Adult Refractory Complex Partial Seizures
Conditions
Keywords
Vigabatrin-associated vision change, Adult refractory complex partial seizures, CPS, Epilepsy, Seizures, Brain diseases, Central Nervous System Diseases, Nervous System Diseases, Neurologic Manifestations, Enzyme Inhibitors, GABA Agents
Brief summary
The purpose of the study is to evaluate the change in visual fields by means of automated static perimetry and to evaluate the change in retinal structure by means of spectral domain optical coherence tomography (SD-OCT) in adult patients with refractory complex partial seizures (CPS) being treated with vigabatrin (Sabril®)
Detailed description
Multicenter, prospective open-label study with approximately 25 sites in the US that specialize in caring for adult patients with refractory CPS * Sites must have access to Humphrey static perimetry and to Spectralis SD-OCT. * All vision test results will be sent to the central readers for evaluation. * Additional study tests: * The Columbia Suicide Severity Rating Scale (C-SSRS) * The National Eye Institute Visual Field Questionnaire-39 (NEI VFQ-39) * A whole blood sample for specific analysis of DNA characteristics * An optional whole blood sample for exploratory analysis of DNA characteristics * Plasma samples for bioanalytical analysis of vigabatrin and blood samples for taurine biomarker analysis
Interventions
DRUGSabril
Sabril: 500 mg tablets, orally. Physicians will dose their patients according to guidance provided in the product label.
Sponsors
Lundbeck LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Important Inclusion Criteria: 1. The patient speaks English or Spanish. 2. The patient has had no prior exposure to Sabril. 3. To begin Sabril therapy for the treatment of CPS. 4. Male or female ≥18 years of age. 5. The patient has refractory CPS: 1. The patient has complex partial epilepsy of more than 1 year duration and no other seizure type within the past year except for partial seizures secondarily generalized. 2. The patient has failed because of lack of efficacy 3 or more prior or concurrent treatment trials including 3 or more anti-epileptic drugs (AEDs) of differing pharmacologic mechanisms administered as monotherapy or polytherapy. 3. The patient is taking at least 1 AED. A vagal nerve stimulator is not counted as an AED. 4. The patient reports an average of 2 or more seizures per month averaged over the prior 3 months. 6. The patient is deemed by the treating neurologist and ophthalmologist to be able to reliably complete perimetry testing. 7. The initial (Visit 1) SD-OCT and static perimetry readings tests must be performed and assessed for technical adequacy by the SD-OCT and perimetry central readers prior to the first dose of Sabril. The initial (Visit 1) tangent corner test must be performed prior to the first dose of Sabril.
Exclusion criteria
1. Prior exposure to Sabril. 2. Pre-existing ocular or neurological disease that might affect bilateral visual fields or interfere with perimetry (e.g., aphakia, visually significant cataract, glaucoma, diabetes mellitus, ischemic optic neuropathy, multiple sclerosis). Patients with stable visual field defects from CNS lesions (e.g., epilepsy surgery more than 6 months prior to receiving Sabril) may be enrolled. 3. Concurrent exposure to medications with known or suspected retinal or optic nerve toxicity. 4. Concurrent use of an investigational agent or device or such use within 30 days of entering the study. 5. Concurrent use of the ketogenic or similar diet. 6. For any reason, the patient is considered by the investigator to be an unsuitable candidate for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | Baseline (Month 0), Month 3, Month 6, Month 9, Month 12 | Mean change from the reference value in 30-2 SITA mean deviation, which was generated using the University of Iowa Visual Field Reading Center (VFRC) normative database and the Humphrey Field Analyzer (HFA) normative database. The reference value was defined as the average of the assessments performed at Visits 1 (baseline), 2 and 3 (first month of dosing). The mean change from the reference value are presented for Months 3, 6, 9 and 12. A negative change from the reference value indicates a decrease in the central visual field. |
| Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Baseline (Month 0), Month 3, Month 6, Month 9, Month 12 | Mean change from the reference value in average RNFL thickness (µm) as measured by SD-OCT. The reference value was defined as the average of the assessments performed at Visits 1 (baseline), 2 and 3 (first month of dosing). Thinning of the RNFL, that is, a negative change from the reference value, has been associated with ophthalmological disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sabril Vigabatrin, 500 mg tablets, orally. Physicians will dose their patients according to guidance provided in the product label. | 65 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative or other reason | 4 |
| Overall Study | Adverse Event | 8 |
| Overall Study | Lack of Efficacy | 13 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Sabril |
|---|---|
| Age, Continuous | 39.8 years STANDARD_DEVIATION 12.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 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 | 58 Participants |
| Region of Enrollment United States | 65 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 65 |
| serious Total, serious adverse events | 9 / 65 |
Outcome results
Primary
Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography)
Mean change from the reference value in average RNFL thickness (µm) as measured by SD-OCT. The reference value was defined as the average of the assessments performed at Visits 1 (baseline), 2 and 3 (first month of dosing). Thinning of the RNFL, that is, a negative change from the reference value, has been associated with ophthalmological disease.
Time frame: Baseline (Month 0), Month 3, Month 6, Month 9, Month 12
Population: All patients who had received at least one dose of IMP and who had a valid reference value assessment and at least one valid post-reference value assessment. The total number of patients included in the analysis set was 55. The actual number of patients analysed for each time point and eye is presented below (N = x).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Left eye, 3 months (N=54) | 0.70 µm | Standard Deviation 2.56 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Left eye, 6 months (N=48) | 4.15 µm | Standard Deviation 4.72 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Left eye, 9 months (N=44) | 5.63 µm | Standard Deviation 4.3 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Left eye, 12 months (N=39) | 6.45 µm | Standard Deviation 4.81 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Right eye, 3 months (N=52) | 0.73 µm | Standard Deviation 2.2 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Right eye, 6 months (N=47) | 4.21 µm | Standard Deviation 3.75 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Right eye, 9 months (N=43) | 6.50 µm | Standard Deviation 4.67 |
| Sabril | Change From Reference Value in Average RNFL (Retinal Nerve Fiber Layer) Thickness (µm) as Measured by SD-OCT (Spectral Domain-Optical Coherence Tomography) | Right eye, 12 months (N=39) | 7.19 µm | Standard Deviation 4.88 |
Primary
Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB)
Mean change from the reference value in 30-2 SITA mean deviation, which was generated using the University of Iowa Visual Field Reading Center (VFRC) normative database and the Humphrey Field Analyzer (HFA) normative database. The reference value was defined as the average of the assessments performed at Visits 1 (baseline), 2 and 3 (first month of dosing). The mean change from the reference value are presented for Months 3, 6, 9 and 12. A negative change from the reference value indicates a decrease in the central visual field.
Time frame: Baseline (Month 0), Month 3, Month 6, Month 9, Month 12
Population: All patients who had received at least one dose of investigational medicinal product and who had a valid reference value assessment and at least one valid post-reference value assessment. The total number of patients included in the analysis set was 55. The actual number of patients analysed for each time point and eye is presented below (N = x).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Left eye, 3 months (N=50) | -0.28 dB | Standard Deviation 1.06 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Left eye, 6 months (N=45) | -0.24 dB | Standard Deviation 1.13 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Left eye, 9 months (N=39) | -0.14 dB | Standard Deviation 1.72 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Left eye, 12 months (N=36) | -0.13 dB | Standard Deviation 1.58 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Right eye, 3 months (N=50) | 0.08 dB | Standard Deviation 1.2 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Right eye, 6 months (N=45) | -0.11 dB | Standard Deviation 1.4 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Right eye, 9 months (N=39) | 0.02 dB | Standard Deviation 1.36 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | VFRC database: Right eye, 12 months (N=36) | -0.27 dB | Standard Deviation 1.61 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Left eye, 3 months (N=51) | -0.32 dB | Standard Deviation 1.13 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Left eye, 6 months (N=45) | -0.37 dB | Standard Deviation 1.15 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Left eye, 9 months (N=40) | -0.33 dB | Standard Deviation 1.61 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Left eye, 12 months (N=37) | -0.15 dB | Standard Deviation 1.68 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Right eye, 3 months (N=51) | 0.00 dB | Standard Deviation 1.18 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Right eye, 6 months (N=45) | -0.23 dB | Standard Deviation 1.4 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Right eye, 9 months (N=40) | -0.07 dB | Standard Deviation 1.33 |
| Sabril | Mean Change From Reference Value in Field Width as Measured by 30-2 SITA Fast in Field Sensitivity (Mean Deviation - MD in dB) | HFA database: Right eye, 12 months (N=37) | -0.47 dB | Standard Deviation 1.6 |