RESTORE: Restoring State-dependent Thalamocortical Oscillations in Epilepsy
The purpose of this research study is to determine the safety and effectiveness of the investigational Cadence Biomarker Targeted Stimulation (BTS) System (Model 5100 EEG Workstation and Alera Model 2000 Biomarker Stimulation System), when used to reduce the frequency of seizures in patients with generalized onset epilepsy.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
- Dispositif: Sham Mediodorsal Thalamic (MD) Deep Brain Stimulation + Centromedian Thalamic (CM) Deep Brain Stimulation
- Dispositif: Low-Frequency Mediodorsal Thalamic Deep Brain Stimulation
- Dispositif: High-Frequency Mediodorsal Thalamic Deep Brain Stimulation
- Dispositif: Mediodorsal Thalamic Deep Brain Stimulation using optimal settings
Description détaillée
This prospective, randomized, sham-controlled study will evaluate the safety, feasibility, and clinical effectiveness of the investigational Cadence Biomarker Targeted Stimulation (BTS) System in adults with drug-resistant generalized epilepsy. The study will enroll 10 adult participants (≥18 years of age) across participating Mayo Clinic sites.
The Cadence BTS System is designed to provide deep brain stimulation (DBS) and record brain electrical activity. The system includes the Model 5100 EEG Workstation and the Alera implantable neural stimulation and recording system. Participants will undergo implantation of four DBS leads targeting the bilateral centromedian (CM) and mediodorsal (MD) nuclei of the thalamus. During implantation, intra-operative neurophysiologic recordings and brief stimulation trials will be used to evaluate brain responses, identify electrophysiologic biomarkers, and help select stimulation contacts and parameters for chronic therapy.
The study will include a baseline/enrollment phase, an implant phase, a CM-DBS optimization phase, a randomized CM+MD DBS evaluation phase, and an open-label phase. During the baseline phase, participants will record seizure frequency and undergo baseline clinical, neurological, neuropsychological, mood, memory, sleep, and quality-of-life assessments. Following implantation, CM stimulation will be optimized using clinical response, seizure counts, electrophysiologic biomarkers, and participant tolerability.
During the randomized evaluation phase, participants will continue optimized CM stimulation while receiving randomized MD stimulation conditions, including sham stimulation, low-frequency stimulation, and high-frequency stimulation. Participants will continue to record seizure frequency, and clinical and neuropsychological assessments will be performed following the randomized treatment periods. Participants will subsequently enter an open-label phase using the therapy determined to be optimal based on findings from the randomized phase.
The primary objective is to evaluate the safety and feasibility of combined bilateral CM and MD thalamic stimulation delivered using the Cadence BTS System. Safety will be assessed through monitoring of device-related, procedure-related, and stimulation-related adverse events and serious adverse events, as well as neurological examinations, neuropsychological testing, mood and behavioral assessments, and device performance.
Clinical effectiveness will be evaluated primarily by comparing disabling seizure frequency during treatment with each participant's baseline seizure frequency. Additional outcomes will include seizure responder rate (≥50% reduction in disabling seizure frequency), seizure freedom, total seizure frequency, seizure severity, quality of life, cognition, memory, mood, sleep, functional outcomes, electrophysiologic biomarkers, and long-term device performance.
Exploratory analyses will examine relationships between suppression of electrophysiologic biomarkers and seizure reduction, associations among sleep, cognition, mood, and seizure outcomes, stimulation parameters associated with clinical response, and longitudinal changes in thalamocortical network activity. These findings are intended to provide preliminary information to support future studies of biomarker-guided and adaptive thalamic neuromodulation for generalized epilepsy.
Type d'étude
Inscription (Estimé)
Phase
- N'est pas applicable
Contacts et emplacements
Coordonnées de l'étude
- Nom: Karla Crockett
- Numéro de téléphone: 507-538-9140
- E-mail: crockett.karla@mayo.edu
Lieux d'étude
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Minnesota
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Rochester, Minnesota, États-Unis, 55905
- Mayo Clinic
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Contact:
- Karla Crockett
- Numéro de téléphone: 507-538-9140
- E-mail: crockett.karla@mayo.edu
-
-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
- Generalized-onset seizures.
- Failure of at least two appropriately selected and adequately dosed anti-seizure medications.
- Distinct, stereotyped seizures that the participant or caregiver can reliably count.
- Ability, independently or with a competent assistant, to maintain a seizure diary and use the BTS System.
- Stable anti-seizure medication doses and ketogenic diet, if applicable, for 1 month before enrollment, except acute intermittent benzodiazepine use.
- At least 3 disabling seizures per month on average. Seizures separated by less than 8 hours are counted as one cluster for this criterion.
- Ability to complete required office and telephone or video visits.
- For participants of childbearing potential: negative serum pregnancy test within 2 weeks before implantation and use of reliable contraception, surgical sterility, or at least 2 years postmenopausal.
- Informed of reasonable alternatives, including surgery, other devices, medication, and dietary options.
- Adequate epilepsy-protocol brain MRI within the previous 2 years.
- Anatomy permits implantation of the INSR within 20 mm of the skin surface.
Exclusion Criteria:
- Substance abuse within the previous 2 years.
- Participation within the previous 30 days in another drug or device study that may confound results.
- Implanted pacemaker, implantable cardioverter-defibrillator, cardiac management product, vagus nerve stimulator, or other medical device that interferes with the BTS System or is affected by it.
- Anatomy that the surgical team determines may preclude safe electrode implantation.
- Use of anticoagulants that cannot be discontinued perioperatively as required.
- Significant platelet dysfunction due to a medical condition or medication unless a hematologist, investigator, and neurosurgeon agree enrollment is advisable.
- Psychogenic or nonepileptic seizures that cannot be distinguished from epileptic events.
- Ineligibility for cranial surgery or a medically or neurologically unstable condition, including brain tumor, multiple sclerosis, dementia, or intracranial vascular lesion.
- Active psychosis, major depression, or suicidal ideation within the previous 6 months.
- Unprovoked convulsive status epilepticus within the previous year, defined as a tonic-clonic seizure lasting at least 5 minutes or repeated tonic-clonic seizures without recovery of consciousness for more than 5 minutes.
- Participant or legally authorized representative cannot demonstrate ability to provide valid informed consent in accordance with regulatory requirements.
- In the investigator's opinion, the individual is a poor candidate for the study.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Faisabilité de l'appareil
- Répartition: Randomisé
- Modèle interventionnel: Affectation croisée
- Masquage: Quadruple
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Expérimental: Sham, High Frequency, Low Frequency
All participants receive four deep brain stimulation leads implanted bilaterally in the centromedian (CM) and mediodorsal (MD) thalamic nuclei. After CM stimulation is optimized, participants complete three blinded, randomized 3-month periods of MD stimulation-sham, low frequency, and high frequency-in a participant-specific sequence while optimized CM stimulation continues. Participants then enter an open-label phase and receive the stimulation settings selected as optimal based on the randomized periods. |
The implanted Cadence BTS System is programmed so that no therapeutic MD stimulation is delivered during the 3-month sham period. Optimized centromedian nucleus thalamus (CM) stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined low-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined high-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. After the randomized periods, all participants enter an open-label phase and receive the stimulation settings selected as optimal. |
|
Expérimental: Sham, Low Frequency, High Frequency
All participants receive four deep brain stimulation leads implanted bilaterally in the centromedian (CM) and mediodorsal (MD) thalamic nuclei. After CM stimulation is optimized, participants complete three blinded, randomized 3-month periods of MD stimulation-sham, low frequency, and high frequency-in a participant-specific sequence while optimized CM stimulation continues. Participants then enter an open-label phase and receive the stimulation settings selected as optimal based on the randomized periods. |
The implanted Cadence BTS System is programmed so that no therapeutic MD stimulation is delivered during the 3-month sham period. Optimized centromedian nucleus thalamus (CM) stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined low-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined high-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. After the randomized periods, all participants enter an open-label phase and receive the stimulation settings selected as optimal. |
|
Expérimental: Low Frequency, Sham, High Frequency
All participants receive four deep brain stimulation leads implanted bilaterally in the centromedian (CM) and mediodorsal (MD) thalamic nuclei. After CM stimulation is optimized, participants complete three blinded, randomized 3-month periods of MD stimulation-sham, low frequency, and high frequency-in a participant-specific sequence while optimized CM stimulation continues. Participants then enter an open-label phase and receive the stimulation settings selected as optimal based on the randomized periods. |
The implanted Cadence BTS System is programmed so that no therapeutic MD stimulation is delivered during the 3-month sham period. Optimized centromedian nucleus thalamus (CM) stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined low-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined high-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. After the randomized periods, all participants enter an open-label phase and receive the stimulation settings selected as optimal. |
|
Expérimental: Low Frequency, High Frequency, Sham
All participants receive four deep brain stimulation leads implanted bilaterally in the centromedian (CM) and mediodorsal (MD) thalamic nuclei. After CM stimulation is optimized, participants complete three blinded, randomized 3-month periods of MD stimulation-sham, low frequency, and high frequency-in a participant-specific sequence while optimized CM stimulation continues. Participants then enter an open-label phase and receive the stimulation settings selected as optimal based on the randomized periods. |
The implanted Cadence BTS System is programmed so that no therapeutic MD stimulation is delivered during the 3-month sham period. Optimized centromedian nucleus thalamus (CM) stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined low-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined high-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. After the randomized periods, all participants enter an open-label phase and receive the stimulation settings selected as optimal. |
|
Expérimental: High Frequency, Sham, Low Frequency
All participants receive four deep brain stimulation leads implanted bilaterally in the centromedian (CM) and mediodorsal (MD) thalamic nuclei. After CM stimulation is optimized, participants complete three blinded, randomized 3-month periods of MD stimulation-sham, low frequency, and high frequency-in a participant-specific sequence while optimized CM stimulation continues. Participants then enter an open-label phase and receive the stimulation settings selected as optimal based on the randomized periods. |
The implanted Cadence BTS System is programmed so that no therapeutic MD stimulation is delivered during the 3-month sham period. Optimized centromedian nucleus thalamus (CM) stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined low-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined high-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. After the randomized periods, all participants enter an open-label phase and receive the stimulation settings selected as optimal. |
|
Expérimental: High Frequency, Low Frequency, Sham
All participants receive four deep brain stimulation leads implanted bilaterally in the centromedian (CM) and mediodorsal (MD) thalamic nuclei. After CM stimulation is optimized, participants complete three blinded, randomized 3-month periods of MD stimulation-sham, low frequency, and high frequency-in a participant-specific sequence while optimized CM stimulation continues. Participants then enter an open-label phase and receive the stimulation settings selected as optimal based on the randomized periods. |
The implanted Cadence BTS System is programmed so that no therapeutic MD stimulation is delivered during the 3-month sham period. Optimized centromedian nucleus thalamus (CM) stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined low-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. The implanted Cadence BTS System delivers protocol-defined high-frequency stimulation to the bilateral MD thalamic nuclei for 3 months while optimized CM stimulation continues. This intervention is administered once to every participant in the period specified by the assigned sequence. After the randomized periods, all participants enter an open-label phase and receive the stimulation settings selected as optimal. |
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Number of Participants With a Device, Procedure, or Stimulation-Related Serious Adverse Events
Délai: From device implantation through Month 21
|
Number of participants who experience at least one serious adverse event assessed by the investigator as related to the Cadence Biomarker Targeted Stimulation System, the device-implantation procedure, or delivered deep brain stimulation. |
From device implantation through Month 21
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Change in Monthly Disabling Seizure Frequency
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
Percent change in number of disabling seizures as reported in seizure diary. Disabling seizures include generalized tonic-clonic seizures, tonic seizures, atonic seizures, focal-to-bilateral tonic-clonic seizures, and other seizure types associated with loss of awareness, falls, injury risk, or clinically significant functional impairment. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
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Percentage of Participants With at Least a 50% Reduction in Disabling Seizure Frequency
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
Percentage of participants whose 28-day disabling seizure frequency is at least 50% lower than baseline during each post-baseline assessment interval. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Percentage of Participants Free of Disabling Seizures
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
Percentage of participants with no diary-recorded disabling seizures during each post-baseline assessment interval. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in Liverpool Seizure Severity Scale 2.0 Total Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The Liverpool Seizure Severity Scale 2.0 is a patient-reported measure of the severity of the participant's most severe seizure during the previous 4 week period. The revised scoring system uses responses to 12 ictal and postictal severity items to calculate a single score that is linearly transformed to a scale from 0 to 100. A score of 0 represents no seizures and a score of 100 represents the most severe possible seizure; higher scores indicate greater seizure severity. A decrease from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in Quality of Life in Epilepsy-31 Total Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The Quality of Life in Epilepsy-31 is a 31-item, patient-reported measure of epilepsy-specific health-related quality of life. It includes seven multi-item scales: seizure worry, overall quality of life, emotional well-being, energy/fatigue, cognitive functioning, medication effects, and social functioning. Item responses are converted to 0-to-100 scale scores according to the QOLIE-31 scoring manual. The overall score is calculated as a weighted average of the seven multi-item scale scores and ranges from 0 to 100. Higher scores indicate better health-related quality of life; a positive change from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in NIH Toolbox Flanker Inhibitory Control and Attention Test Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The NIH Toolbox Flanker Inhibitory Control and Attention test measures attention and inhibitory control by requiring the participant to indicate the direction of a central target while ignoring flanking stimuli that may be congruent or incongruent. The computed score combines response accuracy and reaction time and ranges from 0 to 10. When accuracy is below 80%, the computed score is based on accuracy alone; when accuracy is 80% or higher, accuracy and reaction time are combined. Higher scores indicate better performance, reflecting greater accuracy and, among sufficiently accurate responses, faster reaction time; a positive change from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in Free Recall Memory Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
Change from baseline in the number of protocol-specified proper nouns correctly recalled from a 12-item list. Scores range from 0 to 12; higher scores indicate better free recall. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in NIH Toolbox Picture Sequence Memory Test Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The NIH Toolbox Picture Sequence Memory Test is an examiner-administered measure of episodic memory. The participant views an ordered series of pictures and then reconstructs the sequence. 1 point is awarded for each pair placed in the correct relative order; higher scores indicate better memory and a positive change indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in NIH Toolbox Picture Vocabulary Test score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The NIH Toolbox Picture Vocabulary Test is a computer-adaptive measure of receptive vocabulary. The participant hears a word and selects the picture that best matches it from four choices; subsequent items are selected based on prior responses. Responses are scored using item-response theory to estimate vocabulary ability. Higher scores indicate better receptive vocabulary, and a positive change from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in Beck Depression Inventory Total Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The Beck Depression Inventory-II (BDI-II) is a 21-item, self-reported measure of depressive symptoms experienced during the past 2 weeks. Each item is rated from 0 to 3, and item ratings are summed to produce a total score from 0 to 63. Higher scores indicate greater depressive symptom severity. Common interpretive ranges are 0-13, minimal; 14-19, mild; 20-28, moderate; and 29-63, severe. A negative change from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Change in Beck Anxiety Inventory Total Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The Beck Anxiety Inventory (BAI) is a 21-item, self-reported measure of anxiety symptoms experienced during the past week. Each item is rated from 0 (not at all) to 3 (severely), and item ratings are summed to produce a total score from 0 to 63. Higher scores indicate greater anxiety symptom severity. Common interpretive ranges are 0-7, minimal anxiety; 8-15, mild anxiety; 16-25, moderate anxiety; and 26-63, severe anxiety. A negative change from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
|
Number of Participants With a Device Performance Event
Délai: Post-implementation through 21 months
|
Number of participants with at least one device malfunction, technical problem, lead or system revision, explant, or permanent discontinuation of stimulation attributable to device performance. |
Post-implementation through 21 months
|
|
Change in Epworth Sleepiness Scale Total Score
Délai: Baseline, 3, 6, 9, 12 and 21 months post-implant
|
The Epworth Sleepiness Scale (ESS) is an 8-item, self-reported measure of usual daytime sleep propensity in common situations. Each situation is rated from 0 (would never doze) to 3 (high chance of dozing), and item ratings are summed to produce a total score from 0 to 24. Higher scores indicate greater daytime sleepiness. Common interpretive ranges are 0-10, normal; 11-14, mild sleepiness; 15-17, moderate sleepiness; and 18-24, severe sleepiness. A negative change from baseline indicates improvement. |
Baseline, 3, 6, 9, 12 and 21 months post-implant
|
Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chercheur principal: Gregory Worrell, MD, PhD, Mayo Clinic
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Estimé)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- 25-012211
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Étudie un produit d'appareil réglementé par la FDA américaine
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