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Trial record 14 of 25 for:    Child | "congenital neuronal ceroid lipofuscinosis" OR "Neuronal Ceroid-Lipofuscinoses"

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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ClinicalTrials.gov Identifier: NCT01907087
Recruitment Status : Completed
First Posted : July 24, 2013
Results First Posted : June 11, 2018
Last Update Posted : June 11, 2018
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Jansky-Bielschowsky Disease
Batten Disease
Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2
CLN2 Disease
Intervention Biological: BMN 190
Enrollment 24

Recruitment Details  
Pre-assignment Details  
Arm/Group Title 300 mg BMN 190
Hide 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
Reason Not Completed
Withdrawal by Subject             1
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Baseline Participants 24
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants
4.3  (1.24)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
<=5 years
20
  83.3%
>5 years
4
  16.7%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
Female
15
  62.5%
Male
9
  37.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
Hispanic or Latino
1
   4.2%
Not Hispanic or Latino
23
  95.8%
Unknown or Not Reported
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   4.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
23
  95.8%
Other
0
   0.0%
1.Primary Outcome
Title Motor-Language (ML) Scale Score During 300 mg Dosing Period
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to Treat (ITT) Population : all study subjects receiving > 1 dose
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description:
Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Participants Analyzed 23
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline 3.5  (1.2)
Last Recorded Observation 3.1  (1.41)
Change from Baseline to Last Recorded Observation -0.4  (0.84)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Method exact binomial test
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion of responders
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.66 to 0.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
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 [Not Specified]
2.Secondary Outcome
Title Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume
Hide Description Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period
Time Frame Baseline, Week 49
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description:
Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Participants Analyzed 23
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period
Time Frame Baseline, Week 49
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description:
Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Participants Analyzed 23
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period
Time Frame Baseline, Week 49
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description:
Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Participants Analyzed 23
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period
Time Frame Baseline, Week 49
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description:
Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Participants Analyzed 23
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period
Time Frame Baseline, Week 49
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description:
Intracerebroventricular (ICV) infusion every two weeks.
Overall Number of Participants Analyzed 23
Mean (Standard Deviation)
Unit of Measure: percentage change from baseline
0.02  (0.023)
Time Frame Full study period, a mean of 49 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title 300 mg BMN 190
Hide Arm/Group Description Intracerebroventricular (ICV) infusion every two weeks.
All-Cause Mortality
300 mg BMN 190
Affected / at Risk (%)
Total   0/24 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
300 mg BMN 190
Affected / at Risk (%) # Events
Total   16/24 (66.67%)    
Gastrointestinal disorders   
Dental caries  1  1/24 (4.17%)  1
General disorders   
Pyrexia  1  2/24 (8.33%)  2
Immune system disorders   
Hypersensitivity  1  6/24 (25.00%)  8
Infections and infestations   
Clostridium difficile colitis  1  1/24 (4.17%)  1
Gastroenteritis  1  1/24 (4.17%)  1
Influenza  1  1/24 (4.17%)  1
Pharyngitis  1  1/24 (4.17%)  1
Pharyngitis bacterial  1  2/24 (8.33%)  2
Pneumonia  1  1/24 (4.17%)  1
Propionibacterium infection  1  1/24 (4.17%)  1
Rhinovirus infection  1  1/24 (4.17%)  1
Viral pharyngitis  1  1/24 (4.17%)  1
Injury, poisoning and procedural complications   
Infusion related reaction  1  1/24 (4.17%)  2
Subdural haematoma  1  1/24 (4.17%)  1
Nervous system disorders   
Epilepsy  1  2/24 (8.33%)  2
Haemorrhage intracranial  1  1/24 (4.17%)  1
Hemiparesis  1  1/24 (4.17%)  1
Motor dysfunction  1  1/24 (4.17%)  1
Reproductive system and breast disorders   
Vaginal discharge  1  1/24 (4.17%)  1
Respiratory, thoracic and mediastinal disorders   
Sleep apnoea syndrome  1  1/24 (4.17%)  1
1
Term from vocabulary, MedDRA 18.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
300 mg BMN 190
Affected / at Risk (%) # Events
Total   24/24 (100.00%)    
Blood and lymphatic system disorders   
Anaemia  1  2/24 (8.33%)  3
Cardiac disorders   
Bradycardia  1  2/24 (8.33%)  2
Gastrointestinal disorders   
Abdominal pain  1  2/24 (8.33%)  4
Constipation  1  7/24 (29.17%)  10
Diarrhoea  1  4/24 (16.67%)  5
Dysphagia  1  4/24 (16.67%)  6
Toothache  1  2/24 (8.33%)  2
Vomiting  1  11/24 (45.83%)  20
General disorders   
Developmental delay  1  3/24 (12.50%)  3
Feeling jittery  1  2/24 (8.33%)  4
Gait disturbance  1  7/24 (29.17%)  7
Needle issue  1  2/24 (8.33%)  2
Pyrexia  1  13/24 (54.17%)  87
Immune system disorders   
Hypersensitivity  1  4/24 (16.67%)  6
Infections and infestations   
Conjunctivitis  1  2/24 (8.33%)  2
Gastroenteritis  1  4/24 (16.67%)  4
Nasopharyngitis  1  7/24 (29.17%)  9
Oral herpes  1  2/24 (8.33%)  4
Pharyngitis  1  5/24 (20.83%)  6
Respiratory tract infection  1  2/24 (8.33%)  2
Rhinitis  1  5/24 (20.83%)  7
Tonsillitis  1  2/24 (8.33%)  3
Upper respiratory tract infection  1  10/24 (41.67%)  17
Urinary tract infection  1  2/24 (8.33%)  3
Viral infection  1  5/24 (20.83%)  7
Injury, poisoning and procedural complications   
Fall  1  6/24 (25.00%)  11
Head injury  1  2/24 (8.33%)  3
Laceration  1  2/24 (8.33%)  4
Procedural pain  1  2/24 (8.33%)  2
Investigations   
CSF test abnormal  1  2/24 (8.33%)  2
Metabolism and nutrition disorders   
Decreased appetite  1  2/24 (8.33%)  2
Nervous system disorders   
Atonic seizures  1  2/24 (8.33%)  4
Drop attacks  1  2/24 (8.33%)  2
Dystonia  1  4/24 (16.67%)  4
Epilepsy  1  11/24 (45.83%)  87
Extensor plantar response  1  4/24 (16.67%)  4
Generalised tonic-clonic seizure  1  2/24 (8.33%)  3
Headache  1  3/24 (12.50%)  7
Hypotonia  1  2/24 (8.33%)  2
Language disorder  1  2/24 (8.33%)  2
Myoclonus  1  7/24 (29.17%)  14
Partial seizures  1  2/24 (8.33%)  3
Petit mal epilepsy  1  2/24 (8.33%)  2
Pleocytosis  1  3/24 (12.50%)  3
Seizure  1  14/24 (58.33%)  110
Seizure cluster  1  2/24 (8.33%)  4
Tremor  1  4/24 (16.67%)  4
Psychiatric disorders   
Abnormal behaviour  1  3/24 (12.50%)  3
Agitation  1  2/24 (8.33%)  2
Insomnia  1  4/24 (16.67%)  4
Irritability  1  4/24 (16.67%)  5
Sleep disorder  1  3/24 (12.50%)  4
Respiratory, thoracic and mediastinal disorders   
Cough  1  5/24 (20.83%)  8
Skin and subcutaneous tissue disorders   
Dermatitis contact  1  2/24 (8.33%)  3
Rash  1  2/24 (8.33%)  3
Urticaria  1  2/24 (8.33%)  2
1
Term from vocabulary, MedDRA 18.1
Indicates events were collected by systematic assessment
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Peter Slasor/Sr Director, Biostatistics, Global Clinical Sciences
Organization: BioMarin Pharmaceutical Inc.
Phone: 415-506-6765
Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT01907087     History of Changes
Other Study ID Numbers: 190-201
First Submitted: July 19, 2013
First Posted: July 24, 2013
Results First Submitted: February 15, 2018
Results First Posted: June 11, 2018
Last Update Posted: June 11, 2018