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

• Sponsor: BioMarin Pharmaceutical (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01907087
• Collaborator: (none)
• Enrollment: 24
• Locations: 5
• Arm: 1
• Duration (Months): 26
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Jansky-Bielschowsky Disease; Batten Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2; CLN2 Disease	Biological: BMN 190	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Sep 1, 2013
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa)	Biological: BMN 190; 30-300 mg ICV infusion administered every other week for at least 48 weeks.; Other Names: recombinant human tripeptidyl peptidase-1 (rhTPP1) cerliponase alfa

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 15 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
2	University Hamburg-Eppendorf	Hamburg		Germany	20246
3	Bambino Gesù Children's Hospital	Rome		Italy	00165
4	Guy's & St. Thomas NHS Foundation Trust	London		United Kingdom	SE1 7EH
5	Great Ormond Street Hospital for NHS Foundation Trust	London		United Kingdom	WC1N 3JH

Sponsors and Collaborators

• BioMarin Pharmaceutical

Investigators

• Study Director: David Jacoby, BioMarin Pharmaceutical

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: BioMarin Pharmaceutical
• ClinicalTrials.gov Identifier: NCT01907087
• Other Study ID Numbers: 190-201
• First Posted: Jul 24, 2013
• Last Update Posted: Mar 8, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by BioMarin Pharmaceutical: Late infantile Neuronal Ceroid Lipofuscinosis Type 2; LINCL; NCL2; CLN2; Jansky-Bielschowsky disease
• Additional relevant MeSH terms: Neuronal Ceroid-Lipofuscinoses

Study Results

Participant Flow

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks. This is a study of a single cohort followed for at least 48 weeks at dosing of 300 mg. Subjects 1, 2, and 3 were initially assigned to the 30 mg dose, then escalated to 100 mg (and subsequently 300 mg) after data review. Subjects 4, 5, and 6 were initially assigned to the 100 mg dose, then escalated to 300 mg after data review. Subjects 7, 8 and 9 were initially assigned to the 300 mg dose. One patient withdrew after one dose due to unwillingness to comply with study procedures, requiring the addition of a 10th patient to this group. DMC approved full recruitment at the 300 mg dose (n=24) after data review.
Period Title: Overall Study
STARTED	24
COMPLETED	23
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Overall Participants	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.3 (1.24)
Age, Customized (Count of Participants)
<=5 years	20 83.3%
>5 years	4 16.7%
Sex: Female, Male (Count of Participants)
Female	15 62.5%
Male	9 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.2%
Not Hispanic or Latino	23 95.8%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	23 95.8%
Other	0 0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population : all study subjects receiving > 1 dose

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Measure Participants	23
Baseline	3.5 (1.2)
Last Recorded Observation	3.1 (1.41)
Change from Baseline to Last Recorded Observation	-0.4 (0.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	300 mg BMN 190
	Comments	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.
	Type of Statistical Test	Other
	Comments	Inference is by an exact binomial test of the null hypothesis H0: Prob(response) <= 0.50 vs. the alternative hypothesis H1: Prob(response) > 0.50, where Prob(response) denotes the population probability of a response. The confidence interval is an exact interval with significance level α=0.05.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	exact binomial test
	Comments
Method of Estimation	Estimation Parameter	Proportion of responders
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.66 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	300 mg BMN 190
	Comments	Slopes Analysis using ITT Population: Estimated Rate of Decline (300 mg Dosing Period).
	Type of Statistical Test	Other
	Comments	Subject rate of decline per 48 weeks is estimated: (baseline CLN2 score - last CLN2 score)/(time elapsed in units of 48 weeks). P-value computed as a two-sided t-test for the hypothesis H0: Rate=2.0 points lost/48 weeks vs. H1: Rate not equal 2.0 points lost/48 weeks.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.75
	Parameter Dispersion	Type: Standard Deviation; Value: 0.809
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Measure Participants	23
Mean (Standard Deviation) [percentage change from baseline]	-4.4 (8.46)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Measure Participants	23
Mean (Standard Deviation) [percentage change from baseline]	-9.7 (8.08)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Measure Participants	23
Mean (Standard Deviation) [percentage change from baseline]	-4.2 (9.58)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Measure Participants	23
Mean (Standard Deviation) [percentage change from baseline]	3.6 (15.3)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
Measure Participants	23
Mean (Standard Deviation) [percentage change from baseline]	0.02 (0.023)

Adverse Events

Time Frame	Full study period, a mean of 49 weeks
Arm/Group Title	300 mg BMN 190
Arm/Group Description	Intracerebroventricular (ICV) infusion every two weeks.
All Cause Mortality
	300 mg BMN 190
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Serious Adverse Events
	300 mg BMN 190
	Affected / at Risk (%)	# Events
Total	16/24 (66.7%)
Gastrointestinal disorders
Dental caries	1/24 (4.2%)	1
General disorders
Pyrexia	2/24 (8.3%)	2
Immune system disorders
Hypersensitivity	6/24 (25%)	8
Infections and infestations
Clostridium difficile colitis	1/24 (4.2%)	1
Gastroenteritis	1/24 (4.2%)	1
Influenza	1/24 (4.2%)	1
Pharyngitis	1/24 (4.2%)	1
Pharyngitis bacterial	2/24 (8.3%)	2
Pneumonia	1/24 (4.2%)	1
Propionibacterium infection	1/24 (4.2%)	1
Rhinovirus infection	1/24 (4.2%)	1
Viral pharyngitis	1/24 (4.2%)	1
Injury, poisoning and procedural complications
Infusion related reaction	1/24 (4.2%)	2
Subdural haematoma	1/24 (4.2%)	1
Nervous system disorders
Epilepsy	2/24 (8.3%)	2
Haemorrhage intracranial	1/24 (4.2%)	1
Hemiparesis	1/24 (4.2%)	1
Motor dysfunction	1/24 (4.2%)	1
Reproductive system and breast disorders
Vaginal discharge	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	300 mg BMN 190
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
Anaemia	2/24 (8.3%)	3
Cardiac disorders
Bradycardia	2/24 (8.3%)	2
Gastrointestinal disorders
Abdominal pain	2/24 (8.3%)	4
Constipation	7/24 (29.2%)	10
Diarrhoea	4/24 (16.7%)	5
Dysphagia	4/24 (16.7%)	6
Toothache	2/24 (8.3%)	2
Vomiting	11/24 (45.8%)	20
General disorders
Developmental delay	3/24 (12.5%)	3
Feeling jittery	2/24 (8.3%)	4
Gait disturbance	7/24 (29.2%)	7
Needle issue	2/24 (8.3%)	2
Pyrexia	13/24 (54.2%)	87
Immune system disorders
Hypersensitivity	4/24 (16.7%)	6
Infections and infestations
Conjunctivitis	2/24 (8.3%)	2
Gastroenteritis	4/24 (16.7%)	4
Nasopharyngitis	7/24 (29.2%)	9
Oral herpes	2/24 (8.3%)	4
Pharyngitis	5/24 (20.8%)	6
Respiratory tract infection	2/24 (8.3%)	2
Rhinitis	5/24 (20.8%)	7
Tonsillitis	2/24 (8.3%)	3
Upper respiratory tract infection	10/24 (41.7%)	17
Urinary tract infection	2/24 (8.3%)	3
Viral infection	5/24 (20.8%)	7
Injury, poisoning and procedural complications
Fall	6/24 (25%)	11
Head injury	2/24 (8.3%)	3
Laceration	2/24 (8.3%)	4
Procedural pain	2/24 (8.3%)	2
Investigations
CSF test abnormal	2/24 (8.3%)	2
Metabolism and nutrition disorders
Decreased appetite	2/24 (8.3%)	2
Nervous system disorders
Atonic seizures	2/24 (8.3%)	4
Drop attacks	2/24 (8.3%)	2
Dystonia	4/24 (16.7%)	4
Epilepsy	11/24 (45.8%)	87
Extensor plantar response	4/24 (16.7%)	4
Generalised tonic-clonic seizure	2/24 (8.3%)	3
Headache	3/24 (12.5%)	7
Hypotonia	2/24 (8.3%)	2
Language disorder	2/24 (8.3%)	2
Myoclonus	7/24 (29.2%)	14
Partial seizures	2/24 (8.3%)	3
Petit mal epilepsy	2/24 (8.3%)	2
Pleocytosis	3/24 (12.5%)	3
Seizure	14/24 (58.3%)	110
Seizure cluster	2/24 (8.3%)	4
Tremor	4/24 (16.7%)	4
Psychiatric disorders
Abnormal behaviour	3/24 (12.5%)	3
Agitation	2/24 (8.3%)	2
Insomnia	4/24 (16.7%)	4
Irritability	4/24 (16.7%)	5
Sleep disorder	3/24 (12.5%)	4
Respiratory, thoracic and mediastinal disorders
Cough	5/24 (20.8%)	8
Skin and subcutaneous tissue disorders
Dermatitis contact	2/24 (8.3%)	3
Rash	2/24 (8.3%)	3
Urticaria	2/24 (8.3%)	2

Limitations/Caveats

10 subjects were assigned in 1 of 3 cohorts in Dose Escalation Period for a 4-22 weeks treatment of 30, 100, and/or 300 mg. 9 subjects completing the Dose Escalation Period, plus 14 new subjects, were administered a stable dose of 300mg for 48 weeks.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.