Clinical Trial Results:
A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients with Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2) Disease
Summary
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EudraCT number |
2012-005430-11 |
Trial protocol |
GB DE IT |
Global end of trial date |
30 Nov 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jun 2019
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First version publication date |
30 Jun 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
190-201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01907087 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
BioMarin Pharmaceutical Inc.
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Sponsor organisation address |
105 Digital Drive, Novato, CA, United States, 94949
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Public contact |
Clinical Trials Information, BioMarin Pharmacutical Inc. , clinicaltrials@bmrn.com
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Scientific contact |
Clinical Trials Information, BioMarin Pharmacutical Inc. , clinicaltrials@bmrn.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001362-PIP01-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Apr 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Nov 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Nov 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives of this study include the following:
To evaluate safety and tolerability of BMN 190 administered to subjects with CLN2 by an implanted intracerebroventricular (ICV) reservoir and cannula.
To evaluate effectiveness using a CLN2-specific rating scale score in comparison with natural history data after 12 months of treatment.
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Protection of trial subjects |
This clinical study was designed, conducted, recorded, and reported in compliance with the principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. federal regulations as well as Guidance for Good Clinical Practice, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Sep 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
6 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Germany: 12
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Country: Number of subjects enrolled |
Italy: 6
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
24
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EEA total number of subjects |
21
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
24
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 5 clinic sites in Germany, Italy, United Kingdom and United States. | |||||||||||||||||||||||||
Pre-assignment
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Screening details |
Of the 24 subjects enrolled to study, 23 subjects remained on treatment through the end of the study. | |||||||||||||||||||||||||
Period 1
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Period 1 title |
All Participants Intervention (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Dose Escalation Period - Cohort 1 | |||||||||||||||||||||||||
Arm description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 1 to 3 (Cohort 1) assigned to the 30mg dose, then escalated to 100mg and 300mg after data review. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
BMN 190
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Investigational medicinal product code |
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Other name |
recombinant human tripeptidyl peptidase 1 (rhTPP1)
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intracerebroventricular use
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Dosage and administration details |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5 mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs.
Subjects 1 to 3 (Cohort 1) assigned to the 30mg dose, then escalated to 100mg and 300mg after data review.
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Arm title
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Dose Escalation Period - Cohort 2 | |||||||||||||||||||||||||
Arm description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 4 to 6 (Cohort 2) assigned to the 100mg dose, then escalated to 300mg after data review. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
BMN 190
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Investigational medicinal product code |
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Other name |
recombinant human tripeptidyl peptidase 1 (rhTPP1)
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intracerebroventricular use
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Dosage and administration details |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5 mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs.
Subjects 4 to 6 (Cohort 2) assigned to the 100mg dose, then escalated to 300mg after data review.
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Arm title
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Dose Escalation Period - Cohort 3 | |||||||||||||||||||||||||
Arm description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 7 to 10 (Cohort 3) assigned to the 300mg dose. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
BMN 190
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Investigational medicinal product code |
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Other name |
recombinant human tripeptidyl peptidase 1 (rhTPP1)
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intracerebroventricular use
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Dosage and administration details |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5 mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs.
Subjects 7 to 10 (Cohort 3) assigned to the 300mg dose.
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Arm title
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Stable Dose Period - Stable Dose Only | |||||||||||||||||||||||||
Arm description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Of 9 subjects from Dose Escalation cohorts rolling over into the 48-week Stable Dose Period with 14 subjects enrolled directly, counting 23 during this Stable Dose Period, all subjects were administered BMN 190 infusions of 300 mg for 48 weeks. | |||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||
Investigational medicinal product name |
BMN 190
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Investigational medicinal product code |
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Other name |
recombinant human tripeptidyl peptidase 1 (rhTPP1)
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intracerebroventricular use
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Dosage and administration details |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs.
Of 9 subjects from Dose Escalation cohorts rolling over into the 48-week Stable Dose Period with 14 subjects enrolled directly, counting 23 during this Stable Dose Period, all subjects were administered BMN 190 infusions of 300 mg for 48 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
All Participants Intervention
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dose Escalation Period - Cohort 1
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Reporting group description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 1 to 3 (Cohort 1) assigned to the 30mg dose, then escalated to 100mg and 300mg after data review. | ||
Reporting group title |
Dose Escalation Period - Cohort 2
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Reporting group description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 4 to 6 (Cohort 2) assigned to the 100mg dose, then escalated to 300mg after data review. | ||
Reporting group title |
Dose Escalation Period - Cohort 3
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Reporting group description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 7 to 10 (Cohort 3) assigned to the 300mg dose. | ||
Reporting group title |
Stable Dose Period - Stable Dose Only
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Reporting group description |
All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Of 9 subjects from Dose Escalation cohorts rolling over into the 48-week Stable Dose Period with 14 subjects enrolled directly, counting 23 during this Stable Dose Period, all subjects were administered BMN 190 infusions of 300 mg for 48 weeks. | ||
Subject analysis set title |
300 mg BMN 190
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent-to-treat (ITT) population comprises all study subjects who received any amount of study drug and report any efficacy results, excluding one subject who withdrew from the study after a single infusion of study drug. The defined ITT population has 23 enrolled subjects that received > 1 dose of study drug.
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End point title |
Motor-Language (ML) Scale Score During 300 mg Dosing Period [1] | ||||||||||||||
End point description |
Intent-to-treat (ITT) population
The progression of ceroid lipofuscinosis (CLN2) disease was assessed using adapted motor and language domains of the Hamburg rating scale (ML scale score). Motor and Language are each 0 - 3 point subscales in which 3 represents best function and 0 represents loss of function. The sum of the motor and language scores (ML score, 0-6 points) was used to evaluate the loss of function.
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End point type |
Primary
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End point timeframe |
Baseline, Week 49/Last Assessment
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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: The primary endpoint is a responder analysis based on the ITT population: absence of an unreversed two-point decline or score of zero in CLN2 score by Week 48 (Study Day 340 relative to first 300 mg infusion). The study met the primary endpoint with 20 of 23 (87%) subjects responding compared to an expected response rate of 50% (p = 0.0002). A 'response' is defined as the absence of an unreversed two-point decline or score of 0 in the 0-to-6 point CLN2 score at 48 weeks. |
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No statistical analyses for this end point |
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End point title |
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume | ||||||||
End point description |
ITT Population
Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period
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End point type |
Secondary
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End point timeframe |
Baseline, Week 49
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No statistical analyses for this end point |
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End point title |
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter | ||||||||
End point description |
ITT Population
Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period
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End point type |
Secondary
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End point timeframe |
Baseline, Week 49
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No statistical analyses for this end point |
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End point title |
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume | ||||||||
End point description |
ITT Population
Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period
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End point type |
Secondary
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End point timeframe |
Baseline, Week 49
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No statistical analyses for this end point |
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End point title |
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid | ||||||||
End point description |
ITT population
Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period
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End point type |
Secondary
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End point timeframe |
Baseline, Week 49
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No statistical analyses for this end point |
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End point title |
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient | ||||||||
End point description |
ITT Population
Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period
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End point type |
Secondary
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End point timeframe |
Baseline, Week 49
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to 85 weeks (60 weeks + 6 months safety follow up)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Adverse Events
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 May 2013 |
Amendment 1:
1. To permit sufficient study drug clearance, based on nonclinical data, the follow-up visit was changed from 4 weeks to 6 months.
2. To ensure additional precaution for subject safety, during the first dosing cohort, at least 72 hours must have elapsed between the first and second subjects.
3. To require antihistamine pretreatment, it was clarified that an antipyretic medication may not be substituted but may be added, if appropriate.
4. To be consistent with European ethics committee recommendations, subjects 16 years of age or older were excluded from study participation.
5. To add a precautionary measure for this pediatric study population, females of child-bearing potential were excluded from study participation. |
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26 Jul 2013 |
Amendment 2:
1. Added rationale for investigational drug infusion volume and rate.
2. Added statement regarding subject sedation during infusion at the discretion of the investigator.
3. Added statement regarding monitoring for epileptic seizure during infusion and for interrupting infusion at the discretion of the investigator.
4. For safety variables, removed head circumference assessment and replaced “length” with “height” assessment in complete physical exam.
5. Added statements regarding procedure for evaluating status of ICV access device on a regular basis. Specifically, “Surgical implantation of an ICV access device will take place prior to study drug administration. The investigator will evaluate the patency,
location, and skin integrity of the reservoir at each study drug administration. At the discretion of the investigator and/or neurosurgeon, the ICV access device may be replaced during the clinical study.” |
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07 Jul 2014 |
Amendment 3:
1. The schedule for Magnetic resonance imaging (MRI) during the Stable Dose Period for quantitative analysis was changed be done at four time points: Baseline or Week 1 in the Stable Dose Period, and at Weeks 9, 25, and 49 in the Stable Dose Period. A
screening MRI was required prior to ICV access device placement for anatomic localization. If sedation or anesthesia were required for this image sequence, the ICV access device placement would occur in the same period.
2. All adapted CLN2 scale assessments were videotaped at all site visits where the adapted CLN2 scale assessments are done.
3. For the post-implantation, first dose, and dose-escalation visits, subjects were monitored for 48 hours after infusions (with a minimum of 24 hours in the pediatric intensive care unit [PICU], and the remaining time on an inpatient ward). A follow-up phone call was also conducted within 24 hours after inpatient discharge.
4. Planned enrollment in the study was changed from 22 to “approximately 22” subjects.
5. Language was added concerning the collection of device-related adverse events (AEs) prior to the first administration of study drug.
6. Language was added detailing the risks of intracerebroventricular drug administration.
7. It was clarified that all Screening procedures are to be completed ≤ 3 days prior to the ICV access device implant surgery.
8. Baseline total and drug-specific IgE assessment was added. |
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08 Aug 2014 |
Amendment 4:
1. Device-related AE reporting requirements were amended to include all infusion system components that come into contact with BMN 190.
2. Subjects and their caregivers were given written instructions following ICV placement providing details about signs and symptoms of potential device complications or failure. |
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24 Sep 2014 |
Amendment 5:
1. Device-related AE reporting requirements were amended to include all infusion system components.
2. Language was clarified that, for Stable Dose Period visits, subjects would be closely monitored in an inpatient setting for up to 48 hours following each infusion, but could be discharged after 24 hours if medically stable and if no safety issues were observed. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |