Trial Outcomes & Findings for 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 (NCT NCT01907087)
NCT ID: NCT01907087
Last Updated: 2019-03-08
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
24 participants
Primary outcome timeframe
Baseline, Week 49/Last Assessment
Results posted on
2019-03-08
Participant Flow
Participant milestones
| Measure |
300 mg BMN 190
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.
|
|---|---|
|
Overall Study
STARTED
|
24
|
|
Overall Study
COMPLETED
|
23
|
|
Overall Study
NOT COMPLETED
|
1
|
Reasons for withdrawal
| Measure |
300 mg BMN 190
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.
|
|---|---|
|
Overall Study
Withdrawal by Subject
|
1
|
Baseline Characteristics
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
Baseline characteristics by cohort
| Measure |
300 mg BMN 190
n=24 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
Age, Continuous
|
4.3 years
STANDARD_DEVIATION 1.24 • n=5 Participants
|
|
Age, Customized
<=5 years
|
20 Participants
n=5 Participants
|
|
Age, Customized
>5 years
|
4 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
15 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
9 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
1 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
23 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
1 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
0 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
23 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Other
|
0 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Baseline, Week 49/Last AssessmentPopulation: Intent to Treat (ITT) Population : all study subjects receiving \> 1 dose
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.
Outcome measures
| Measure |
300 mg BMN 190
n=23 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
Motor-Language (ML) Scale Score During 300 mg Dosing Period
Baseline
|
3.5 units on a scale
Standard Deviation 1.2
|
|
Motor-Language (ML) Scale Score During 300 mg Dosing Period
Last Recorded Observation
|
3.1 units on a scale
Standard Deviation 1.41
|
|
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
|
SECONDARY outcome
Timeframe: Baseline, Week 49Population: ITT Population
Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period
Outcome measures
| Measure |
300 mg BMN 190
n=23 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
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
|
SECONDARY outcome
Timeframe: Baseline, Week 49Population: ITT Population
Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period
Outcome measures
| Measure |
300 mg BMN 190
n=23 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
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 outcome
Timeframe: Baseline, Week 49Population: ITT Population
Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period
Outcome measures
| Measure |
300 mg BMN 190
n=23 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
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 outcome
Timeframe: Baseline, Week 49Population: ITT Population
Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period
Outcome measures
| Measure |
300 mg BMN 190
n=23 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
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 outcome
Timeframe: Baseline, Week 49Population: ITT Population
Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period
Outcome measures
| Measure |
300 mg BMN 190
n=23 Participants
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
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
|
Adverse Events
300 mg BMN 190
Serious events: 16 serious events
Other events: 24 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
300 mg BMN 190
n=24 participants at risk
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
Gastrointestinal disorders
Dental caries
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
General disorders
Pyrexia
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Immune system disorders
Hypersensitivity
|
25.0%
6/24 • Number of events 8 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Clostridium difficile colitis
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Gastroenteritis
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Influenza
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Pharyngitis
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Pharyngitis bacterial
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Pneumonia
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Propionibacterium infection
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Rhinovirus infection
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Viral pharyngitis
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Injury, poisoning and procedural complications
Infusion related reaction
|
4.2%
1/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Injury, poisoning and procedural complications
Subdural haematoma
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Epilepsy
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Haemorrhage intracranial
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Hemiparesis
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Motor dysfunction
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Reproductive system and breast disorders
Vaginal discharge
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
|
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome
|
4.2%
1/24 • Number of events 1 • Full study period, a mean of 49 weeks
|
Other adverse events
| Measure |
300 mg BMN 190
n=24 participants at risk
Intracerebroventricular (ICV) infusion every two weeks.
|
|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Cardiac disorders
Bradycardia
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Gastrointestinal disorders
Abdominal pain
|
8.3%
2/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Gastrointestinal disorders
Constipation
|
29.2%
7/24 • Number of events 10 • Full study period, a mean of 49 weeks
|
|
Gastrointestinal disorders
Diarrhoea
|
16.7%
4/24 • Number of events 5 • Full study period, a mean of 49 weeks
|
|
Gastrointestinal disorders
Dysphagia
|
16.7%
4/24 • Number of events 6 • Full study period, a mean of 49 weeks
|
|
Gastrointestinal disorders
Toothache
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Gastrointestinal disorders
Vomiting
|
45.8%
11/24 • Number of events 20 • Full study period, a mean of 49 weeks
|
|
General disorders
Developmental delay
|
12.5%
3/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
General disorders
Feeling jittery
|
8.3%
2/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
General disorders
Gait disturbance
|
29.2%
7/24 • Number of events 7 • Full study period, a mean of 49 weeks
|
|
General disorders
Needle issue
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
General disorders
Pyrexia
|
54.2%
13/24 • Number of events 87 • Full study period, a mean of 49 weeks
|
|
Immune system disorders
Hypersensitivity
|
16.7%
4/24 • Number of events 6 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Conjunctivitis
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Gastroenteritis
|
16.7%
4/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Nasopharyngitis
|
29.2%
7/24 • Number of events 9 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Oral herpes
|
8.3%
2/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Pharyngitis
|
20.8%
5/24 • Number of events 6 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Respiratory tract infection
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Rhinitis
|
20.8%
5/24 • Number of events 7 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Tonsillitis
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Upper respiratory tract infection
|
41.7%
10/24 • Number of events 17 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Urinary tract infection
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Infections and infestations
Viral infection
|
20.8%
5/24 • Number of events 7 • Full study period, a mean of 49 weeks
|
|
Injury, poisoning and procedural complications
Fall
|
25.0%
6/24 • Number of events 11 • Full study period, a mean of 49 weeks
|
|
Injury, poisoning and procedural complications
Head injury
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Injury, poisoning and procedural complications
Laceration
|
8.3%
2/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Injury, poisoning and procedural complications
Procedural pain
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Investigations
CSF test abnormal
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Metabolism and nutrition disorders
Decreased appetite
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Atonic seizures
|
8.3%
2/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Drop attacks
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Dystonia
|
16.7%
4/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Epilepsy
|
45.8%
11/24 • Number of events 87 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Extensor plantar response
|
16.7%
4/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Generalised tonic-clonic seizure
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Headache
|
12.5%
3/24 • Number of events 7 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Hypotonia
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Language disorder
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Myoclonus
|
29.2%
7/24 • Number of events 14 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Partial seizures
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Petit mal epilepsy
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Pleocytosis
|
12.5%
3/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Seizure
|
58.3%
14/24 • Number of events 110 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Seizure cluster
|
8.3%
2/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Nervous system disorders
Tremor
|
16.7%
4/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Psychiatric disorders
Abnormal behaviour
|
12.5%
3/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Psychiatric disorders
Agitation
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
|
Psychiatric disorders
Insomnia
|
16.7%
4/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Psychiatric disorders
Irritability
|
16.7%
4/24 • Number of events 5 • Full study period, a mean of 49 weeks
|
|
Psychiatric disorders
Sleep disorder
|
12.5%
3/24 • Number of events 4 • Full study period, a mean of 49 weeks
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
20.8%
5/24 • Number of events 8 • Full study period, a mean of 49 weeks
|
|
Skin and subcutaneous tissue disorders
Dermatitis contact
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Skin and subcutaneous tissue disorders
Rash
|
8.3%
2/24 • Number of events 3 • Full study period, a mean of 49 weeks
|
|
Skin and subcutaneous tissue disorders
Urticaria
|
8.3%
2/24 • Number of events 2 • Full study period, a mean of 49 weeks
|
Additional Information
Peter Slasor/Sr Director, Biostatistics, Global Clinical Sciences
BioMarin Pharmaceutical Inc.
Phone: 415-506-6765
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60