Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43862   clinical trials with a EudraCT protocol, of which   7285   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular AX 250 in Patients with Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)

    Summary
    EudraCT number
    		 2015-001985-25
    Trial protocol
    		 GB   DE   ES  
    Global end of trial date
    23 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    250-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02754076
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allievex Corporation
    Sponsor organisation address
    P.O. Box 1056, Marblehead, United States, MA, 01945
    Public contact
    Clinical Trials Information, Allievex Corporation, inquiries@allievex.com
    Scientific contact
    Clinical Trials Information, Allievex Corporation, inquiries@allievex.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of AX 250 administered to subjects with MPS IIIB by an implanted intracerebroventricular (ICV) reservoir and catheter. To evaluate the impact of AX 250 on cognitive function in patients with MPS IIIB as assessed by development quotient (DQ).
    Protection of trial subjects
    Non-pharmacological methods (distraction, iPads, movies, etc.) were used whenever possible to facilitate IMP administration. If necessary, subjects were pretreated, at the discretion of the investigator, with age-appropriate sedative medication or general anesthesia administered by a health care professional certified for pediatric sedation/anesthesia by the local institution administered approximately 30 minutes before IMP infusion according to the institution’s standard practices.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2016
    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
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    22
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    22
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Subjects were screened and enrolled into study according to the inclusion and exclusion criteria listed in the protocol

    Pre-assignment
    Screening details
    		 Twenty-three subjects were screened for entry into Study 250-201. One subject withdrew consent after Screening but prior to ICV device implantation; the analysis population excludes this subject.

    Period 1
    Period 1 title
    Overall study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N.A

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Stable Dose Period
    Arm description
    		 The Part 1 - Dose Escalation subjects and 19 subjects previously enrolled in Study 250-901 received weekly AX 250 infusions at the MTTD (300mg) for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AX 250
    Investigational medicinal product code
    Other name
    RHNAGLU-IGF2
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intraventricular use
    Dosage and administration details
    Subjects were treated weekly with the maximum tolerated tested dose (MTTD) of 300 mg for 48 weeks by intracerebroventricular infusion. The surgical implantation of an ICV device took place prior to the study drug administration.

    Arm title
    		 Dose Escalation
    Arm description
    		 In this period, 3 subjects received at least 4 weekly doses of AX 250 at up to 3 escalating dose levels (30, 100, and 300 mg) until the maximum tolerated tested dose (MTTD) was established.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AX 250
    Investigational medicinal product code
    Other name
    RHNAGLU-IGF2
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intraventricular use
    Dosage and administration details
    3 subjects received at least 4 weekly doses of AX 250 at up to 3 escalating dose levels (30, 100, and 300 mg) until the maximum tolerated tested dose (MTTD) was established

    Number of subjects in period 1
    		Stable Dose Period Dose Escalation
    Started
    22
    3
    Completed
    21
    3
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall study period
    Reporting group description
    		 -

    Reporting group values
    		 Overall study period Total
    Number of subjects
    		 22 22
    Age categorical
    All 22 subjects met inclusion criteria and were enrolled into study 250-201; 19 of these subjects were 1 to < 6 years of age and 3 subjects were 6 to < 11 years of age
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 22 22
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    All 22 subjects met inclusion criteria and were enrolled into study 250-201; 19 of these subjects were 1 to < 6 years of age and 3 subjects were 6 to < 11 years of age
    Units: years
        arithmetic mean (standard deviation)
    		 4.96 ± 2.032 -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 13 13
    Race
    Units: Subjects
        White
    		 18 18
        Black or African American
    		 0 0
        Asian
    		 3 3
        American Indian or Alaska native
    		 0 0
        Native Hawaiian or Pacific Islander
    		 0 0
        Other
    		 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2
        Not Hispanic or Latino
    		 20 20
    Initial presenting symptoms
    Units: Subjects
        Behavior problem
    		 1 1
        Speech/language problem
    		 11 11
        Sleep problem
    		 0 0
        Failure to achieve developmental milestone
    		 1 1
        Loss of milestone that had previously been achieve
    		 0 0
        Hepatomegaly
    		 2 2
        Hearing loss/deafness
    		 1 1
        Abnormal facies
    		 2 2
        Other
    		 4 4
    Method of first diagnosis
    Units: Subjects
        Enzyme testing
    		 9 9
        Glycoaminoglycans
    		 7 7
        Genetic testing
    		 6 6
    Subject had a history of seizures
    Units: Subjects
        Yes
    		 0 0
        No
    		 22 22
    Age at MPS IIIB onset
    Mean (SD) = 23.0 (12.85)
    Units: month
        median (full range (min-max))
    		 20.0 (4 to 54) -
    Duration from onset of initial symptom of MPS IIIB to First Dose of Study Drug (months)
    Units: month
        arithmetic mean (standard deviation)
    		 39.26 ± 17.46 -
    Development Quotient (DQ) score
    Units: DQ Score
        arithmetic mean (standard deviation)
    		 55.43 ± 21.096 -
    Age equivalent (AEq) score
    Units: month
        arithmetic mean (standard deviation)
    		 30.5 ± 12.1 -
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    		 111.53 ± 13.079 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 23.10 ± 5.457 -
    Body Mass index (BMI)
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 18.49 ± 2.107 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Stable Dose Period
    Reporting group description
    		 The Part 1 - Dose Escalation subjects and 19 subjects previously enrolled in Study 250-901 received weekly AX 250 infusions at the MTTD (300mg) for 48 weeks.

    Reporting group title
    Dose Escalation
    Reporting group description
    		 In this period, 3 subjects received at least 4 weekly doses of AX 250 at up to 3 escalating dose levels (30, 100, and 300 mg) until the maximum tolerated tested dose (MTTD) was established.

    Subject analysis set title
    250-901
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Study 250-901 is an observational study of progressive MPS IIIB symptomology in the same set of subjects.

    Primary: The rate of change in DQ score after the treatment with data for the same subjects from pre-treatment

    		 Close Top of page
    End point title
    		 The rate of change in DQ score after the treatment with data for the same subjects from pre-treatment [1]
    End point description
    The rate of change in DQ score after the treatment with data for the same subjects from Study pre-treatment; Change in baseline. Cognitive DQ decline from Baseline to Week 48 was greater than that measured in 250-901 subjects. These data suggest that 48 weeks of treatment with AX 250 is not sufficient to curb cognitive impairment that begins at younger ages; further studies are needed to determine whether treatment with AX 250 for longer durations results in cognitive benefit
    End point type
    Primary
    End point timeframe
    Overall Study period
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period 250-901
    Number of subjects analysed
    19
    19
    Units: Development Quotient
    arithmetic mean (standard deviation)
        Baseline Values
    56.24 ± 17.662
    68.31 ± 19.709
        Week 48 Values
    38.83 ± 22.864
    58.35 ± 18.468
        Change from Baseline to Week 48
    -17.41 ± 13.109
    -11.80 ± 10.804
    Statistical analysis title
    		 DQ; Rate of Change; Within-subject Comparison
    Statistical analysis description
    Comparison of Rate of Change of Development Quotient (DQ) vs. Study 250-901 Within-Subject Comparison Set
    Comparison groups
    Stable Dose Period v 250-901
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.0545
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.47
         upper limit
    		 0.15
    Variability estimate
    Standard deviation
    Dispersion value
    13.241
    Notes
    [2] - Within subject difference Mean change from Baseline to Week 48 (SD) = -6.66 (13.241)
    Statistical analysis title
    		 Sensitivity Analysis; Rate of Change in DQ
    Statistical analysis description
    As a sensitivity analysis, the effect of treatment with AX 250 on DQ score over time will be determined from an analysis of covariance. The effect of treatment will be summarized by LSMEANs of Treated vs. Not Treated status as of 730 days after the start of Study 250-901 (2 years, approximately the end of Study 250-201). The test for a difference between the 2 LSMEANs at Day 730 will be the test of the effect of treatment. LS Mean at Day 730 In Treated and untreated Status = 40.586 and 45.514
    Comparison groups
    Stable Dose Period v 250-901
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0492 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - The following linear model will be fit to the pooled DQ data of Study 250-901 and Study 250-201: yijk = αi + (βi * tij) + γk + εij where yijk is the DQ score for subject i at who is either being "Treated" (k=l) or "Not Treated" (k=0) at Visit j αi is the fixed intercept for Subject i βi is a fixed regression slope on tij for Subject i tij is day of Visit j in either study where Day 1 is Day 1 of Study 901 γk is a constant effect of treatment and ε j ~ N(0,σ^2).
    [4] - The model includes a fixed intercept for each subject, a linear slope on Day and an effect of being in Treated Status vs. Not Treated Status. Estimated Diff. LS Means: 'Treated'-'Not Treated' = -4.928 Standard Error of Estimate = 2.4881 No CI

    Primary: Age equivalent score (AEq); Rate of Change of Cognitive Age Equivalent score from Baseline to Week 48

    		 Close Top of page
    End point title
    		 Age equivalent score (AEq); Rate of Change of Cognitive Age Equivalent score from Baseline to Week 48 [5]
    End point description
    Age Equivalent score based on BSID-III (Bayley Scales of Infant and Toddler Development, Third Edition) cognitive test or KABC-II (Kaufman Assessment Battery for Children, Second Edition) Nonverbal Index (NVI). The majority of 250-201 subjects showed arrested, below normal cognitive development with AEq scores of 25 to 30 months at Baseline that declined from Baseline to Week 48. This trend is contrary to that seen in Study 250-901, where subjects experienced modest increases in cognitive ability from Baseline to Week 48. Adaptive behavior AEq scores were below normal for age and declined in most treated subjects, again suggesting that 48 weeks of treatment with AX 250 is not sufficient to curb adaptive behavior impairment that begins at younger ages. Further studies are needed to determine whether treatment with AX 250 for longer durations results in adaptive behavior benefit
    End point type
    Primary
    End point timeframe
    Overall study period
    Notes
    [5] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period 250-901
    Number of subjects analysed
    19
    17
    Units: month
    arithmetic mean (standard deviation)
        Baseline
    32.5 ± 11.42
    29.5 ± 9.89
        Week 48
    27.3 ± 14.99
    32.6 ± 12.44
        Change from Baseline to Week 48
    -5.2 ± 7.56
    1.9 ± 5.02
    Statistical analysis title
    		 AEq: Within Subject Difference; Baseline to Week48
    Statistical analysis description
    Comparison of Rate of Change of Cognitive Age Equivalent (AEq) Score vs. Study 250-901 Within-Subject Comparison Set
    Comparison groups
    Stable Dose Period v 250-901
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 = 0.0004
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 -4
    Variability estimate
    Standard deviation
    Dispersion value
    6.98
    Notes
    [6] - Within subject difference Mean change from Baseline to Week 48 (SD) = -7.6 (6.98)
    Statistical analysis title
    		 Sensitivity Analysis of Rate of Change of AEq
    Statistical analysis description
    Sensitivity Analysis of Rate of Change of Cognitive Age Equivalent (AEq) Score vs. Study 250-901 Within-Subject Comparison Set The effect of treatment will be summarized by LSMEANs of Treated vs. Not Treated status as of 730 days after the start of Study 250-901 (2 years, approximately the end of Study 250-201). The test for a difference between the 2 LSMEA at Day 730 will be the test of the effect of treatment.
    Comparison groups
    Stable Dose Period v 250-901
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0237 [8]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [7] - The following linear model will be fit to the pooled DQ data of Study 250-901 and Study 250-201: yijk = αi + (βi * tij) + γk + εij where yijk is the DQ score for subject i at who is either being "Treated" (k=l) or "Not Treated" (k=0) at Visit j αi is the fixed intercept for Subject i βi is a fixed regression slope on tij for Subject i tij is day of Visit j in either study where Day 1 is Day 1 of Study 901 γk is a constant effect of treatment and ε j ~ N(0,σ^2
    [8] - LS Mean at Day 730 In Treated and Not treated Status = 29.102 and 32.124 Estimated Diff. in Treated and Not Treated LS Means = -3.021 Standard error of estimate = 1.3239 No confidence interval.

    Primary: Maximum concentration of AX 250 detected in Plasma - Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Maximum concentration of AX 250 detected in Plasma - Part 2 - Stable Period Dose [9] [10]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 15, 14, 14 & 15 respectively.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    16
    Units: nanogram(s)/millilitre
    arithmetic mean (standard error)
        Week 1
    1120 ± 59
        Week 5
    575 ± 102
        Week 12
    603 ± 110
        Week 36
    273 ± 139
    No statistical analyses for this end point

    Primary: Time (hours) for maximum AX 250 concentration in CSF -Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Time (hours) for maximum AX 250 concentration in CSF -Part 2 - Stable Period Dose [11] [12]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 16, 14, 15 & 16 respectively.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    16
    Units: hour
    arithmetic mean (full range (min-max))
        Week 1
    0.67 (0.33 to 4.33)
        Week 5
    0.64 (0.42 to 10.28)
        Week 12
    0.67 (0.58 to 0.77)
        Week 36
    0.64 (0.25 to 4.17)
    No statistical analyses for this end point

    Primary: Time (hours) for maximum AX 250 concentration in Plasma -Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Time (hours) for maximum AX 250 concentration in Plasma -Part 2 - Stable Period Dose [13] [14]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 16, 13, 13 & 10 respectively.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    16
    Units: hour
    arithmetic mean (full range (min-max))
        Week 1
    10.00 (3.97 to 10.62)
        Week 5
    10.27 (4.18 to 24.42)
        Week 12
    10.23 (4.12 to 24.28)
        Week 36
    17.10 (4.00 to 48.08)
    No statistical analyses for this end point

    Primary: Area under the AX 250 CSF concentration-time curve from time 0 to infinity - Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Area under the AX 250 CSF concentration-time curve from time 0 to infinity - Part 2 - Stable Period Dose [15] [16]
    End point description
    Weeks 5, 12 and 36 values not applicable for this data set; values not entered.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    17
    Units: hour. nanogram(s) / millilitre(s)
    arithmetic mean (standard error)
        Week 1
    19100000 ± 55
    No statistical analyses for this end point

    Primary: Area under the AX 250 Plasma concentration-time curve from time 0 to infinity - Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Area under the AX 250 Plasma concentration-time curve from time 0 to infinity - Part 2 - Stable Period Dose [17] [18]
    End point description
    Weeks 5, 12 and 36 values not applicable for this data set; values not entered.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    6
    Units: hour(s). nanogram(s)/Millilitre(s)
    arithmetic mean (standard error)
        Week 1
    18300 ± 41
    No statistical analyses for this end point

    Primary: Area under the AX 250 CSF concentration-time curve from 0 to time of last measurable concentration - Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Area under the AX 250 CSF concentration-time curve from 0 to time of last measurable concentration - Part 2 - Stable Period Dose [19] [20]
    End point description
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    17
    Units: hour(s). nanogram(s) / milligram(s)
    arithmetic mean (standard error)
        Week 1
    19100000 ± 55
        Week 5
    16000000 ± 43
        Week 12
    20400000 ± 50
        Week 36
    19000000 ± 39
    No statistical analyses for this end point

    Primary: AX 250 CSF: Elimination half-life - Part 2 - Stable Dose Period

    		 Close Top of page
    End point title
    		 AX 250 CSF: Elimination half-life - Part 2 - Stable Dose Period [21] [22]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 17, 12, 15 & 1 respectively
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    17
    Units: hour
    arithmetic mean (standard error)
        Week 1
    4.92 ± 33
        Week 5
    4.71 ± 18
        Week 12
    5.22 ± 29
        Week 36
    5.58 ± 32
    No statistical analyses for this end point

    Primary: AX 250 Plasma: Elimination half-life - Part 2 - Stable Dose Period

    		 Close Top of page
    End point title
    		 AX 250 Plasma: Elimination half-life - Part 2 - Stable Dose Period [23] [24]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 6, 3, 3 & <3 respectively. As Week 36 has <3 applicable observations, no value was calculated and reported as '0' zero value.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [24] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint. t.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    6
    Units: hour
    arithmetic mean (standard error)
        Week 1
    82.5 ± 45
        Week 5
    58.2 ± 82
        Week 12
    31.7 ± 30
        Week 36
    0 ± 0
    No statistical analyses for this end point

    Primary: Clearance of AX 250 from CSF - Part 2 - Stable Dose Period

    		 Close Top of page
    End point title
    		 Clearance of AX 250 from CSF - Part 2 - Stable Dose Period [25] [26]
    End point description
    Number of applicable observations varied over time: Week 1, 5, 12 & 36 = 17, 15, 16 & 16 respectively Note, Week 5 mean value was affected by a single outlier value; Median value = 17.4ml/h
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [25] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [26] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    17
    Units: millilitre(s)/hour
    arithmetic mean (standard error)
        Week 1
    20.2 ± 59
        Week 5
    107 ± 317
        Week 12
    18.5 ± 53
        Week 36
    17.3 ± 26
    No statistical analyses for this end point

    Primary: Clearance of AX 250 from Plasma - Part 2 - Stable Dose Period

    		 Close Top of page
    End point title
    		 Clearance of AX 250 from Plasma - Part 2 - Stable Dose Period [27] [28]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 6, 13, 13 & 11 respectively
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [27] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [28] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    13
    Units: Litre(s)/hour
    arithmetic mean (standard error)
        Week 1
    18.2 ± 30
        Week 5
    76.7 ± 105
        Week 12
    91.2 ± 113
        Week 36
    240 ± 156
    No statistical analyses for this end point

    Primary: Apparent volume of distribution in CSF of AX 250 - Part 2- Stable Dose Period

    		 Close Top of page
    End point title
    		 Apparent volume of distribution in CSF of AX 250 - Part 2- Stable Dose Period [29] [30]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 6, 3, 3 & >3 respectively As Week 36 has <3 applicable observations, no value was calculated and reported as '0' zero value.
    End point type
    Primary
    End point timeframe
    Part 2- Stable Dose Period
    Notes
    [29] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [30] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    17
    Units: litre(s)
    arithmetic mean (standard error)
        Week 1
    138 ± 63
        Week 5
    131 ± 32
        Week 12
    131 ± 48
        Week 36
    135 ± 36
    No statistical analyses for this end point

    Primary: RCmax: Accumulation ratio (in percent) for Cmax of AX 250 in CSF - Part 2 - Stable Dose Period

    		 Close Top of page
    End point title
    		 RCmax: Accumulation ratio (in percent) for Cmax of AX 250 in CSF - Part 2 - Stable Dose Period [31] [32]
    End point description
    Week 1 not applicable in this instance, and therefore not tabulated.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [31] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [32] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    13
    Units: percent
    arithmetic mean (standard error)
        Week 1
    0 ± 0
        Week 5
    92.1 ± 71
        Week 12
    93.4 ± 36
        Week 36
    83.3 ± 46
    No statistical analyses for this end point

    Primary: RCmax: Accumulation ratio (in percent) for Cmax of AX 250 in Plasma - Part 2 - Stable Dose Period

    		 Close Top of page
    End point title
    		 RCmax: Accumulation ratio (in percent) for Cmax of AX 250 in Plasma - Part 2 - Stable Dose Period [33] [34]
    End point description
    Week 1 not applicable in this instance, and therefore not tabulated.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [33] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [34] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    13
    Units: percent
    arithmetic mean (standard error)
        Week 1
    0 ± 0
        Week 5
    55.2 ± 122
        Week 12
    58.1 ± 108
        Week 36
    21.2 ± 143
    No statistical analyses for this end point

    Primary: RAUC(0-τ) accumulation ratio (in percent) for AUC(0-τ) for AX 250 in CSF

    		 Close Top of page
    End point title
    		 RAUC(0-τ) accumulation ratio (in percent) for AUC(0-τ) for AX 250 in CSF [35] [36]
    End point description
    Week 1 not applicable in this instance, and therefore not tabulated.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [35] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [36] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    14
    Units: percent
    arithmetic mean (standard error)
        Week 1
    0 ± 0
        Week 5
    104 ± 37
        Week 12
    114 ± 44
        Week 36
    114 ± 50
    No statistical analyses for this end point

    Primary: RAUC(0-τ) accumulation ratio (in percent) for AUC(0-τ) for AX 250 in Plasma

    		 Close Top of page
    End point title
    		 RAUC(0-τ) accumulation ratio (in percent) for AUC(0-τ) for AX 250 in Plasma [37] [38]
    End point description
    Week 1 not applicable in this instance, and therefore not tabulated.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [37] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [38] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    15
    Units: percent
    arithmetic mean (standard error)
        Week 1
    0.0379 ± 74
        Week 5
    0.0260 ± 101
        Week 12
    0.0252 ± 111
        Week 36
    0.0103 ± 143
    No statistical analyses for this end point

    Primary: PCRatioCmax plasma to CSF ratio (in percent) for Cmax

    		 Close Top of page
    End point title
    		 PCRatioCmax plasma to CSF ratio (in percent) for Cmax [39] [40]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 15, 14, 13 & 15 respectively
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [39] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [40] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    15
    Units: percent
    arithmetic mean (standard error)
        Week 1
    0.130 ± 57
        Week 5
    0.0669 ± 97
        Week 12
    0.0608 ± 109
        Week 36
    0.0463 ± 151
    No statistical analyses for this end point

    Primary: PC Ratio AUC(0-τ) plasma to CSF ratio (in percent) for AUC(0-τ)

    		 Close Top of page
    End point title
    		 PC Ratio AUC(0-τ) plasma to CSF ratio (in percent) for AUC(0-τ) [41] [42]
    End point description
    Week 1 not applicable in this instance, and therefore not tabulated.
    End point type
    Primary
    End point timeframe
    Part 2 - Stable Dose Period
    Notes
    [41] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    [42] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    12
    Units: percent
    arithmetic mean (standard error)
        Week 1
    0 ± 0
        Week 5
    49.7 ± 99
        Week 12
    41.3 ± 131
        Week 36
    36.2 ± 188
    No statistical analyses for this end point

    Secondary: Maximum concentration of AX 250 detected in CSF - Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Maximum concentration of AX 250 detected in CSF - Part 2 - Stable Period Dose [43]
    End point description
    Number of applicable observations varies across the categories: Week 1,5,12 & 36 = 16,14,15 & 16 respectively.
    End point type
    Secondary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [43] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    16
    Units: nano
    arithmetic mean (standard error)
        Week 1
    3440000 ± 43
        Week 5
    2500000 ± 56
        Week 12
    3010000 ± 39
        Week 36
    3010000 ± 42
    No statistical analyses for this end point

    Secondary: Area under the AX 250 Plasma concentration-time curve from 0 to time of last measurable concentration - Part 2 - Stable Period Dose

    		 Close Top of page
    End point title
    		 Area under the AX 250 Plasma concentration-time curve from 0 to time of last measurable concentration - Part 2 - Stable Period Dose [44]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 15, 14, 14 & 16 respectively
    End point type
    Secondary
    End point timeframe
    Part 2 - Stable Period Dose
    Notes
    [44] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    15
    Units: hour(s). nanogram(s)/Milliliter(s)
    arithmetic mean (standard error)
        Week 1
    19200 ± 40
        Week 5
    10900 ± 108
        Week 12
    9700 ± 113
        Week 36
    7260 ± 146
    No statistical analyses for this end point

    Secondary: Apparent volume of distribution in Plasma of AX 250 - Part 2- Stable Dose Period

    		 Close Top of page
    End point title
    		 Apparent volume of distribution in Plasma of AX 250 - Part 2- Stable Dose Period [45]
    End point description
    Number of applicable observations varies over time: Week 1, 5, 12 & 36 = 6, 3, 3 & <3 respectively. As Week 36 has <3 applicable observations, no value was calculated and reported as '0' zero value.
    End point type
    Secondary
    End point timeframe
    Part-2
    Notes
    [45] - 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: This is a pharmacokinetic parameter, no statistical analysis planned for this endpoint.
    End point values
    		 Stable Dose Period
    Number of subjects analysed
    6
    Units: litre(s)
    arithmetic mean (standard error)
        Week 1
    2100 ± 46
        Week 5
    2420 ± 82
        Week 12
    1840 ± 124
        Week 36
    0 ± 0
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Overall Study Period
    Adverse event reporting additional description
    Participants of Part 1 and Part 2 are combined under 'Group Part 2' in the reporting of AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Stable Dose Period
    Reporting group description
    		 The Part 1 - Dose Escalation subjects and 19 subjects previously enrolled in Study 250-901 received weekly AX 250 infusions at the MTTD (300mg) for 48 weeks.

    Serious adverse events
    		 Stable Dose Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 22 (68.18%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    CSF culture positive
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Pleocytosis
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences causally related to treatment / all
    8 / 15
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Consciousness fluctuating
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Retained deciduous tooth
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Stable Dose Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    General disorders and administration site conditions
    Pyrexia
    Additional description: Note; there are instances of Pyrexia that have been designated as SAEs have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    20 / 22 (90.91%)
         occurrences all number
    91
    adverse drug reaction
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    4
    medical device site swelling
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Infusion site extravasation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Localised oedema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Medical device site erythema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Social circumstances
    Loss of personal independence in daily activities
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast swelling
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    11
    Nasal congestion
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Aspiration
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Epistaxis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Atelectasis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Bronchospasm
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Choking
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Psychiatric disorders
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Affect lability
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Aggression
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hallucination
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Mania
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Stereotypy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Product issues
    Device malfunction
    Additional description: Note; there are instances of Device Malfunction that have been designated as SAEs have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Thrombosis in device
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Investigations
    CSF culture positive
    Additional description: Note; there are instances of CSF culture positive that have been designated as SAEs have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    CSF protein increased
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    CSF granulocyte count abnormal
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    CSF lymphocyte count increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    CSF neutrophil count increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Transaminases increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    12
    Head injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    6
    Contusion
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Injury
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Procedural pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Scratch
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Foreign body
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Laceration
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Multiple injuries
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Postoperative fever
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Thermal burn
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Tooth injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Laryngomalacia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    8
    Nervous system disorders
    Pleocytosis
    Additional description: Note; there are instances of Pleocytosis that have been designated as SAEs and have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    10 / 22 (45.45%)
         occurrences all number
    19
    Subdural hygroma
    Additional description: Note; there are instances of Subdural hygroma that have been designated as SAEs and have also been recorded accordingly. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Cerebrospinal fluid leakage
    Additional description: Note; there are instances of CSF leakage that have been designated as SAEs and have been recorded accordingly. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    27
    Psychomotor hyperactivity
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Somnolence
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Epilepsy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Lethargy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Speech disorder
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Abdominal lymphadenopathy
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Anaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
    Additional description: Note; there are instances of Vomiting that have been designated as SAEs and have been recorded accordingly. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    21 / 22 (95.45%)
         occurrences all number
    130
    Constipation
    Additional description: Note; there are instances of Constipation that have been designated as SAEs and have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    8 / 22 (36.36%)
         occurrences all number
    14
    Abdominal pain
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Anal haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Anal incontinence
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Anorectal discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Chronic gastritis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Mucous stools
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    7
    Erythema
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Dermatitis allergic
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Papule
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Scab
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Hyperthyroidism
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Joint range of motion decreased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Infections and infestations
    Gastroenteritis
    Additional description: Note; there are instances of Gastroenteritis that have been designated as SAEs and have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    7
    Urinary tract infection
    Additional description: Note; there are instances of UTI's that have been designated as SAEs have also been recorded in that section. Both serious and non-serious adverse events are reported below.
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Upper respiratory fungal infection
         subjects affected / exposed
    12 / 22 (54.55%)
         occurrences all number
    37
    Rhinitis
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    12
    Otitis media
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    10
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    7
    Nasopharyngitis
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    5
    Ear infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    4
    Viral infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    4
    Respiratory tract infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    2
    Acute sinusitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Bronchiolitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hordeolum
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Otitis externa
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Otitis media acute
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Viral diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Polydipsia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2015
    Amendment 1 Date: 28 October 2015 RATIONALE AND SUMMARY OF MAJOR CHANGES The major changes and rationale for amending Protocol 250-201 (original protocol) are as follows: 1. In the original protocol, Section 9.3.3.1 (Stopping Criteria) provided guidance on the disposition of subjects who experience unacceptable drug-related toxicity. 2. In the original protocol, Section 9.4.4.1 (Safety Monitoring) provided guidance on monitoring infusions
    11 Jun 2017
    Amendment 2 Date: 1 June 2017 A summary of major changes covered by Amendment 2 to the 250-201 protocol is provided below: 1. CSF glucose measurements have been added to the intensive sampling of CSF for GAG and PK analysis. 2. Language has been added to improve the monitoring of neurological symptoms during Part 2 of the study in three ways as detailed in the Protocol 3. Details concerning the use of an independent Data Monitoring Committee (DMC) during Part 2 of the study have been added. 4. It has been clarified that, for Part 2 of the study, pre-ICV placement imaging could be either a CT scan or an MRI, but that such a scan is mandatory. 5. Text has been added requesting that, as much as possible, subjects keep a consistent antipsychotic medication regimen during the study, and that an attempt should be made prior to enrollment to ensure that the subject is receiving a stable antipsychotic medication regimen. 6. Language has been added to clarify that sedatives and general anesthesia should be given to aid in BMN 250 dosing only when absolutely necessary. The use of sedation should be minimized in favor of distraction techniques. 7. Evaluation of the impact of BMN 250 on cognitive function in patients with MPS IIIB as assessed by age equivalent score (AEq) has been added as a secondary efficacy variable. 8. The Part 2 Baseline, Week 24, and Week 48 visits may occur over 2-3 days (rather than 3 days). 9. The Parenting Stress Index (PSI) has been removed as an outcome measure. 10. Anti-BMN250 total antibodies (TAb) and neutralizing antibodies (NAb) in CSF and anti-BMN250 TAb in serum will be measured at Week 2 of Part 2 in all subjects. 11. Hypoglycemia-specific stopping criteria have been added. 12. Language around the age requirements for enrollment has been modified for clarity. 13. To correct an inconsistency in previous versions of the protocol, the Vineland Adaptive Behavior Scales, 14. The identity of the Medical Monitor has been changed.
    11 Sep 2017
    Amendment 3 Date: 11 September 2017 A summary of major changes covered by Amendment 3 to the 250-201 protocol is provided below: 1. Cell count and protein were added as analyses to be performed on cerebrospinal fluid (CSF) samples already collected 4, 10, 24, 48, 72, and 96 hours post-dose as part of serial PK analyses at Part 2 Baseline and Weeks 5, 12, and 36. 2. Glycosaminoglycans (GAGs) were removed from analyses to be performed on CSF samples collected 4, 10, 24, 48, and 96 hours post-dose as part of serial PK analyses at Part 2 Baseline and Weeks 5, 12, and 36. 3. Section 12.2.4 (Part 2 Treatment Visits) has been amended with the addition of a bowel habits questionnaire to be administered by the site staff at Part 2 Baseline and every 4 weeks thereafter. 4. Section 12.2.4 (Part 2 Treatment Visits) has been amended to specify that for subjects below 14.3 kg in weight at the 250-201 Part 2 Baseline, blood normally collected for exploratory analyses will not be drawn at Week 4 or Week 8. 5. Section 9.3.3.1 (Stopping Criteria) has been amended. This change strengthens trial subject safety monitoring by more clearly defining BioMarin actions and DMC involvement in the face of potential treatment-related SAEs. 6. Language has been added in Section 9.4.6 (Selection of Doses Used in the Study) to allow for dose reductions in individual subjects should they experience serious treatment-related adverse events. 7. Language has been added to Section 9.3.4 (Subject Identification and Replacement of Subjects) stating, “Subjects previously enrolled in Study 250-901 before enrolling into Part 2 of this study will receive a new subject ID for the 250-201 study.” Additional major changes listed within Summary of Changes documentation.
    06 Dec 2019
    Amendment 4 Date: 06 December 2019 A summary of major changes covered by Amendment 4 to the 250-201 protocol is provided below: Sponsor change from BioMarin Pharmaceutical Inc to Allievex Corporation
    31 Jan 2020
    Amendment 5 Date: 31 January 2020 A summary of the major changes in Amendment 5 of the 250-201 protocol is provided below: 1. Brain imaging (MRI or CT) should be performed up to Q4W to monitor for asymptomatic subdural hygroma formation. 2. Immediate pre-infusion, immediate post-infusion and 24 hour post-infusion brain imaging (MRI or CT) will be performed up to once for each patient. 3. The amount of CSF withdrawn prior to administering AX 250 has been changed from “10mL” to “up to 10mL”. 4. BMN 250 is now referred to as AX 250. 5. The contact information for Pharmacovigilance has been updated consistent with the change in sponsor from BioMarin to Allievex. 6. For the Children’s Sleep Health Questionnaire (CSHQ), 3 additional subscale scores (sleep initiation, sleep distress, and sleep transition) based on regrouping of item scores on the standard CSHQ are added to the score outputs. 7. Mentions of a version of the CSHQ adapted by researchers at the University of Minnesota were removed from the protocol. 8. Change to language in Appendix 1; These changes clarify how subjects who score below the range at which the KABC can accurately determine age equivalent scores will be evaluated at subsequent study visits. This ensures that cognitive test data will be as accurate as possible. 9. Nonclinical study data have been updated. 10. The Summary of Overall Risks and Benefits (Section 7.4) has been updated. 11. Minor changes have been made for purposes of clarity and consistency.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Apr 26 11:23:54 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA