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The purpose of this research is to study the safety and effectiveness of bilateral stimulation of the anterior nucleus of the thalamus as adjunctive therapy for reducing the frequency of seizures in adults diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to antiepileptic medications.
Medtronic, Inc. is sponsoring an investigational study of the Medtronic DBS Therapy for epilepsy, the company's deep brain stimulation (DBS) therapy for patients with refractory epilepsy. Epilepsy is a condition that affects 2.3 million Americans, and about one-third of these patients are refractory, or continue to experience seizures despite a wide range of treatment options.
The prospective, randomized, double-blind trial uses existing technology to test whether bilateral stimulation of the anterior nucleus of the thalamus can safely and effectively reduce seizure frequency in patients with epilepsy. It includes enrollment of 157 patients at 17 sites in the U.S. 110 patients were implanted and monitored for 13 months following implant, with long-term follow-up until the device is approved or the study is stopped. 109 of the 110 implanted subjects were randomized to Active stimulation or Control.
Patients in the active group, who received neurostimulation, were monitored for a reduction in seizure rates compared to the control group, who did not receive neurostimulation during the three-month double-blind phase. After the double-blind phase, all patients received neurostimulation.
Candidates for the trial were adults with partial-onset epilepsy for whom at least three antiepileptic drugs have proven ineffective. They were to have had an average of six or more seizures per month. Candidates continued to receive their epilepsy medications while participating in the trial.
Deep 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. Deep brain stimulation is not approved in the United States for the treatment of epilepsy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Experimental | Active Stimulation |
|
| 2 | Sham Comparator | No Stimulation |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Medtronic DBS Therapy for epilepsy | Device | Stimulation On |
| |
| Medtronic DBS Therapy for epilepsy |
| Measure | Description | Time Frame |
|---|---|---|
| Primary Analysis: Change in Seizure Rate | A protocol-prespecified generalized estimating equations (GEE) analysis was used to evaluate the treatment effect on seizure frequency. The final GEE model for the primary objective evaluation included treatment effect, log of the baseline seizure count, log of age, visit (categorical), treatment-by-visit interaction (categorical), and the offset (the number of days the diary was recorded in each month). | Through the end of the three-month blinded phase |
| Alternative Primary Analysis: Change in Seizure Rate | A generalized estimating equations (GEE) analysis was used to evaluate the treatment effect on seizure frequency. With one outlier subject removed, the GEE model for this alternative analysis included treatment effect, log of the baseline seizure count, log of age, visit (categorical), and the offset (the number of days the diary was recorded in each month). | Through the end of the three-month blinded phase |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events Experienced With the Medtronic DBS System | The results are for the follow-up after device implantation through Year 2 and summarized are events that occurred in greater than 5% of subjects. Only events related to the device, therapy, or surgery are included. These abbreviations were used:
For this summary, adverse events are reported as 'MedDRA System Organ Class - adverse event'. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Most Severe Seizures | Seizures were recorded on daily seizure diaries. The subject recorded the number of seizures by seizure type on the seizure diary. The subject also noted at baseline, of those they had ever experienced, which seizure they considered to be "most severe." | Through the end of the three-month blinded phase |
Relevant Inclusion and Exclusion Criteria are listed below.
Inclusion Criteria
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19752594 | Background | Miller PM, Gross RE. Wire tethering or 'bowstringing' as a long-term hardware-related complication of deep brain stimulation. Stereotact Funct Neurosurg. 2009;87(6):353-9. doi: 10.1159/000236369. Epub 2009 Sep 10. | |
| 20331461 | Result | Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010 May;51(5):899-908. doi: 10.1111/j.1528-1167.2010.02536.x. Epub 2010 Mar 17. |
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47 of 157 subjects exited prior to implant due to not meeting in/exclusion criteria, withdrawal of consent to participate, etc. Of the remaining 110 subjects, 109 subjects were randomized. Those 109 subjects were used for objectives between randomization groups while all 110 implanted subjects were used for long term safety objectives.
157 subjects were enrolled in the study from 11 DEC 2003 through 23 FEB 2007 from 17 centers in US.
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| ID | Title | Description |
|---|---|---|
| FG000 | Active Stimulation | This group contains subjects who were implanted and randomized to receive active stimulation during the blinded phase of the study. |
| FG001 | No Stimulation | This group contains subjects who were implanted and randomized to receive no stimulation during the blinded phase of the study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Active Stimulation | This group contains subjects who were implanted and randomized to receive active stimulation during the blinded phase of the study. |
| BG001 | No Stimulation |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Primary Analysis: Change in Seizure Rate | A protocol-prespecified generalized estimating equations (GEE) analysis was used to evaluate the treatment effect on seizure frequency. The final GEE model for the primary objective evaluation included treatment effect, log of the baseline seizure count, log of age, visit (categorical), treatment-by-visit interaction (categorical), and the offset (the number of days the diary was recorded in each month). | This analysis used the protocol-prespecified "Primary analysis data set" which required that subjects had at least 70 days of diary in the blinded phase. One control subject was not included in this analysis as they had 66 of the required 70 days. | Posted | Median | Inter-Quartile Range | Percentage change from baseline | Through the end of the three-month blinded phase |
|
Adverse events were collected throughout the study. The summaries below include events that occurred during the blinded phase. A summary of device related events (operative phase through Year 2) is in the safety characterization objective.
Adverse events collected during the blinded phase have been included, regardless of causality.
Because the primary purpose of this adverse event summary is to compare the randomization groups, and because the additional non-randomized subject did not have a similar follow-up schedule, the subject has not been included in these analyses.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active Stimulation | This group contains subjects who were implanted and randomized to receive active stimulation during the blinded phase of the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Implant site infection | Infections and infestations | MedDRA (8.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | MedDRA (8.0) | Non-systematic Assessment |
No limitations leading to unreliable data were identified.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jim Vollhaber, Clinical Study Manager | Medtronic Neuromodulation | 763-526-8093 | medtronicneurotrials@medtronic.com |
| ID | Term |
|---|---|
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| Device |
Stimulation Off |
|
| Through Year 2 of the long-term follow-up phase |
| Incidence of Sudden Unexplained Death in Epilepsy (SUDEP) | The number presented is for Definite and Probable SUDEP. The rate is calculated per 1000 subject years of follow-up. The confidence interval is the 95% Poisson confidence interval. Per protocol, only definite and probable SUDEP classifications were included in the calculation. The results shown are for the entire study follow-up after device implantation. | Inclusive of all study follow-up after device implantation (mean follow-up 3.7 years) |
| Seizure Responder Rate | A responder is defined as a subject with greater than or equal to 50% reduction in seizures as compared with baseline. | Through the end of the three-month blinded phase |
| Change in Percentage of Days Seizure-free | Difference between active group and control group in percentage change in seizure-free days over the entire blinded phase as compared to the entire baseline phase. The number of seizure-free days was normalized to 84-day baseline and blinded phases for each subject. | Through the end of the three-month blinded phase |
| Percentage Change in the Maximum Length of Seizure-free Intervals | Difference between active group and control group in percentage change in the maximum length of seizure-free intervals over the entire blinded phase as compared to the entire baseline phase. | Through the end of the three-month blinded phase |
| Proportion of Treatment Failures | A treatment failure was defined in the protocol as a subject who 1) required 3 or more doses of rescue medication within 48 hours, 3 times during the blinded phase; or 2) had 3 episodes of convulsive status epilepticus during the blinded phase. | Through the end of the three-month blinded phase |
| 28061418 | Result | Troster AI, Meador KJ, Irwin CP, Fisher RS; SANTE Study Group. Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy. Seizure. 2017 Feb;45:133-141. doi: 10.1016/j.seizure.2016.12.014. Epub 2016 Dec 23. |
| 25663221 | Result | Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, Labar D, Sperling MR, Sharan A, Sandok E, Handforth A, Stern JM, Chung S, Henderson JM, French J, Baltuch G, Rosenfeld WE, Garcia P, Barbaro NM, Fountain NB, Elias WJ, Goodman RR, Pollard JR, Troster AI, Irwin CP, Lambrecht K, Graves N, Fisher R; SANTE Study Group. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015 Mar 10;84(10):1017-25. doi: 10.1212/WNL.0000000000001334. Epub 2015 Feb 6. |
This group contains subjects who were implanted and randomized to receive no stimulation during the blinded phase of the study.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | No Stimulation | This group contains subjects who were implanted and randomized to receive no stimulation during the blinded phase of the study. |
|
|
|
| Secondary | Adverse Events Experienced With the Medtronic DBS System | The results are for the follow-up after device implantation through Year 2 and summarized are events that occurred in greater than 5% of subjects. Only events related to the device, therapy, or surgery are included. These abbreviations were used:
For this summary, adverse events are reported as 'MedDRA System Organ Class - adverse event'. | This analysis used all subjects who were implanted and received stimulation. One subject was implanted but was not subsequently randomized, but did receive stimulation. This subject has been included for the purposes of this analysis for a total of 110 subjects, as opposed to the 109 stated in the participant flow. | Posted | Number | participants | Through Year 2 of the long-term follow-up phase |
|
|
|
| Secondary | Incidence of Sudden Unexplained Death in Epilepsy (SUDEP) | The number presented is for Definite and Probable SUDEP. The rate is calculated per 1000 subject years of follow-up. The confidence interval is the 95% Poisson confidence interval. Per protocol, only definite and probable SUDEP classifications were included in the calculation. The results shown are for the entire study follow-up after device implantation. | This analysis used all subjects who were implanted and received stimulation. One subject was implanted but was not subsequently randomized, but did receive stimulation. This subject has been included for the purposes of this analysis for a total of 110 subjects included in this analysis. | Posted | Number | Number of subjects experiencing SUDEP | Inclusive of all study follow-up after device implantation (mean follow-up 3.7 years) |
|
|
|
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| Secondary | Seizure Responder Rate | A responder is defined as a subject with greater than or equal to 50% reduction in seizures as compared with baseline. | This analysis used the "Primary analysis data set" which required that subjects had at least 70 days of diary in the blinded phase. One control subject was not included in this analysis as they had 66 of the required 70 days. | Posted | Jan 2011 | Number | Number of participants | Through the end of the three-month blinded phase |
|
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|
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| Secondary | Change in Percentage of Days Seizure-free | Difference between active group and control group in percentage change in seizure-free days over the entire blinded phase as compared to the entire baseline phase. The number of seizure-free days was normalized to 84-day baseline and blinded phases for each subject. | This analysis used the "Primary analysis data set" which required that subjects had at least 70 days of diary in the blinded phase. In addition, percentage change was not calculated for subjects who had no seizure-free days during the baseline phase. | Posted | Median | Inter-Quartile Range | Percentage change from baseline | Through the end of the three-month blinded phase |
|
|
|
|
| Secondary | Percentage Change in the Maximum Length of Seizure-free Intervals | Difference between active group and control group in percentage change in the maximum length of seizure-free intervals over the entire blinded phase as compared to the entire baseline phase. | This analysis used the "Primary analysis data set" which required that subjects had at least 70 days of diary in the blinded phase. One control subject was not included in this analysis as they had 66 of the required 70 days. | Posted | Median | Inter-Quartile Range | Percentage change from baseline | Through the end of the three-month blinded phase |
|
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| Secondary | Proportion of Treatment Failures | A treatment failure was defined in the protocol as a subject who 1) required 3 or more doses of rescue medication within 48 hours, 3 times during the blinded phase; or 2) had 3 episodes of convulsive status epilepticus during the blinded phase. | This analysis used the "Primary analysis data set" which required that subjects had at least 70 days of diary in the blinded phase. One control subject was not included in this analysis as they had 66 of the required 70 days. | Posted | Number | participants | Through the end of the three-month blinded phase |
|
|
|
|
| Primary | Alternative Primary Analysis: Change in Seizure Rate | A generalized estimating equations (GEE) analysis was used to evaluate the treatment effect on seizure frequency. With one outlier subject removed, the GEE model for this alternative analysis included treatment effect, log of the baseline seizure count, log of age, visit (categorical), and the offset (the number of days the diary was recorded in each month). | This analysis used the protocol-prespecified "Primary analysis data set" with one additional outlier subject removed from the active group. This subject had 210 stimulation initiated seizures within 48 hours of the device being turned on and was determined to be an outlier using both a statistical and clinical rationale. | Posted | Median | Inter-Quartile Range | Percentage change from baseline | Through the end of the three-month blinded phase |
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| Other Pre-specified | Change in Most Severe Seizures | Seizures were recorded on daily seizure diaries. The subject recorded the number of seizures by seizure type on the seizure diary. The subject also noted at baseline, of those they had ever experienced, which seizure they considered to be "most severe." | This analysis used the "Primary analysis data set". In addition, the protocol prespecified that if a subject did not experience the severe seizure in the baseline phase that they would not be included in the calculation of the blinded phase median seizure frequency percentage change from baseline. | Posted | Median | Inter-Quartile Range | Percentage change from baseline | Through the end of the three-month blinded phase |
|
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|
| 2 |
| 54 |
| 42 |
| 54 |
| EG001 | No Stimulation | This group contains subjects who were implanted and randomized to receive no stimulation during the blinded phase of the study. | 6 | 55 | 41 | 55 |
| Anxiety | Psychiatric disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Depression | Psychiatric disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Complex partial seizures | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Muscle contractions involuntary | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Partial seizures with secondary generalization | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Status epilepticus | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Upper respiratory infection | Infections and infestations | MedDRA (8.0) | Non-systematic Assessment |
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| Influenza | Infections and infestations | MedDRA (8.0) | Non-systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Complex partial seizures | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Memory impairment | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Paresthesia | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Partial seizures with secondary generalization | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
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| Simple partial seizures | Nervous system disorders | MedDRA (8.0) | Non-systematic Assessment |
|
| Injury | Injury, poisoning and procedural complications | MedDRA (8.0) | Non-systematic Assessment |
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| Anticonvulsant toxicity | Injury, poisoning and procedural complications | MedDRA (8.0) | Non-systematic Assessment |
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| Contusion | Injury, poisoning and procedural complications | MedDRA (8.0) | Non-systematic Assessment |
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| Excoriation | Injury, poisoning and procedural complications | MedDRA (8.0) | Non-systematic Assessment |
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The disclosure restrictions on the PI allow for the sponsor to review results communications prior to public release and to embargo communications regarding trial results for a period that is less than or equal to 45 days from the time submitted to sponsor for review. The sponsor is also allowed to require changes for technical correctness and to protect confidential information, copyrightable or patentable material; and when reasonably requested, extend the embargo up to an additional 60 days.
| Title | Measurements |
|---|---|
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| Nervous system disorders-Sensory disturbance |
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| Nervous system disorders-Dizziness |
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| Nervous system disorders-Memory impairment |
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| General dis...-Implant site pain |
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| General dis...-Discomfort |
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| General dis...-Lead(s) not within target |
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| General dis...-Implant site inflammation |
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| Injury, poison...-Post procedural pain |
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