RNS System Pivotal Trial
Responsive cortical stimulation for the treatment of medically intractable partial epilepsy
Year of Publication: 2011
Authors: Martha J. Morrell, on behalf of the RNS System in Epilepsy Study Group
Journal: Neurology
Citation: Neurology. 2011;77:1295-1304
Link: https://doi.org/10.1212/WNL.0b013e3182302056
PDF: https://seizure.mgh.harvard.edu/wp-conte...votal-trial.pdf
PDF: Clinical Question
Is responsive cortical stimulation safe and effective as adjunctive therapy for reducing partial onset seizures in adults with medically refractory epilepsy who have failed multiple AEDs and have 1-2 localized seizure foci?
Bottom Line
Responsive cortical stimulation significantly reduces disabling partial seizures (37.9% vs 17.3% reduction, P=0.012) in adults with medically intractable epilepsy, with sustained benefit at 2 years (46% responder rate), significant improvements in quality of life, and no adverse effects on mood or cognition. Safety was acceptable compared to alternative neurosurgical procedures. This provides Class I evidence supporting responsive neurostimulation as an adjunctive treatment option.
Major Points
- First randomized controlled trial of responsive cortical stimulation for partial epilepsy (Class I evidence)
- 191 adults implanted at 31 US centers; randomized 1:1 to treatment vs sham stimulation
- Primary endpoint achieved: 37.9% seizure reduction vs 17.3% sham during 12-week blinded period (P=0.012)
- Treatment effect increased over time during blinded period (month 3: 41.5% vs 9.4%, P=0.008)
- Transient implant effect observed in both groups during first postoperative month, resolving by month 5 in sham group
- Responder rate (≥50% reduction) at 1 year: 43% (n=177); at 2 years: 46% (n=102)
- 7.1% seizure-free over most recent 3 months at data cutoff
- Significant QOL improvements in both groups at end of blinded period (P=0.040 and P=0.032)
- SAE rate 12% at 28 days (not worse than 15% comparator); 18.3% at 84 days (not worse than 36% DBS comparator)
- No difference in neuropsychological function or mood between treatment and sham groups; improvements in cognition at 1-2 years
Design
Study Type: Multicenter, randomized, double-blind, sham-stimulation controlled trial with open-label extension
Randomization: 1
Blinding: Double-blind: Subject blinding maintained via sham programming sessions; blinded physician gathered outcome data, nonblinded physician managed neurostimulator; blinding index 0.572
Enrollment Period: December 2005 to November 2008
Follow-up Duration: 12-week blinded evaluation period (BEP) + 84-week open-label period (OLP); data cutoff June 4, 2010
Centers: 31
Countries: United States
Sample Size: 191
Analysis: Intent-to-treat; Generalized Estimating Equation (GEE) model with group-by-time interaction as primary endpoint variable, accounting for onset zone, number of seizure foci, and prior resection; Fisher exact test for AE comparisons; paired t-test for within-group changes; 2-sample t-test for between-group comparisons
Inclusion Criteria
- Age 18-70 years
- Partial onset seizures not controlled with ≥2 trials of AEDs
- ≥3 disabling seizures per month on average
- Standard diagnostic testing localized 1 or 2 epileptogenic regions
- Disabling seizures defined as: simple partial motor, complex partial, or secondarily generalized tonic-clonic seizures
Exclusion Criteria
- Not explicitly detailed in manuscript
- More than 2 seizure foci (implied)
- Non-localizable seizures (implied)
Baseline Characteristics
| Characteristic | Treatment (n=97) | Sham (n=94) |
|---|---|---|
| Sex - female | 48% | 47% |
| Age - mean (SD), years | 34.0 ± 11.5 (range 18-60) | 35.9 ± 11.6 (range 18-66) |
| Years with epilepsy - mean (SD) | 20.0 ± 11.2 (range 2-57) | 21.0 ± 12.2 (range 2-54) |
| Number of AEDs at enrollment - mean (SD) | 2.8 ± 1.3 (range 1-8) | 2.8 ± 1.1 (range 0-6) |
| Baseline seizures per day - mean (SD) | 1.2 ± 2.0 (range 0.1-10.5) | 1.2 ± 2.4 (range 0.1-12.1) |
| Mesial temporal seizure onset | 49% | 50% |
| Two seizure foci (vs one) | 49% | 62% |
| Prior therapeutic surgery for epilepsy | 35% | 30% |
| Prior intracranial EEG monitoring | 65% | 53% |
| Prior VNS | 31% | 36% |
Arms
| Field | Control | Responsive Stimulation (Treatment) |
|---|---|---|
| Intervention | RNS System implanted with neurostimulator programmed to sense and record electrocorticogram but NOT deliver stimulation during blinded period | RNS System implanted with neurostimulator programmed to detect abnormal electrocorticographic activity and deliver responsive cortical stimulation; physician-adjusted detection and stimulation parameters for each patient; stimulation enabled 99% of time |
| Duration | 4-week postop stabilization + 4-week stimulation optimization (sham) + 12-week BEP; then stimulation enabled for 84-week OLP | 4-week postop stabilization + 4-week stimulation optimization + 12-week BEP + 84-week OLP |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Difference between treatment and sham groups in mean percentage reduction of seizure frequency during blinded evaluation period (BEP) relative to preimplant period (12 weeks); measured by group-by-time interaction term in GEE model | Primary | -17.3% (95% CI: -29.9%, -2.3%) | -37.9% (95% CI: -46.7%, -27.7%) | 20.60% | 0.012 |
| Seizure reduction - Month 1 of BEP (3rd month postop) | Secondary | -25.2% (95% CI: -37.1%, -11.1%) | -34.2% (95% CI: -44.1%, -22.6%) | 0.279 | |
| Seizure reduction - Month 2 of BEP (4th month postop) | Secondary | -17.2% (95% CI: -30.5%, -1.3%) | -38.1% (95% CI: -47.3%, -27.3%) | 0.016 | |
| Seizure reduction - Month 3 of BEP (5th month postop) | Secondary | -9.4% (95% CI: -29.5%, +16.4%) | -41.5% (95% CI: -52.0%, -28.7%) | 0.008 | |
| ≥50% responder rate during BEP | Secondary | 27% | 29% | ||
| Seizure-free during 12-week BEP | Secondary | 0% | 2.1% (2 subjects) | ||
| Change in proportion of seizure-free days (month 3 of BEP) | Secondary | 16% fewer days with seizures | 27% fewer days with seizures | 0.048 | |
| ≥50% responder rate at 1 year postimplant (all subjects) | Secondary | N/A (combined) | 43% (n=177) | ||
| ≥50% responder rate at 2 years postimplant | Secondary | N/A (combined) | 46% (n=102) | ||
| Seizure-free over most recent 3 months at data cutoff | Secondary | N/A | 7.1% (13 subjects) | ||
| Sham group seizure reduction when stimulation began in OLP | Secondary | Significant reduction vs preimplant | N/A | 0.04 | |
| QOLIE-89 overall t-score improvement at end of BEP - Treatment | Secondary | Improved (P=0.032) | Improved (P=0.040) | ||
| QOLIE-89 overall improvement at 1 year (all subjects) | Secondary | N/A (combined) | Improved | <0.001 | |
| QOLIE-89 overall improvement at 2 years (all subjects) | Secondary | N/A (combined) | Improved | 0.016 | |
| QOLIE-89 Language subscale improvement at 1 year/2 years | Secondary | N/A | Improved | <0.001 / 0.025 | |
| QOLIE-89 Memory subscale improvement at 1 year/2 years | Secondary | N/A | Improved | <0.001 / 0.004 | |
| QOLIE-89 Attention/Concentration improvement at 1 year/2 years | Secondary | N/A | Improved | <0.001 / 0.019 | |
| QOLIE-89 Work/Driving/Social Function at 1 year/2 years | Secondary | N/A | Improved | 0.001 / 0.002 | |
| SAE rate - first 28 days | Adverse | N/A (combined) | 12% (vs 15% literature comparator) | ||
| SAE rate - first 84 days | Adverse | N/A (combined) | 18.3% (vs 36% DBS comparator) | ||
| Intracranial hemorrhage (overall) | Adverse | N/A | 4.7% (9/191 subjects) | ||
| Serious intracranial hemorrhage (not seizure-related) | Adverse | N/A | 2.1% (no permanent sequelae) | ||
| Implant/incision site infection (SAEs) | Adverse | N/A | 5.2% (10/191); 4 explanted; all soft tissue only | ||
| Device-related SAEs during BEP | Adverse | 1 subject (3 events - change in seizures) | 1 subject (1 event - change in seizures) | NS | |
| Implant site pain (through 1 year) | Adverse | N/A (combined) | 15.7% (30 subjects) | ||
| Headache (through 1 year) | Adverse | N/A | 10.5% (20 subjects) | ||
| Procedural headache | Adverse | N/A | 9.4% (18 subjects) | ||
| Dysesthesia | Adverse | N/A | 6.3% (12 subjects) | ||
| Memory impairment | Adverse | N/A | 4.2% (8 subjects) | ||
| Depression AEs (all mild) | Adverse | N/A | 13.6% (26 subjects; 16 had history of depression) | ||
| Suicidality AEs | Adverse | N/A | 6.8% (13 subjects); 3.1% SAEs; all had history of depression/anxiety | ||
| Deaths | Adverse | N/A | 6 total: lymphoma (1), suicide (1 - history of depression), SUDEP (4; 3 had stimulation enabled) | ||
| SUDEP | Adverse | N/A | 4 deaths over 340 patient-years (within expected range for population) |
Subgroup Analysis
Treatment response did not depend on: mesial temporal vs other brain region seizure onset, 1 vs 2 seizure foci, or prior epilepsy surgery or VNS (GEE interaction terms). Preimplant neuropsychological assessment showed 52.7% had verbal memory dysfunction and 56.2% had visuospatial memory dysfunction. At baseline, 49.7% had history of depression, 5.2% history of suicidality, 42.0% met criteria for depression (BDI-II or CES-D), and 10.2% endorsed passive suicidality. No deterioration in any neuropsychological measure at BEP end or at 1-2 years; significant improvements in verbal functioning, visuospatial ability, and memory at 1-2 years (P<0.05). No adverse changes in mood inventories at any timepoint.
Criticisms
- Sponsored by NeuroPace, Inc., with company involvement in data acquisition, statistical analysis, study supervision, and manuscript approval
- Lead author is NeuroPace employee with stock options
- Modest difference in responder rates during blinded period (29% vs 27%)
- Transient implant/surgical effect complicates interpretation of early results
- Open-label extension lacks placebo control for long-term efficacy assessment
- Patient experience (340 years) insufficient to calculate confident SUDEP rate
- Blinding success was only moderate (blinding index 0.572); 43% guessed correctly
- Primary endpoint comparison based on percentage change rather than absolute seizure reduction
- Predominantly US-based population limits generalizability
- High baseline rate of psychiatric comorbidity (50% depression history) may limit generalizability
- 32% had prior epilepsy surgery, 34% prior VNS - highly selected population
- Device lead damage occurred in 2.6% by 1 year
Funding
NeuroPace, Inc. (Mountain View, CA)
Based on: RNS System Pivotal Trial (Neurology, 2011)
Authors: Martha J. Morrell, on behalf of the RNS System in Epilepsy Study Group
Citation: Neurology. 2011;77:1295-1304
Content summarized and formatted by NeuroTrials.ai.