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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

Primary Purpose

Jansky-Bielschowsky Disease, Batten Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
BMN 190
Sponsored by
BioMarin Pharmaceutical
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Jansky-Bielschowsky Disease focused on measuring Late infantile Neuronal Ceroid Lipofuscinosis Type 2, LINCL, NCL2, CLN2, Jansky-Bielschowsky disease

Eligibility Criteria

3 Years - 15 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Has a diagnosis of CLN2 determined by TPP1 enzyme activity (dried blood spot) available at study entry. If no genotype information is available, blood will be collected for CLN2 gene analysis at baseline. In addition, blood for TPP1 enzyme activity (dried blood spot) will be collected at baseline to be analyzed centrally
  • Has mild to moderate disease documented by a two-domain score of 3- 6 on motor and language domains of the Hamburg Scale, with a score of at least 1 in each of these two domains
  • Written informed consent from parent or legal guardian and assent from subject, if appropriate
  • Has the ability to comply with protocol requirements, in the opinion of the investigator
  • Seizures are stable in the judgement of the investigator

Exclusion Criteria:

  • Is less than 3 years old at enrollment
  • Is 16 years old or older at enrollement
  • Has another inherited neurologic disease, e.g. other forms of CLN or seizures unrelated to CLN2 (patients with febrile seizures may be eligible)
  • Has another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before study entry
  • Requires ventilation support, except for noninvasive support at night
  • Has received stem cell, gene therapy, or ERT for CLN2
  • Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities)
  • Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
  • Has generalized motor status epilepticus within 4 weeks before the First Dose visit, taking care that status epilepticus is on clinical examination and not only electroencephalogram (EEG) (enrollment may be postponed)
  • Has severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed)
  • Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts
  • Has known hypersensitivity to any of the components of BMN 190
  • Has received any investigational medication within 30 days before the first infusion of study drug or is scheduled to receive any investigational drug other than BMN 190 during the course of the study
  • Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's well being, safety, or clinical interpretability
  • Pregnancy any time during the study

Sites / Locations

  • Nationwide Children's Hospital
  • University Hamburg-Eppendorf
  • Bambino Gesù Children's Hospital
  • Guy's & St. Thomas NHS Foundation Trust
  • Great Ormond Street Hospital for NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BMN190

Arm Description

recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa)

Outcomes

Primary Outcome Measures

Motor-Language (ML) Scale Score During 300 mg Dosing Period
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.

Secondary Outcome Measures

Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume
Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter
Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume
Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid
Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient
Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period

Full Information

First Posted
July 19, 2013
Last Updated
March 6, 2019
Sponsor
BioMarin Pharmaceutical
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1. Study Identification

Unique Protocol Identification Number
NCT01907087
Brief Title
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
Official Title
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 Type 2 (CLN2) Disease
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
November 2015 (Actual)
Study Completion Date
November 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
BioMarin Pharmaceutical

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine whether BMN 190 is safe and effective in the treatment of patients with Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease.
Detailed Description
The purpose of this study is to determine whether BMN 190 is safe and effective in the treatment of patients with Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease. This is an open label Phase 1/2 study conducted in patients with CLN2 disease. Efficacy measures (disease rating scale and MRI) will be compared to a natural history control. The study will be conducted under cGCP and patients will be closely monitored.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Jansky-Bielschowsky Disease, Batten Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2, CLN2 Disease
Keywords
Late infantile Neuronal Ceroid Lipofuscinosis Type 2, LINCL, NCL2, CLN2, Jansky-Bielschowsky disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BMN190
Arm Type
Experimental
Arm Description
recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa)
Intervention Type
Biological
Intervention Name(s)
BMN 190
Other Intervention Name(s)
recombinant human tripeptidyl peptidase-1 (rhTPP1), cerliponase alfa
Intervention Description
30-300 mg ICV infusion administered every other week for at least 48 weeks.
Primary Outcome Measure Information:
Title
Motor-Language (ML) Scale Score During 300 mg Dosing Period
Description
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.
Time Frame
Baseline, Week 49/Last Assessment
Secondary Outcome Measure Information:
Title
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume
Description
Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period
Time Frame
Baseline, Week 49
Title
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter
Description
Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period
Time Frame
Baseline, Week 49
Title
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume
Description
Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period
Time Frame
Baseline, Week 49
Title
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid
Description
Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period
Time Frame
Baseline, Week 49
Title
Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient
Description
Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period
Time Frame
Baseline, Week 49

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Has a diagnosis of CLN2 determined by TPP1 enzyme activity (dried blood spot) available at study entry. If no genotype information is available, blood will be collected for CLN2 gene analysis at baseline. In addition, blood for TPP1 enzyme activity (dried blood spot) will be collected at baseline to be analyzed centrally Has mild to moderate disease documented by a two-domain score of 3- 6 on motor and language domains of the Hamburg Scale, with a score of at least 1 in each of these two domains Written informed consent from parent or legal guardian and assent from subject, if appropriate Has the ability to comply with protocol requirements, in the opinion of the investigator Seizures are stable in the judgement of the investigator Exclusion Criteria: Is less than 3 years old at enrollment Is 16 years old or older at enrollement Has another inherited neurologic disease, e.g. other forms of CLN or seizures unrelated to CLN2 (patients with febrile seizures may be eligible) Has another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before study entry Requires ventilation support, except for noninvasive support at night Has received stem cell, gene therapy, or ERT for CLN2 Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities) Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain) Has generalized motor status epilepticus within 4 weeks before the First Dose visit, taking care that status epilepticus is on clinical examination and not only electroencephalogram (EEG) (enrollment may be postponed) Has severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed) Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts Has known hypersensitivity to any of the components of BMN 190 Has received any investigational medication within 30 days before the first infusion of study drug or is scheduled to receive any investigational drug other than BMN 190 during the course of the study Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's well being, safety, or clinical interpretability Pregnancy any time during the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Jacoby
Organizational Affiliation
BioMarin Pharmaceutical
Official's Role
Study Director
Facility Information:
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
University Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Bambino Gesù Children's Hospital
City
Rome
ZIP/Postal Code
00165
Country
Italy
Facility Name
Guy's & St. Thomas NHS Foundation Trust
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
Great Ormond Street Hospital for NHS Foundation Trust
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33980287
Citation
Gissen P, Specchio N, Olaye A, Jain M, Butt T, Ghosh W, Ruban-Fell B, Griffiths A, Camp C, Sisic Z, Schwering C, Wibbeler E, Trivisano M, Lee L, Nickel M, Mortensen A, Schulz A. Investigating health-related quality of life in rare diseases: a case study in utility value determination for patients with CLN2 disease (neuronal ceroid lipofuscinosis type 2). Orphanet J Rare Dis. 2021 May 12;16(1):217. doi: 10.1186/s13023-021-01829-x.
Results Reference
derived
PubMed Identifier
29688815
Citation
Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 May 17;378(20):1898-1907. doi: 10.1056/NEJMoa1712649. Epub 2018 Apr 24.
Results Reference
derived

Learn more about this trial

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

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