Epilepsy
Conditions
Keywords
Epilepsy, Responsive neurostimulation, RNS System, NeuroPace, Brain stimulation, Seizures
Brief summary
The RNS® System LTT study is designed to assess the ongoing safety and to evaluate the long-term efficacy of the RNS® System as an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures that are refractory to two or more antiepileptic medications. Candidates will continue to receive their epilepsy medications while participating in the trial.
Detailed description
NeuroPace, Inc. is sponsoring an investigational device study of the RNS® System, the first closed loop responsive brain stimulator designed to treat refractory epilepsy. The RNS® System LTT study is an open-label multi-center prospective 7-year clinical investigation which follows completion of the RNS® System Pivotal or Feasibility study. Data regarding safety and efficacy are collected at 6-month intervals, and data regarding quality of life are collected at yearly intervals. The study is designed to assess the ongoing safety and to evaluate the long-term efficacy of the RNS® System as an adjunctive therapy in reducing the frequency of medically uncontrolled and disabling partial onset seizures that start from one or two areas of the brain. The RNS® System LTT study will provide additional data on the safety and efficacy of the RNS® System for 7 years following a subject's completion of the RNS® System Feasibility or Pivotal studies. Data from the RNS® System LTT study will be combined with data collected during the RNS® System Feasibility and Pivotal studies, resulting in 9 total years of post-implant follow-up data. These data will be used to calculate long-term SAE rate, percent change in seizure frequency (from pre-implant baseline), as well as the frequency of sudden unexplained death in epilepsy (SUDEP). The RNS® Neurostimulator (a pacemaker-like device) and NeuroPace® Leads (tiny wires with electrodes) are implanted in the head. The Neurostimulator is a battery powered, microprocessor controlled device that detects and stores records of electrographic patterns (such as epileptiform, or seizure-like, activity) from the Leads within the brain. When the device detects an electrographic pattern, it responds by sending electrical stimulation through the Leads to a small part of the patient's brain to interrupt the electrographic pattern. This type of treatment is called responsive stimulation, but it is not yet known if it will work for the treatment of epilepsy. Direct brain stimulation therapy has already received approval in the United States, Europe, Canada, and Australia for the treatment of Essential Tremor and Parkinson's disease. Direct brain stimulation is not approved for the treatment of epilepsy.
Interventions
DEVICERNS® System
The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Sponsors
NeuroPace
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject has completed either the RNS® System Pivotal or Feasibility study 2. Subject has an implanted RNS® System 3. Subject has elected to continue to receive responsive neurostimulation therapy after completion of the RNS® System Pivotal or Feasibility study 4. Subject is able to attend scheduled appointments for the RNS® System LTT study
Exclusion criteria
1. Subject has active psychiatric or medical illness that makes it inadvisable for the subject to continue to receive responsive neurostimulation therapy with the RNS® System 2. Subject has been diagnosed with psychogenic or non-epileptic seizures, or primarily generalized seizures during the RNS® System Pivotal or Feasibility study 3. Subject has been noncompliant with scheduled appointments during the RNS® System Pivotal or Feasibility study 4. Subject has been noncompliant with maintaining seizure diaries during the RNS® System Pivotal or Feasibility study 5. Informed consent cannot be obtained from subject or caregiver
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAE) | 2 years post-implant through 9 years post-implant (7 years) | The number of subjects having an SAE during the RNS® System LTT study. |
| Percentage Change From Baseline in Seizure Frequency | 6 months post-implant through 9 years post-implant (8.5 years) | The average percentage change in the mean frequency of total disabling seizures relative to pre-implant baseline. The percent change will be calculated for each subject over 6-month intervals beginning 6 months after RNS® System implant and continuing through completion of the RNS® System LTT study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responder Rate | 6 months post-implant through 9 years post-implant (8.5 years) | The proportion of subjects with greater than or equal to 50% reduction in total disabling seizures compared to pre-implant baseline. |
| QOLIE (Quality of Life in Epilepsy) | 1 year post-implant through 9 years post-implant (8 years) | QOLIE 89 (for English-speaking subjects) or QOLIE 31 P (for Spanish speaking subjects) scores collected at each year of follow-up after implantation of the RNS® System compared to the QOLIE 89 / QOLIE 31 P at pre-implant baseline. A QOLIE overall score was obtained using a weighted average of multi-item scale scores. The QOLIE overall score was converted to a T-score, a normally distributed scale with a mean score of 50 and standard deviation (SD) of 10. Higher scores reflect a better quality of life. |
| Adverse Event Rate | 6 months post-implant through 9 years post-implant (8.5 years) | The rate of occurrence of any adverse event (AE) observed during the Long-term Treatment Investigation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Evaluation Group (Stimulation ON) Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term.
RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day. | 230 |
| Total | 230 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 9 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Withdrawal by Subject | 50 |
Baseline characteristics
| Characteristic | Evaluation Group (Stimulation ON) | — |
|---|---|---|
| Age, Categorical <=18 years | 6 Participants | — |
| Age, Categorical >=65 years | 1 Participants | — |
| Age, Categorical Between 18 and 65 years | 223 Participants | — |
| Age, Continuous | 34.2 Years STANDARD_DEVIATION 11.4 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 230 participants | — |
| Sex: Female, Male Female | 115 Participants | — |
| Sex: Female, Male Male | 115 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 230 |
| other Total, other adverse events | 228 / 230 |
| serious Total, serious adverse events | 177 / 230 |
Outcome results
Primary
Number of Participants With Serious Adverse Events (SAE)
The number of subjects having an SAE during the RNS® System LTT study.
Time frame: 2 years post-implant through 9 years post-implant (7 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evaluation Group (Stimulation ON) | Number of Participants With Serious Adverse Events (SAE) | 177 Participants |
95% CI: [71.1, 81.9]
Primary
Percentage Change From Baseline in Seizure Frequency
The average percentage change in the mean frequency of total disabling seizures relative to pre-implant baseline. The percent change will be calculated for each subject over 6-month intervals beginning 6 months after RNS® System implant and continuing through completion of the RNS® System LTT study.
Time frame: 6 months post-implant through 9 years post-implant (8.5 years)
Population: N represents the number of subjects who have data during that period.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 6-12 Months | -31.5 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 12-18 Months | -46.2 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 18-24 Months | -46.7 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 24-30 Months | -50.3 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 30-36 Months | -58.3 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 36-42 Months | -61.1 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 42-48 Months | -61.7 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 48-54 Months | -60.5 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 54-60 Months | -63.1 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 60-66 Months | -65.4 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 66-72 Months | -67.7 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 72-78 Months | -71.0 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 78-84 Months | -72.8 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 84-90 Months | -69.7 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 90-96 Months | -73.1 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 96-102 Months | -72.1 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 102-108 Months | -74.5 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 108-114 Months | -85.9 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 114-120 Months | -77.7 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 120-126 Months | -94.1 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 126-132 Months | -86.1 Percentage of Change |
| Evaluation Group (Stimulation ON) | Percentage Change From Baseline in Seizure Frequency | 132-138 Months | -95.7 Percentage of Change |
p-value: <0.05Wilcoxon Signed Rank Test
Secondary
Adverse Event Rate
The rate of occurrence of any adverse event (AE) observed during the Long-term Treatment Investigation.
Time frame: 6 months post-implant through 9 years post-implant (8.5 years)
Population: N represents the number of subjects who have data during that period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Evaluation Group (Stimulation ON) | Adverse Event Rate | 228 Participants |
Secondary
QOLIE (Quality of Life in Epilepsy)
QOLIE 89 (for English-speaking subjects) or QOLIE 31 P (for Spanish speaking subjects) scores collected at each year of follow-up after implantation of the RNS® System compared to the QOLIE 89 / QOLIE 31 P at pre-implant baseline. A QOLIE overall score was obtained using a weighted average of multi-item scale scores. The QOLIE overall score was converted to a T-score, a normally distributed scale with a mean score of 50 and standard deviation (SD) of 10. Higher scores reflect a better quality of life.
Time frame: 1 year post-implant through 9 years post-implant (8 years)
Population: N represents the number of subjects who have data during that period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Baseline | 46.1 Score on a scale | Standard Deviation 9.7 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 1 | 49.2 Score on a scale | Standard Deviation 10.5 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 2 | 49.3 Score on a scale | Standard Deviation 10.3 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 3 | 48.8 Score on a scale | Standard Deviation 10.4 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 4 | 48.1 Score on a scale | Standard Deviation 10.6 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 5 | 48.4 Score on a scale | Standard Deviation 10.9 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 6 | 48.4 Score on a scale | Standard Deviation 11.7 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 7 | 47.4 Score on a scale | Standard Deviation 11 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 8 | 47.9 Score on a scale | Standard Deviation 11.3 |
| Evaluation Group (Stimulation ON) | QOLIE (Quality of Life in Epilepsy) | Year 9 | 47.2 Score on a scale | Standard Deviation 11.6 |
p-value: <0.000195% CI: [46.8, 49.2]Generalized estimating equation (GEE)
p-value: 0.672995% CI: [-0.2, 0.1]Generalized estimating equation (GEE)
Secondary
Responder Rate
The proportion of subjects with greater than or equal to 50% reduction in total disabling seizures compared to pre-implant baseline.
Time frame: 6 months post-implant through 9 years post-implant (8.5 years)
Population: N represents the number of subjects who have data during that period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evaluation Group (Stimulation ON) | Responder Rate | 48-54 Months | 60.2 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 6-12 Months | 33.2 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 12-18 Months | 46.7 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 18-24 Months | 47.6 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 24-30 Months | 50.2 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 30-36 Months | 56.4 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 36-42 Months | 57.8 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 42-48 Months | 61.2 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 54-60 Months | 61.1 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 60-66 Months | 58.4 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 66-72 Months | 67.0 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 72-78 Months | 66.9 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 78-84 Months | 65.7 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 84-90 Months | 64.9 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 90-96 Months | 70.2 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 96-102 Months | 68.5 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 102-108 Months | 70.9 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 108-114 Months | 74.5 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 114-120 Months | 66.7 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 120-126 Months | 75.0 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 126-132 Months | 83.3 Percentage of patients |
| Evaluation Group (Stimulation ON) | Responder Rate | 132-138 Months | 100.0 Percentage of patients |