Batten Disease
Conditions
Keywords
Batten disease, CLN3, treatment, miglustat, safety
Brief summary
This is an open label study in approximately 6 subjects in 2 centers to assess the safety, PK, and efficacy of the maximum tolerable dose (MTD) of oral miglustat (100 mg once daily \[QD\] to 200 mg 3 times daily \[TID\]) in subjects ≥ 17 years of age with CLN3 disease over a period of 104 weeks.
Interventions
DRUGMiglustat 100 milligrams (mg) Oral Capsule
Subjects will initiate miglustat at Week 1 and dosing will be escalated until 600mg/d. If a subject has not reached the maximum dose (600 mg/d) by Week 8, the Week 8 dose will be subject's MTD.
Sponsors
Theranexus
Beyond Batten Disease Foundation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
17 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Individuals 1. Have provided informed consents (TCH and NIH) by subject or parent/legal guardian/legally authorized representative (as appropriate). 2. Are males or females ≥ 17 years of age at the time of screening 3. Have genetically confirmed diagnosis of syndromic CLN3 disease with EITHER: A. Two pathogenic mutations in the CLN3 gene, OR B. One confirmed pathogenic AND one variant of unknown significance, OR 2 variants of unknown significance, PLUS (+) secondary confirmation with evidence of characteristic inclusions on electron microscopy AND characteristic clinical course. There is no restriction on the specific CLN3 mutations for eligibility to enroll in the study. The mutations will be recorded in the electronic case report form (eCRF) for potential use in determining if CLN3 genotype is associated with tolerability and/or effectiveness of Beyond Batten Disease Foundation-1 (BBDF-1) (miglustat) therapy. 4. Male and female participants must use a highly effective method of contraception and must continue for the duration of the trial (and for 30 days after the end of treatment). 5. Are able to complete study assessments (subject or caregiver) and return to the clinic as scheduled
Exclusion criteria
Individuals 1. Have a medical condition that in the opinion of the PI would interfere with the safety assessments or increase the subject's risk of adverse events (AEs) 2. Use of any therapy (approved, off-label, or unapproved) intended to modify the course of any neuronal ceroid lipofuscinosis disease, including but not limited to flupirtine or flupirtine derivatives, cerliponase alfa (Brineura) 3. Have, in the opinion of the PI, a clinically significant abnormality in their clinical laboratory values (hematology, chemistry, or urinalysis) at screening that would preclude their participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-emergent Adverse Events. | 78 weeks | Number of treatment-emergent adverse events (TEAEs) assessed at all visits and phone calls, with severity classified according to CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Miglustat PK Parameter Tmax | 8 weeks | Time of Maximum concentration observed T max |
| Miglustat PK Parameter Area Under Curve (AUC) | 8 weeks | Area under the plasma concentration versus time curve Area Under Curve from pre-administration to 8 hours post-administration (AUC0-8hour). Blood draws were taken at the following time points: pre-miglustat dose (0), 1, 2, 2.5, 3, 4, 6, and 8 hours after 8 weeks of treatment. |
| Miglustat Pharmacokinetic (PK) Parameter Cmax | 8 weeks | Maximum plasma concentration Cmax |
| Clinical Efficacy Based on Unified Batten Disease Rating Scale Subscores | 78 weeks | Change from baseline of the modified Unified Batten Disease Rating Scale (UBDRS) Physical Assessment subscale (score from 0 to 112), specifically developed to assess motor symptoms in subjects with Batten Ceroid Lipofuscinosis, Neuronal 3 (CLN3) disease. Higher scores indicate more severe disease. |
| Clinical Efficacy With the Seizure Frequency | 78 weeks | Seizure frequency were to be assessed using a seizure diary |
| Miglustat PK Parameter T1/2 | 8 weeks | Miglustat elimination half life T1/2 |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at hospital. The first participant was recruited on 10 March 2022 and the last participant was recruited on 08 September 2022.
Pre-assignment details
Participants had their first enrolment visit to determine their eligibility, then a second visit within the next 42 days to confirm eligibility and perform baseline efficacy assessments. If eligibility was confirmed at the second visit, they started treatment within the next 15 days after this visit.
Participants by arm
| Arm | Count |
|---|---|
| Oral Miglustat The proposed dosing regimen is daily oral miglustat (MTD, up to 200 mg TID)
Miglustat 100Mg Oral Capsule: Participants initiated miglustat at Week 1 and dosing was to be escalated until 600mg/d. If a participant had not reached the maximum dose (600 mg/d) by Week 8, the Week 8 dose will be participant's MTD. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Oral Miglustat |
|---|---|
| Age, Continuous | 18.8 years STANDARD_DEVIATION 0.98 |
| Body Mass Index | 23.63 kilogram/meter square STANDARD_DEVIATION 4.74 |
| Body weight | 70.45 kilogram STANDARD_DEVIATION 6.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
Number of Treatment-emergent Adverse Events.
Number of treatment-emergent adverse events (TEAEs) assessed at all visits and phone calls, with severity classified according to CTCAE v5.0
Time frame: 78 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Miglustat | Number of Treatment-emergent Adverse Events. | 6 Participants |
Secondary
Clinical Efficacy Based on Unified Batten Disease Rating Scale Subscores
Change from baseline of the modified Unified Batten Disease Rating Scale (UBDRS) Physical Assessment subscale (score from 0 to 112), specifically developed to assess motor symptoms in subjects with Batten Ceroid Lipofuscinosis, Neuronal 3 (CLN3) disease. Higher scores indicate more severe disease.
Time frame: 78 weeks
Population: 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Miglustat | Clinical Efficacy Based on Unified Batten Disease Rating Scale Subscores | 1.76 units on a scale | Standard Deviation 4.96 |
Secondary
Clinical Efficacy With the Seizure Frequency
Seizure frequency were to be assessed using a seizure diary
Time frame: 78 weeks
Population: 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Miglustat | Clinical Efficacy With the Seizure Frequency | 1.83 number of seizures / 3 months | Standard Deviation 3.13 |
Secondary
Miglustat Pharmacokinetic (PK) Parameter Cmax
Maximum plasma concentration Cmax
Time frame: 8 weeks
Population: Descriptive statistical analyses were performed for miglustat plasma concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Miglustat | Miglustat Pharmacokinetic (PK) Parameter Cmax | 2870 ng/ml | Geometric Coefficient of Variation 35.2 |
Secondary
Miglustat PK Parameter Area Under Curve (AUC)
Area under the plasma concentration versus time curve Area Under Curve from pre-administration to 8 hours post-administration (AUC0-8hour). Blood draws were taken at the following time points: pre-miglustat dose (0), 1, 2, 2.5, 3, 4, 6, and 8 hours after 8 weeks of treatment.
Time frame: 8 weeks
Population: 6
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Miglustat | Miglustat PK Parameter Area Under Curve (AUC) | 19000 h*ng/ml | Geometric Coefficient of Variation 40.3 |
Secondary
Miglustat PK Parameter T1/2
Miglustat elimination half life T1/2
Time frame: 8 weeks
Population: 6
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Miglustat | Miglustat PK Parameter T1/2 | 7.59 hour | Geometric Coefficient of Variation 19 |
Secondary
Miglustat PK Parameter Tmax
Time of Maximum concentration observed T max
Time frame: 8 weeks
Population: 6
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Miglustat | Miglustat PK Parameter Tmax | 3.09 hour | Geometric Coefficient of Variation 44.1 |