Batten Disease, CLN2 Disease, Jansky-Bielschowsky Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2
Conditions
Keywords
Late infantile Neuronal Ceroid Lipofuscinosis Type 2, LINCL, NCL2, CLN2, Jansky-Bielschowsky disease
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.
Interventions
BIOLOGICALBMN 190
30-300 mg ICV infusion administered every other week for at least 48 weeks.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 15 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Motor-Language (ML) Scale Score During 300 mg Dosing Period | Baseline, Week 49/Last Assessment | 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume | Baseline, Week 49 | 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 | Baseline, Week 49 | 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 | Baseline, Week 49 | 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 | Baseline, Week 49 | 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 | Baseline, Week 49 | Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period |
Countries
Germany, Italy, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 300 mg BMN 190 Intracerebroventricular (ICV) infusion every two weeks. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | 300 mg BMN 190 |
|---|---|
| Age, Continuous | 4.3 years STANDARD_DEVIATION 1.24 |
| Age, Customized <=5 years | 20 Participants |
| Age, Customized >5 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized White | 23 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 16 / 24 |
Outcome results
Primary
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.
Time frame: Baseline, Week 49/Last Assessment
Population: Intent to Treat (ITT) Population : all study subjects receiving \> 1 dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 300 mg BMN 190 | Motor-Language (ML) Scale Score During 300 mg Dosing Period | Baseline | 3.5 units on a scale | Standard Deviation 1.2 |
| 300 mg BMN 190 | Motor-Language (ML) Scale Score During 300 mg Dosing Period | Last Recorded Observation | 3.1 units on a scale | Standard Deviation 1.41 |
| 300 mg BMN 190 | Motor-Language (ML) Scale Score During 300 mg Dosing Period | Change from Baseline to Last Recorded Observation | -0.4 units on a scale | Standard Deviation 0.84 |
Comparison: Responder Analysis using ITT Population: Proportion of Subjects without an Unreversed Two-point Decline or Score of 0 in ML Scale Score at 48 Weeks.~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.p-value: 0.000295% CI: [0.66, 0.97]exact binomial test
Comparison: Slopes Analysis using ITT Population: Estimated Rate of Decline (300 mg Dosing Period).p-value: <0.000195% CI: [0.05, 0.75]t-test, 2 sided
Secondary
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
Time frame: Baseline, Week 49
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 300 mg BMN 190 | Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume | -4.2 percentage change from baseline | Standard Deviation 9.58 |
Secondary
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
Time frame: Baseline, Week 49
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 300 mg BMN 190 | Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid | 3.6 percentage change from baseline | Standard Deviation 15.3 |
Secondary
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
Time frame: Baseline, Week 49
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 300 mg BMN 190 | Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter | -9.7 percentage change from baseline | Standard Deviation 8.08 |
Secondary
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
Time frame: Baseline, Week 49
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 300 mg BMN 190 | Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient | 0.02 percentage change from baseline | Standard Deviation 0.023 |
Secondary
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
Time frame: Baseline, Week 49
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 300 mg BMN 190 | Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume | -4.4 percentage change from baseline | Standard Deviation 8.46 |