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    Clinical Trial Results:
    A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy

    Summary
    EudraCT number
    		 2011-002044-28
    Trial protocol
    		 DE   DK  
    Global end of trial date
    20 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2017
    First version publication date
    12 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-MLD-070
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01510028
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, MA, United States, 02421
    Public contact
    Study Physician, Shire, 1 866-842-5335,
    Scientific contact
    Study Physician, Shire, 1 866-842-5335,
    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
    20 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to determine the safety of ascending doses of SHP611 administered by intrathecal (IT) injection for 38 weeks in children with metachromatic leukodystrophy (MLD) in cohorts 1 to 3 and to determine the safety of SHP611 produced with a revised drug substance manufacturing process administered by IT injection for 38 weeks in cohort 4.
    Protection of trial subjects
    This study was conducted in accordance with current applicable regulations, International Council for Harmonisation (ICH) of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2012
    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
    Australia: 3
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 4
    Worldwide total number of subjects
    24
    EEA total number of subjects
    19
    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)
    9
    Children (2-11 years)
    15
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 5 main sites for cohorts 1 to 3 in Brazil, Denmark, Germany, France, and Australia and 3 main sites for cohort 4 in Denmark, France, and Germany between 02 February 2012 (first subject first visit) and 20 January 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 34 subjects were screened and 24 subjects were enrolled in the study. Out of which 23 subjects completed the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SHP611 10 mg (Process A)
    Arm description
    		 Subjects received 10 milligram (mg) dose of SHP611 (HGT-1110, recombinant human arylsulfatase A [rhASA]) every other week (EOW) by intrathecal drug delivery device (IDDD) for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human arylsulfatase A (rhASA)
    Investigational medicinal product code
    SHP611
    Other name
    HGT-1110
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received SHP611 injection every other week (EOW ) by intrathecal drug delivery device (IDDD) for 38 weeks.

    Arm title
    		 SHP611 30 mg (Process A)
    Arm description
    		 Subjects received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human arylsulfatase A (rhASA)
    Investigational medicinal product code
    SHP611
    Other name
    HGT-1110
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received SHP611 injection every other week (EOW ) by intrathecal drug delivery device (IDDD) for 38 weeks.

    Arm title
    		 SHP611 100 mg (Process A)
    Arm description
    		 Subjects received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human arylsulfatase A (rhASA)
    Investigational medicinal product code
    SHP611
    Other name
    HGT-1110
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received SHP611 injection every other week (EOW ) by intrathecal drug delivery device (IDDD) for 38 weeks.

    Arm title
    		 SHP611 100 mg (Process B)
    Arm description
    		 Subjects received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the revised drug substance manufacturing process referred to as Process B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human arylsulfatase A (rhASA)
    Investigational medicinal product code
    SHP611
    Other name
    HGT-1110
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received SHP611 injection every other week (EOW ) by intrathecal drug delivery device (IDDD) for 38 weeks.

    Number of subjects in period 1
    		SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Started
    6
    6
    6
    6
    Completed
    5
    6
    6
    6
    Not completed
    1
    0
    0
    0
         Lack of efficacy
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SHP611 10 mg (Process A)
    Reporting group description
    		 Subjects received 10 milligram (mg) dose of SHP611 (HGT-1110, recombinant human arylsulfatase A [rhASA]) every other week (EOW) by intrathecal drug delivery device (IDDD) for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 30 mg (Process A)
    Reporting group description
    		 Subjects received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 100 mg (Process A)
    Reporting group description
    		 Subjects received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 100 mg (Process B)
    Reporting group description
    		 Subjects received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the revised drug substance manufacturing process referred to as Process B.

    Reporting group values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B) Total
    Number of subjects
    		 6 6 6 6
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 31.5 ± 11.5 47.3 ± 20.23 52.2 ± 31.17 48.5 ± 24.22 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3 1 2 9
        Male
    		 3 3 5 4 15

    End points

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    End points reporting groups
    Reporting group title
    SHP611 10 mg (Process A)
    Reporting group description
    		 Subjects received 10 milligram (mg) dose of SHP611 (HGT-1110, recombinant human arylsulfatase A [rhASA]) every other week (EOW) by intrathecal drug delivery device (IDDD) for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 30 mg (Process A)
    Reporting group description
    		 Subjects received 30 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 100 mg (Process A)
    Reporting group description
    		 Subjects received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 100 mg (Process B)
    Reporting group description
    		 Subjects received 100 mg dose of SHP611 (HGT-1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the revised drug substance manufacturing process referred to as Process B.

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) by Type and Severity

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) by Type and Severity [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Drug-related and device-related types of TEAEs were analyzed and reported. The severity of AEs was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 grading scale. Severity of all AEs or SAEs was recorded as grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or fatal. Here SDI refers to surgical device implantation. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    From start of study treatment up to Week 42
    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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        TEAE
    6
    6
    6
    6
        SHP611-related TEAE
    3
    4
    4
    2
        SDI-related TEAE
    5
    3
    4
    4
        IDDD-related TEAE
    3
    3
    4
    0
        SOPH-A-PORT IDDD-related TEAE
    0
    0
    4
    0
        IT administration process related TEAE
    4
    3
    1
    1
        Severe TEAE
    2
    3
    1
    1
        Serious TEAE
    5
    4
    3
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [2]
    End point description
    Clinical laboratory test included serum chemistry, hematology and urinalysis. Clinical laboratory abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    From start of study treatment up to Week 40
    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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Gamma-glutamyltransferase (GGT) increased
    2
    1
    1
    0
        Alanine aminotransferase (ALT) increased
    1
    1
    0
    1
        Aspartate aminotransferase (AST) increased
    0
    1
    1
    0
        Blood iron decreased
    0
    1
    1
    0
        Amylase increased
    0
    1
    1
    0
        Blood alkaline phosphatase increased
    1
    0
    0
    0
        Blood creatine phosphokinase increased
    0
    0
    0
    3
        Hepatic enzymes increased
    0
    0
    0
    1
        Eosinophil count increased
    0
    1
    1
    0
        Eosinophilia
    0
    2
    0
    0
        Mean cell volume decreased
    0
    1
    0
    0
        Neutrophil count increased
    0
    1
    0
    0
        White blood cell count increased
    0
    1
    0
    0
        Lymphopenia
    0
    1
    0
    0
        Leukocytosis
    0
    1
    0
    0
        Proteinuria
    0
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [3]
    End point description
    Vital sign assessments included blood pressure, heart rate, respiratory rate and body temperature. Vital sign abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    From start of study treatment up to Week 40
    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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Pyrexia
    5
    3
    5
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [4]
    End point description
    12-lead ECG was recorded and measured with the subject in rested supine position for at least 10 minutes. ECG abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    From start of study treatment up to Week 40
    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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAEs) [5]
    End point description
    Complete physical examination included evaluation of the port and catheter track. Height or length and weight were recorded and used to calculate growth. Body weight and height measurements were used to calculate the body mass index (BMI). Head circumference was measured in uniform manner for all subjects. Clinical significance was defined as any variation in physical findings that had medical relevance resulting in an alteration in medical care. Physical examination abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    From Start of Study Treatment up to Week 40
    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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [6]
    End point description
    CSF chemistry assessments (including cell counts, glucose and protein) was measured. CSF chemistry abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    From start of study treatment up to Week 40
    Notes
    [6] - 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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        CSF Protein Increased
    0
    0
    1
    1
        CSF Albumin Increased
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum

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    End point title
    		 Number of Subjects With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum [7]
    End point description
    Number of subjects with positive anti-SHP611 antibody results in serum and in CSF were reported. A subject was considered positive if they had at least 1 positive result during the study. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 40
    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 were done, no inferential statistical analyses were performed.
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Serum anti-SHP611 antibody (Ab) positive
    4
    3
    1
    2
        Serum neutralizing anti-SHP611 antibody positive
    3
    2
    1
    1
        CSF anti-SHP611 antibody positive
    3
    1
    0
    2
        CSF neutralizing anti-SHP611 antibody positive
    0
    0
    0
    0
        Serum or CSF anti-SHP611 antibody positive
    4
    3
    1
    2
        Serum and CSF anti-SHP611 antibody positive
    3
    1
    0
    2
        Serum or CSF neutralizing anti-SHP611 Ab positive
    3
    2
    1
    1
        Serum and CSF neutralizing anti-SHP611 Ab positive
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40

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    End point title
    		 Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40
    End point description
    The GMFM-88 was used to measure motor function. The GMFM-88 item scores were used to calculate domain-specific percent score for each of the 5 GMFM-88 dimensions (lying and rolling; sitting; crawling and kneeling; standing; walking, running, and jumping), and a total GMFM-88 (percent) score was calculated based on each dimension score. Each of the 88 items was rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The GMFM-88 total scores ranged from 0% (no mobility) to a score of 100%, that is (i.e,) the score that can be obtained by an average 5-year-old or older child with normal motor abilities. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Score on a scale
        least squares mean (standard error)
    -31.9 ± 8.76
    -29 ± 8.58
    -19.5 ± 8.54
    -18.1 ± 9.14
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40

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    End point title
    		 Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40
    End point description
    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each subject had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for texture utilized was evaluated. Data was presented only for the shifts observed. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Thin Liquids to Thin Liquids
    2
    2
    2
    4
        Thin Liquids to Thickened Liquids
    1
    2
    0
    0
        Thin Liquids to Puree Texture
    1
    2
    1
    4
        Thin Liquids to Solids
    0
    2
    0
    0
        Thickened Liquids to Thin Liquids
    1
    2
    1
    1
        Thickened Liquids to Thickened Liquids
    0
    2
    3
    0
        Thickened Liquids to Puree Texture
    1
    2
    3
    1
        Thickened Liquids to Solids
    0
    2
    0
    0
        Puree Texture to Thin Liquids
    1
    2
    3
    2
        Puree Texture to Thickened Liquids
    1
    2
    2
    0
        Puree Texture to Puree Texture
    3
    4
    4
    3
        Puree Texture to Solids
    0
    2
    0
    0
        Solids to Thin Liquids
    0
    2
    0
    1
        Solids to Thickened Liquids
    0
    2
    0
    0
        Solids to Puree Texture
    0
    2
    0
    1
        Solids to Solids
    0
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40

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    End point title
    		 Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40
    End point description
    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each subject had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for laryngeal penetration was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery. '99999' indicates data was not available for this texture as the assessment was considered normal.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Normal to Normal (TL)
    0
    0
    2
    1
        Normal to Without Cough (TL)
    0
    0
    0
    1
        Without Cough to Without Cough (TL)
    1
    0
    0
    0
        WCC to Without Cough (TL)
    1
    0
    0
    0
        WCC to WCC (TL)
    0
    2
    0
    1
        Normal to WCC (THL)
    0
    0
    1
    0
        Without Cough to Normal (THL)
    0
    0
    1
    0
        WCC to Normal (THL)
    0
    0
    1
    0
        WCC to WCC (THL)
    0
    2
    0
    0
        Normal to Normal (PT)
    0
    1
    1
    1
        Normal to WCC (PT)
    0
    0
    1
    0
        Normal to WCNC (PT)
    1
    0
    0
    0
        Without Cough to Normal (PT)
    0
    0
    2
    0
        Without Cough to WCC (PT)
    1
    0
    0
    0
        WCC to Normal (PT)
    0
    0
    0
    1
        WCC to WCC (PT)
    0
    2
    0
    0
        WCNC to Normal (PT)
    0
    1
    0
    0
        WCNC to Without Cough (PT)
    1
    0
    0
    0
        WCC to WCC (Solids)
    99999
    2
    99999
    99999
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40

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    End point title
    		 Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40
    End point description
    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each subject had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for aspiration through vocal cords were assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery. '99999' indicates data was not available for this texture as the assessment was considered normal.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Normal to Normal (TL)
    0
    0
    2
    3
        Without Cough to Without Cough (TL)
    1
    0
    0
    0
        WCC to WCC (TL)
    0
    2
    0
    0
        Normal to Normal (THL)
    0
    0
    1
    0
        Without Cough to Normal (THL)
    0
    0
    1
    0
        WCC to Normal (THL)
    0
    0
    1
    0
        WCC to WCC (THL)
    0
    2
    0
    0
        Normal to Normal (PT)
    0
    2
    2
    2
        Without Cough to Normal (PT)
    0
    0
    2
    0
        WCC to WCC (PT)
    0
    2
    0
    0
        WCNC to Normal (PT)
    1
    0
    0
    0
        WCC to WCC (Solids)
    99999
    2
    99999
    99999
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40

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    End point title
    		 Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40
    End point description
    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each subject had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for dose residue clear after subsequent swallowing was assessed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture. Data was presented only for the shifts observed. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery. '99999' indicates data was not available for this texture as the assessment was considered normal.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Normal to Normal (TL)
    0
    0
    1
    0
        Normal to Yes (TL)
    0
    0
    1
    0
        Yes to Yes (TL)
    1
    2
    0
    1
        Yes to No (TL)
    0
    0
    0
    1
        No to Yes (TL)
    0
    0
    0
    1
        No to No (TL)
    1
    0
    0
    0
        Normal to Yes (THL)
    0
    0
    2
    0
        Yes to Normal (THL)
    0
    0
    1
    0
        Yes to Yes (THL)
    0
    2
    0
    0
        Normal to Normal (PT)
    0
    1
    0
    1
        Normal to Yes (PT)
    0
    0
    2
    0
        Normal to No (PT)
    1
    0
    0
    0
        Yes to Normal (PT)
    0
    0
    1
    0
        Yes to Yes (PT)
    1
    2
    0
    1
        Yes to No (PT)
    1
    0
    0
    0
        No to Normal (PT)
    0
    1
    1
    0
        Yes to Yes (Solids)
    99999
    2
    99999
    99999
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40

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    End point title
    		 Number of Subjects With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40
    End point description
    The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each subject had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for aspiration risk was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery. '99999' indicates data was not available for this texture as the assessment was considered normal.
    End point type
    Secondary
    End point timeframe
    Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Low to Low (TL)
    2
    2
    2
    3
        Low to high (TL)
    0
    0
    0
    1
        Low to Low (THL)
    0
    2
    3
    0
        Low to Low (PT)
    1
    3
    3
    3
        Low to high (PT)
    1
    0
    0
    0
        Moderate to Low (PT)
    0
    1
    1
    0
        Moderate to Moderate (PT)
    1
    0
    0
    0
        Low to Low (Solids)
    99999
    2
    99999
    99999
    No statistical analyses for this end point

    Secondary: Number of Subjects With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40

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    End point title
    		 Number of Subjects With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40
    End point description
    Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for the number of subjects who reported change in amplitude greater than (>) 0. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        Median Motor Wrist Amplitude (Baseline)
    6
    5
    5
    6
        Median Motor Wrist Amplitude (Week 40)
    3
    5
    6
    5
        Median Motor Elbow Amplitude (Baseline)
    0
    2
    4
    6
        Median Motor Elbow Amplitude (Week 40)
    0
    4
    6
    4
        Median Sensory Wrist Amplitude (Baseline)
    2
    3
    4
    4
        Median Sensory Wrist Amplitude (Week 40)
    1
    5
    3
    3
        Peroneal Motor Fibular Head Amplitude (Baseline)
    0
    2
    4
    6
        Peroneal Motor Fibular Head Amplitude (Week 40)
    0
    4
    5
    4
        Peroneal Motor Ankle Amplitude (Baseline)
    6
    5
    5
    6
        Peroneal Motor Ankle Amplitude (Week 40)
    4
    5
    5
    4
        Sural Sensory B-point (Baseline)
    2
    2
    3
    4
        Sural Sensory B-point (Week 40)
    2
    2
    3
    4
        Tibial Motor Ankle Amplitude (Baseline)
    4
    3
    3
    3
        Tibial Motor Ankle Amplitude (Week 40)
    2
    3
    4
    1
        Tibial Motor Knee Amplitude (Baseline)
    0
    0
    3
    3
        Tibial Motor Knee Amplitude (Week 40)
    0
    2
    4
    1
        Ulnar Motor Wrist Amplitude (Baseline)
    4
    3
    3
    3
        Ulnar Motor Wrist Amplitude (Week 40)
    2
    3
    3
    1
        Ulnar Motor Elbow Amplitude (Baseline)
    0
    0
    3
    3
        Ulnar Motor Elbow Amplitude (Week 40)
    0
    2
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40

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    End point title
    		 Number of Subjects With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40
    End point description
    Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized nerve conduction velocity values were assessed. Data was presented only for the number subjects who reported change in nerve conduction velocity > 0. Here MME refers to median motor elbow, WCV for wrist conduction velocity, PMA for peroneal motor ankle, FHCV to fibular head conduction velocity, TMA for tibial motor ankle, KCV for knee conduction velocity and UME for ulnar motor elbow. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        MME to WCV (Baseline)
    6
    6
    6
    6
        MME to WCV (Week 40)
    3
    5
    6
    5
        PMA to FHCV (Baseline)
    6
    6
    6
    6
        PMA to FHCV (Week 40)
    4
    5
    5
    4
        TMA to KCV (Baseline)
    4
    4
    4
    3
        TMA to KCV (Week 40)
    2
    3
    4
    1
        UME to WCV (Baseline)
    4
    4
    4
    3
        UME to WCV (Week 40)
    2
    3
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40

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    End point title
    		 Number of Subjects With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40
    End point description
    Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP), distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for the number of subjects who reported change in distal latency > 0. Here MMW refers to median motor wrist, APB for abductor pollicis brevis, MSW for median sensory wrist, DDL for digit distal latency, PMA for peroneal motor ankle, EDB for extensor digitorum brevis, SSB-point DL for sural sensory B-point distal latency, TMA for tibial motor ankle, abductor hallucis for AH distal latency and, UMW for ulnar motor wrist. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Subject
        MMW to APB distal latency (Baseline)
    6
    5
    5
    6
        MMW to APB distal latency (Week 40)
    3
    5
    6
    5
        MSW to DDL (Baseline)
    0
    1
    2
    3
        MSW to DDL (Week 40)
    0
    3
    2
    3
        PMA to EDB Distal Latency (Baseline)
    6
    5
    5
    6
        PMA to EDB Distal Latency (Week 40)
    4
    5
    5
    3
        SS B-Point Distal Latency (Baseline)
    2
    2
    2
    3
        SS B-Point Distal Latency (Week 40)
    1
    2
    1
    4
        TMA to AH Distal Latency (Baseline)
    0
    0
    3
    3
        TMA to AH Distal Latency (Week 40)
    0
    2
    4
    0
        UMW to ADM Distal Latency (Baseline)
    4
    3
    3
    3
        UMW to ADM Distal Latency (Week 40)
    2
    3
    3
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40

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    End point title
    		 Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40 [8]
    End point description
    VABS-II survey interview form was used to measure the personal and social skills of subjects serially over time; these scales were organized within a 4-domain structure: communication, daily living, socialization, and motor skills. Each domain score was standardized by age. A higher score indicates a higher level of function. CSS refers to composite standard score. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery. '99999' indicates standard deviation (SD) which was not calculated due to insufficient number of subjects. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    Notes
    [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: Subjects from SHP611 10 mg and SHP611 30 mg were excluded from the analysis. Since, analysis was planned for subjects received SHP611 100 mg with different manufacturing processes (Process A and B).
    End point values
    		 SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Communication(Baseline) (n=1,3)
    52 ± 99999
    97.3 ± 2.52
        Communication(Week 40) (n=1,3)
    -10 ± 99999
    -25 ± 18.19
        Daily Living Skills(Baseline) (n=2,3)
    49 ± 1.41
    80.3 ± 9.02
        Daily Living Skills(Week 40) (n=2,3)
    -4 ± 5.66
    -27 ± 19.47
        Socialization(Baseline) (n=2,3)
    50 ± 1.41
    86 ± 3.61
        Socialization(Week 40) (n=2,3)
    -0.5 ± 0.71
    -18 ± 17.09
        Motor Skills(Baseline) (n=2,3)
    31 ± 0
    83.7 ± 24.83
        Motor Skills(Week 40) (n=2,3)
    6 ± 16.97
    -43.3 ± 23.18
        Adaptive Behavior CSS(Baseline) (n=1,3)
    43 ± 99999
    84 ± 10.54
        Adaptive Behavior CSS(Week 40) (n=1,3)
    -5 ± 99999
    -25.3 ± 16.44
    No statistical analyses for this end point

    Secondary: Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40

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    End point title
    		 Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40 [9]
    End point description
    COMFORT questionnaire was used to assess health status and the impact of disease on the ability of subjects with MLD to carry out activities of daily life. The questionnaire was organized by 8 domains (ie, personal care; positioning, transfer, or mobility; eating; pain and discomfort during the day; sleep; emotions; communication; and play and leisure activities). The COMFORT scores range from 0 to 100, with higher scores indicating a decline in the functioning. Safety set consisted of subjects who received at least 1 dose of investigational product or underwent device implant surgery. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 40
    Notes
    [9] - 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: Subjects from SHP611 10 mg and SHP611 30 mg were excluded from the analysis. Since, analysis was planned for subjects received SHP611 100 mg with different manufacturing processes (Process A and B).
    End point values
    		 SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Communication (Baseline) (n=5,6)
    27.3 ± 13.27
    16.9 ± 8.65
        Communication (Week 40) (n=5,6)
    24.7 ± 26.81
    21.4 ± 20.92
        Eating difficulty (Baseline) (n=5,6)
    21.1 ± 22.94
    2.4 ± 5.77
        Eating difficulty (Week 40) (n=5,6)
    25.1 ± 22.44
    11.8 ± 10.29
        Emotions (Baseline) (n=5,6)
    60 ± 9.13
    55.6 ± 12.55
        Emotions (Week 40) (n=5,6)
    -15 ± 21.57
    -1.4 ± 6.27
        Pain and discomfort during day (Baseline) (n=5,6)
    16.6 ± 10.16
    6.9 ± 11.05
        Pain and discomfort during day (Week 40) (n=5,6)
    13.5 ± 15.23
    0 ± 11.74
        Personal care (Baseline) (n=5,6)
    48 ± 21.26
    36 ± 17.99
        Personal care (Week 40) (n=5,6)
    18.1 ± 37.94
    7.3 ± 18.95
        Play and leisure activities (Baseline) (n=5,6)
    46 ± 19.81
    16.7 ± 16.33
        Play and leisure activities (Week 40) (n=5,6)
    1 ± 28.15
    30 ± 25.88
        Positioning, transfer/mobility(Baseline) (n=5,6)
    42.2 ± 19.44
    18 ± 18.8
        Positioning, transfer/mobility (Week 40) (n=5,6)
    6.7 ± 21.82
    8.8 ± 13.14
        Sleep (Baseline) (n=5,6)
    11.9 ± 5.52
    18.9 ± 6.52
        Sleep (Week 40) (n=5,6)
    6.8 ± 17.08
    4.5 ± 15.6
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of SHP611

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of SHP611
    End point description
    Cmax is the maximum observed serum concentration of SHP611. Pharmacokinetic (PK) set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=6,6,6,5)
    214.53 ± 162.104
    500.83 ± 260.978
    715.17 ± 339.856
    799.6 ± 494.452
        Week 38 (n=2,5,4,4)
    157.5 ± 36.062
    275.4 ± 156.329
    888.75 ± 225.457
    1494.83 ± 1297.295
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma

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    End point title
    		 Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma
    End point description
    Tmax is the time to reach maximum observed drug concentration of SHP611 during a dosing interval. Pharmacokinetic (PK) set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Hour (h)
    arithmetic mean (standard deviation)
        Baseline (n=6,6,6,5)
    7.06 ± 1.086
    6.81 ± 3.462
    5.97 ± 4.802
    9.61 ± 8.344
        Week 38 (2,5,4,4)
    5.08 ± 1.45
    11.22 ± 1.78
    18.16 ± 11.661
    7.02 ± 3.824
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of SHP611

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    End point title
    		 Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of SHP611
    End point description
    The AUC 0-inf is the area under the concentration-time curve from time zero to infinity of SHP611. Pharmacokinetic (PK) set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points. '99999' indicates standard deviation (SD) which was not calculated due to insufficient number of subjects and ‘88888’ indicates mean and SD were not calculated as the number of subjects analyzed were 0.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Hour*nanogram/milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=1,4,2,3)
    4355 ± 99999
    10105 ± 3307.4
    22123 ± 4217.4
    23117 ± 10380.1
        Week 38 (n=1,1,0,2)
    2767 ± 99999
    9589 ± 99999
    88888 ± 88888
    48648 ± 6906.8
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611

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    End point title
    		 Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611
    End point description
    AUC0-last is the area under the concentration-time curve from the time of dosing to the last measurable concentration of SHP611. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Hour*nanogram per milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=6,6,6,5)
    2532 ± 1178.4
    8738 ± 3106.4
    15022 ± 10755.2
    16288 ± 10691.4
        Week 38 (n=2,5,4,4)
    1972 ± 211.5
    6156 ± 3904.5
    24820 ± 16954.3
    29219 ± 21261.5
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611

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    End point title
    		 Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611
    End point description
    Area under the concentration-time curve over the interval from 0 to 24 hours after dosing of SHP611. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Hour*nanogram per milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=6,6,5,5)
    2530 ± 1178
    6258 ± 2995.3
    11918 ± 6376.1
    13114 ± 8012
        Week 38 (n=2,4,3,3)
    1960 ± 224
    4596 ± 2316.1
    18264 ± 2162.7
    31115 ± 15805.6
    No statistical analyses for this end point

    Secondary: First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611

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    End point title
    		 First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611
    End point description
    Lambda z is first order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points. '99999' indicates standard deviation (SD) which was not calculated due to insufficient number of subjects and ‘88888’ indicates mean and SD were not calculated as the number of subjects analyzed were 0.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Per hour (/h)
    arithmetic mean (standard deviation)
        Baseline (n=1,4,2,3)
    0.0934 ± 99999
    0.0561 ± 0.019
    0.0461 ± 0.02439
    0.0607 ± 0.01949
        Week 38 (n=1,1,0,2)
    0.0506 ± 99999
    0.064 ± 99999
    88888 ± 88888
    0.0857 ± 0.04415
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half Life (t1/2) of SHP611

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    End point title
    		 Terminal Elimination Half Life (t1/2) of SHP611
    End point description
    The t1/2 is the time in hours required for the concentration of the drug to reach half of its original value. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points. '99999' indicates standard deviation (SD) which was not calculated due to insufficient number of subjects and ‘88888’ indicates mean and SD were not calculated as the number of subjects analyzed were 0.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Hour (h)
    arithmetic mean (standard deviation)
        Baseline (n=1,4,2,3)
    7.42 ± 99999
    13.6 ± 4.932
    17.47 ± 9.238
    12.34 ± 4.373
        Week 38 (n=1,1,0,2)
    13.7 ± 99999
    10.83 ± 99999
    88888 ± 88888
    9.32 ± 4.8
    No statistical analyses for this end point

    Secondary: Total Body Clearance (CL/F) After Intrathecal Administration of SHP611

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    End point title
    		 Total Body Clearance (CL/F) After Intrathecal Administration of SHP611
    End point description
    CL/F was defined as the total body clearance of the drug for extravascular administration divided by the fraction of dose absorbed. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points. '99999' indicates standard deviation (SD) which was not calculated due to insufficient number of subjects and ‘88888’ indicates mean and SD were not calculated as the number of subjects analyzed were 0.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Liter per hour (L/h)
    arithmetic mean (standard deviation)
        Baseline (n=1,4,2,3)
    2.3 ± 99999
    3.25 ± 1.185
    4.6 ± 0.878
    5.28 ± 3.179
        Week 38 (n=1,1,0,2)
    3.61 ± 99999
    3.13 ± 99999
    88888 ± 88888
    2.08 ± 0.295
    No statistical analyses for this end point

    Secondary: Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611

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    End point title
    		 Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611
    End point description
    Volume of distribution was associated with the terminal slope following extravascular administration of SHP611 divided by the fraction of dose absorbed. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points. '99999' indicates standard deviation (SD) which was not calculated due to insufficient number of subjects and ‘88888’ indicates mean and SD were not calculated as the number of subjects analyzed were 0.
    End point type
    Secondary
    End point timeframe
    Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Liter (L)
    arithmetic mean (standard deviation)
        Baseline (n=1,4,2,3)
    24.58 ± 99999
    69.97 ± 49.912
    121.88 ± 83.481
    106.95 ± 100.026
        Week 38 (n=1,1,0,2)
    71.41 ± 99999
    48.88 ± 99999
    88888 ± 88888
    28.95 ± 18.345
    No statistical analyses for this end point

    Secondary: Concentration of SHP611 in Cerebrospinal Fluid

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    End point title
    		 Concentration of SHP611 in Cerebrospinal Fluid
    End point description
    Concentration of SHP611 in CSF were determined using validated enzyme-linked immunosorbent assay (ELISA) method. PK set consisted of subjects who received at least 1 dose of investigational product and had at least 1 measurable serum concentration or 1 measurable CSF concentration of SHP611. Here 'n' represents those subjects who were evaluated for this measure at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks
    End point values
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Number of subjects analysed
    6
    6
    6
    6
    Units: Nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=6,6,6,5)
    280 ± 685.857
    0 ± 0
    0 ± 0
    0 ± 0
        Week 4 (n=6,6,6,4)
    182.93 ± 165.913
    78 ± 102.516
    2935.17 ± 2632.398
    6152.5 ± 6546.986
        Week 8 (n=6,6,5,4)
    85.47 ± 79.316
    1854.07 ± 2633.858
    4171.2 ± 4874.122
    3825 ± 2182.056
        Week 12 (n=5,6,6,5)
    57.5 ± 57.365
    1556.17 ± 1557.666
    2310 ± 2544.814
    2304 ± 2155.558
        Week 16 (n=6,6,6,5)
    93.83 ± 147.188
    2805.68 ± 3499.878
    2395 ± 1550.648
    2606.2 ± 1212.857
        Week 20 (n=6,6,6,3)
    112.78 ± 143.216
    1364.65 ± 2784.474
    5182.5 ± 5081.08
    4423.33 ± 4195.406
        Week 24 (n=6,6,6,5)
    132.57 ± 235.783
    802.67 ± 903.025
    5402.5 ± 7352.246
    7914.6 ± 8243.114
        Week 28 (n=5,6,6,4)
    525.06 ± 874.71
    3274.62 ± 4493.212
    6273.83 ± 6839.101
    3682.58 ± 4331.13
        Week 32 (n=5,6,5,5)
    70.12 ± 126.513
    573.62 ± 376.224
    1831.4 ± 988.294
    6110 ± 4099.5
        Week 36 (n=5,6,6,3)
    72.4 ± 125.574
    1046.05 ± 1087.321
    3917.5 ± 4650.791
    3116.67 ± 336.502
        Week 40 (n=6,2,6,4)
    659.15 ± 1602.414
    243.6 ± 313.107
    2931.83 ± 4098.389
    6663.75 ± 7947.148
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to safety follow up (Week 42)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    SHP611 10 mg (Process A)
    Reporting group description
    		 Subjects received 10 milligram (mg) dose of SHP611 (HGT1110, recombinant human arylsulfatase A [rhASA]) every other week (EOW) by intrathecal drug delivery device (IDDD) for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 30 mg (Process A)
    Reporting group description
    		 Subjects received 30 mg dose of SHP611 (HGT1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 100 mg (Process A)
    Reporting group description
    		 Subjects received 100 mg dose of SHP611 (HGT1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the original drug substance manufacturing process referred to as Process A.

    Reporting group title
    SHP611 100 mg (Process B)
    Reporting group description
    		 Subjects received 100 mg dose of SHP611 (HGT1110, rhASA) EOW by IDDD for 38 weeks. In this cohort, subjects received SHP611 produced with the revised drug substance manufacturing process referred to as Process B.

    Serious adverse events
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SHP611 10 mg (Process A) SHP611 30 mg (Process A) SHP611 100 mg (Process A) SHP611 100 mg (Process B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Complication of device removal
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Crying
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Device dislocation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Device malfunction
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Disease progression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    2
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Implant site cyst
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Implant site effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    6
    1
    Implant site pain
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    5 / 6 (83.33%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    5 / 6 (83.33%)
         occurrences all number
    15
    17
    6
    11
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Vulvovaginal erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Choking
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Laryngeal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pharyngeal erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Decreased eye contact
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    1
    Sleep disorder
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    1
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Albumin csf increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    0
    4
    Blood iron decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Body temperature increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Csf lymphocyte count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    2
    Csf mononuclear cell count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Csf protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Csf white blood cell count increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    1
    Eosinophil count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Mean cell volume decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Red blood cells csf positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Incision site oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post procedural complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post procedural oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Postoperative fever
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Postoperative wound complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
         occurrences all number
    2
    2
    3
    5
    Vaccination complication
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Wrong technique in drug usage process
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Talipes
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Areflexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ataxia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cerebellar syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Clonus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Convulsion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Drooling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dystonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Epilepsy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Febrile convulsion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    2
    2
    Hypotonia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Motor dysfunction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle spasticity
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    4
    3
    1
    2
    Myoclonus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Neuralgia
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Speech disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Speech disorder developmental
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anal fissure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
         occurrences all number
    4
    7
    3
    5
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    0
    1
    Dysphagia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    4
    1
    Pancreatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Salivary duct obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 6 (66.67%)
    5 / 6 (83.33%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
         occurrences all number
    5
    7
    11
    6
    Hepatobiliary disorders
    Cytolytic hepatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Erythema nodosum
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hirsutism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Keloid scar
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Kyphosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Lordosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Tendinous contracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tendon disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    3
    Bronchitis
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Enterovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Febrile infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    1
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Impetigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Implant site infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    1
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    5
    1
    5
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Viral pharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2011
    Study design was updated to indicate that subjects randomized to receive investigational drug product would have the IDDD implanted between Days 7 and 1, eliminating the 7 day window; removal of patients from the trial or investigational product section was updated ; safetyrelated stopping rules section was updated.
    17 Aug 2011
    Exclusion criterion was replaced for subjects who were 8 years of age or older would not be eligible for the study.
    20 Oct 2011
    Exclusion criterion was modified to additionally restrict subject participation in any other study using an investigational device or agent during the conduct of this study.
    05 Apr 2012
    Protocol was updated to remove the no-treatment natural history cohort; study design was changed to open label, uncontrolled study; Change in title and removal of all references to randomization; change in sample size and all references to “treated subjects” or “untreated subjects” were removed and revised to read “subjects” only; for a subject with initial screen failure or withdrew prior to device implantation, 1 additional opportunity was allowed to get screened.
    24 Jun 2013
    Protocol was amended to incorporate new IDDD (the SOPH-A-PORT Mini S device); Two secondary clinical endpoints were added; age of the study population was increased from less than 8 years of age to less than 12 years of age.
    31 Jul 2013
    Protocol was amended to clarify the GMFM-88 scoring terminology by adding more detailed description; Descriptions of the VABS-II and COMFORT questionnaire domains were added for consistency; Reporting guidance for medical device reports was added.
    10 Feb 2015
    Protocol was amended to add descriptive exploratory analyses of GIMF-S and GIMF-C; Protocol was amended to add a fourth cohort of subjects to evaluate the SHP611 investigational drug product produced with the revised drug substance manufacturing process (referred to as Process B); Dose timing section was added to allow catch-up dosing in the cohorts receiving the 100 mg dose level.
    26 Aug 2015
    Protocol was amended to update the study design prior to enrollment start for Cohort 4; The revised study design for Cohort 4 changed the following: The age inclusion criterion (from <12 years of age to <8 years of age); Enrolled subjects with GMFM-88 total score (percent) ≥40 at screening with eligibility confirmed at baseline with a GMFM-88 score ≥35 and an additional inclusion criteria based on the walking dimension of the GMFM-88 permitted subjects to initiate treatment via lumbar puncture (LP), if IDDD implantation was delayed; Allowed use of local laboratories to confirm MLD diagnosis and eligibility with central laboratory confirmation.

    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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