from Cohorts 1 and 2. No data was available for Cohort 3 from Weeks 12 to 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    End point values
    Baseline (Maximum Inspiratory Pressure [MIP]) Week 12 Change from Baseline (MIP) Week 24 Change from Baseline (MIP) Week 36 Change from Baseline (MIP) Week 48 Change from Baseline (MIP)
    Number of subjects analysed
    36
    36
    35
    31
    32
    Units: cm H2O
        arithmetic mean (standard deviation)
    45.0 ± 20.23
    3.6 ± 32.68
    3.0 ± 25.00
    9.0 ± 18.40
    8.7 ± 20.30
    No statistical analyses for this end point

    Secondary: Peak Expiratory Flow (PEF) by Time Point

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    End point title
    Peak Expiratory Flow (PEF) by Time Point
    End point description
    Summary includes data from Cohorts 1 and 2. No data was available for Cohort 3 from Weeks 12 to 48.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 48
    End point values
    Baseline (Peak Expiratory Flow [PEF]) Week 12 Change from Baseline (PEF) Week 24 Change from Baseline (PEF) Week 36 Change from Baseline (PEF) Week 48 Change from Baseline (PEF)
    Number of subjects analysed
    35
    32
    34
    32
    32
    Units: percent
        arithmetic mean (standard deviation)
    82.5 ± 29.64
    0.5 ± 20.65
    -0.1 ± 23.86
    -0.4 ± 23.46
    9.6 ± 30.09
    No statistical analyses for this end point

    Secondary: Number of Patients Meeting Specific Changes From Baseline with Vital Sign Parameters

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    End point title
    Number of Patients Meeting Specific Changes From Baseline with Vital Sign Parameters
    End point description
    Summary includes data from Cohorts 1 and 2. Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded. Two Cohort 3 patients had post-baseline measurements recorded, and all were within 20% of their baseline value except 1 pulse measurement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    Cohort 1 and Cohort 2 Total
    Number of subjects analysed
    40
    Units: Participants
        Systolic Blood Pressure (SBP): < 20% Change
    28
        SBP: >= 20% Reduction and < 20% Increase
    2
        SBP: >= 20% Increase and < 20% Reduction
    10
        SBP: >= 20% Reduction and >= 20% Increase
    0
        Diastolic Blood Pressure (DBP): < 20% Change
    19
        DBP: >= 20% Reduction and < 20% Increase
    11
        DBP: >= 20% Increase and < 20% Reduction
    10
        DBP: >= 20% Reduction and >= 20% Increase
    0
        Pulse: < 20% Change
    21
        Pulse: >= 20% Reduction and < 20% Increase
    6
        Pulse: >= 20% Increase and < 20% Reduction
    13
        Pulse: >= 20% Reduction and >= 20% Increase
    0
    No statistical analyses for this end point

    Secondary: Number of Patients with Abnormal Echocardiogram Measurements

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    End point title
    Number of Patients with Abnormal Echocardiogram Measurements
    End point description
    Summary includes data from Cohorts 1 and 2. Data was not collected for Cohort 3.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    End point values
    Cohort 1 and Cohort 2 Total
    Number of subjects analysed
    40
    Units: Participants
        Baseline: Normal
    38
        Baseline: Abnormal, Not Clinically Significant
    2
        Baseline: Abnormal, Clinically Significant
    0
        Week 24: Normal
    33
        Week 24: Abnormal, Not Clinically Significant
    5
        Week 24: Abnormal, Clinically Significant
    0
        Week 24: Missing the Visit
    2
        Week 48: Normal
    33
        Week 48: Abnormal, Not Clinically Significant
    2
        Week 48: Abnormal, Clinically Significant
    1
        Week 48: Missing the Visit
    4
    No statistical analyses for this end point

    Secondary: Number of Patients with Liver Function Test Results of Potential Clinical Concern

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    End point title
    Number of Patients with Liver Function Test Results of Potential Clinical Concern
    End point description
    Laboratory measurements for alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), alkaline phosphatase (ALP), and glutamate dehydrogenase (GLDH).
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study
    End point values
    All Patients
    Number of subjects analysed
    Units: Participants
        ALT >= ULN (Upper Limit of Normal)
    43
        ALT >= 2*ULN
    43
        ALT >= 3*ULN
    42
        AST >= ULN
    43
        AST >= 2*ULN
    42
        AST >= 3*ULN
    42
        TB >= ULN
    0
        ALP >= 1.5*ULN
    0
        GLDH >= ULN Excluding Hemolysed Samples
    28
        GLDH >= ULN Including Hemolysed Samples
    31
        GLDH >= 2.5*ULN Excluding Hemolysed Samples
    1
        GLDH >= 2.5*ULN Including Hemolysed Samples
    1
        GLDH >= 3*ULN Excluding Hemolysed Samples
    3
        GLDH >= 3*ULN Including Hemolysed Samples
    3
        Patients Meeting Hy's Law
    0
    No statistical analyses for this end point

    Secondary: Number of Patients Meeting Specific Levels of Changes from Baseline for Electrocardiogram (ECG) Parameters

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    End point title
    Number of Patients Meeting Specific Levels of Changes from Baseline for Electrocardiogram (ECG) Parameters
    End point description
    Summary includes data from Cohorts 1 and 2. ECG results included PR interval (PR), heart rate (HR), and heart rate corrected QT interval using Fridericia’s formula (QTcF). Cohort 3 patients were a different study population (i.e. different eligibility criteria), and as only limited data was available, their data has been excluded. All three Cohort 3 patients had post-baseline measurements recorded, of which 1 had an increase in HR ≥20% recorded and another had both an increase and decrease in HR ≥20% recorded (means of replicates were all <20% different to baseline).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    Cohort 1 and Cohort 2 Total
    Number of subjects analysed
    40
    Units: Participants
        PR: < 170 ms
    37
        PR: >= 170 ms
    3
        PR: < 20% Change
    35
        PR: >= 20% Reduction and < 20% Increase
    2
        PR: >= Increase and < 20% Reduction
    3
        PR: >= 20% Reduction and >= 20% Increase
    0
        HR: < 20% Change
    7
        HR: >= 20% Reduction and < 20% Increase
    6
        HR: >= 20% Increase and < 20% Reduction
    22
        HR: >= 20% Reduction and >= 20% Increase
    5
        Maximum QTcF: < 450 ms
    40
        Maximum QTcF: >= 450 ms
    0
        Maximum Increase from Baseline in QTcF: < 30 ms
    32
        Maximum Increase from Baseline in QTcF: 30 - 59 ms
    8
        Maximum Increase from Baseline in QTcF: >= 60 ms
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The condition of each patient was monitored throughout the study. All TEAEs to the end of the study are presented. Treatment related events are those considered as at least possibly related to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    All Patients
    Reporting group description
    -

    Serious adverse events
    All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 43 (9.30%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis viral
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 43 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Pallor
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Surgical and medical procedures
    Eyeglasses therapy
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Eye haemangioma
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Melanocytic naevus
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Skin papilloma
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Immune system disorders
    Multiple allergies
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Catheter site bruise
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Chest pain
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Facial pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    5
    Feeling hot
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Impaired healing
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    8 / 43 (18.60%)
         occurrences all number
    12
    Thirst
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Unevaluable event
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Vessel puncture site pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gait disturbance
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Anger
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Abnormal behaviour
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    3
    Anxiety
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Asocial behaviour
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Belligerence
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Enuresis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Initial insomnia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Mood altered
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Depressed mood
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    5
    Ear injury
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    8 / 43 (18.60%)
         occurrences all number
    16
    Foot fracture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Head injury
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Humerus fracture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Joint injury
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Post procedural contusion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Procedural nausea
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    7
    Skin abrasion
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Spinal fracture
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Torus fracture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Scratch
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Thermal burn
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Blood urea increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Glutamate dehydrogenase increased
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Protein urine present
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Thyroxine increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 43 (27.91%)
         occurrences all number
    15
    Dyspnoea
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    5
    Nasal congestion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    10
    Pharyngeal erythema
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Sinus congestion
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Rhinorrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Throat irritation
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    11 / 43 (25.58%)
         occurrences all number
    27
    Lethargy
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Sensory processing disorder
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Eye disorders
    Astigmatism
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Cataract
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Chalazion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Erythema of eyelid
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Eye inflammation
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Hypermetropia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Scleral disorder
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Vitreous floaters
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Excessive cerumen production
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Motion sickness
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Tinnitus
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Abdominal distension
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    12 / 43 (27.91%)
         occurrences all number
    24
    Constipation
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    18 / 43 (41.86%)
         occurrences all number
    21
    Dental plaque
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Faeces discoloured
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Faeces pale
         subjects affected / exposed
    24 / 43 (55.81%)
         occurrences all number
    29
    Frequent bowel movements
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Gingival recession
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Lip swelling
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    13
    Oral mucosal eruption
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Rectal haemorrhage 
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Rectal prolapse
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Toothache
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Abdominal pain
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    11
    Vomiting
         subjects affected / exposed
    23 / 43 (53.49%)
         occurrences all number
    79
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gastric hypomotility
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Chromaturia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Eczema
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Ingrowing nail
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    17
    Rash pruritic
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Skin discolouration
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Swelling face
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Urticaria
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    14
    Flank pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Musculoskeletal pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    8 / 43 (18.60%)
         occurrences all number
    12
    Spinal pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Growth hormone deficiency
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Increased appetite
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    3
    Overweight
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Vitamin D deficiency
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Eye infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Gingival abscess
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Impetigo
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Localised infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Molluscum contagiosum
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Nail infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 43 (25.58%)
         occurrences all number
    14
    Otitis media
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Paronychia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Post procedural infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Sinusitis
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    6
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Adenovirus infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Dec 2015
    Amendment 1 (dated 08 December 2015) added additional information on potential interactions of ezutromid with the Cytochrome P-450 pathway, particularly CYP2B6, and introduced the prohibition of taking medications known to be Cytochrome P450 inhibitors, inducers, and substrates during the study.
    24 Feb 2016
    Amendment 2 (dated 24 February 2016) resolved minor administrative issues identified after the finalization of the protocol. These issues did not impact the conduct of the study.
    07 Oct 2016
    Amendment 3 (dated 07 October 2016) added Cohort 2 (10 subjects) to study a microfluidized aqueous oral suspension at a dose of 1000 mg twice daily. Cohort 2 subjects were only enrolled at US sites. The number of subjects in the original cohort was correspondingly reduced from 40 to 30. The amendment also provided additional information on Summit Study ezutromid, in which the suspension formulation was previously tested, and made various minor administrative changes.
    24 Feb 2017
    Amendment 4 (24 February 2017) added Cohort 3 (15 subjects), which consisted of patients who had previously received ezutromid and were not eligible for Cohorts 1 or 2. These patients entered a safety arm and underwent additional cardiac MRI scans and pulmonary function tests. Cohort 3 patients were only enrolled at UK sites. The amendment also added the Extension Phase into the study design. All patients were eligible to continue into the Extension Phase. The amendment also made various minor administrative changes.

    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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