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Spinal cord injury (SCI) is associated with severe neuropathic pain that is often refractory to pharmacological intervention. Preliminary data suggest brivaracetam is a mechanism-based pharmacological intervention for neuropathic pain in SCI. Based on this and other reports in the literature, SCI-related neuropathic pain is hypothesized to occur largely because of upregulation of synaptic vesicle protein 2A (SV2A) within the substantia gelatinosa of the injured spinal cord. Furthermore, compared to placebo, brivaracetam treatment is hypothesized to reduce severe below-level SCI neuropathic pain and increases parietal operculum (partsOP1/OP4) connectivity strength measured by resting-state functional Magnetic Resonance Imaging (rsfMRI). Circulating miRNA-485 levels may be associated with change in pain intensity due to brivaracetam treatment. The study aims to determine the efficacy of brivaracetam treatment for SCI-related neuropathic pain.
Purpose:
Spinal cord injury (SCI) is associated with severe neuropathic pain that is often refractory to pharmacological intervention. Our preliminary data suggest brivaracetam is a mechanism-based pharmacological intervention for neuropathic pain in SCI. Based on our data and other reports in the literature, we hypothesize that SCI-related neuropathic pain occurs largely because of upregulation of synaptic vesicle protein 2A (SV2A) within the substantia gelatinosa of the injured spinal cord. We further hypothesize that, compared to placebo, brivaracetam treatment reduces severe below-level SCI neuropathic pain and increases parietal operculum (parts OP1/OP4) connectivity strength measured by resting-state functional Magnetic Resonance Imaging (rsfMRI). We also hypothesize that circulating miRNA-485 levels may be associated with change in pain intensity due to brivaracetam treatment. To test these hypotheses, we will conduct a randomized, double-blind, placebo-controlled clinical trial to determine the efficacy of brivaracetam treatment for SCI-related neuropathic pain. We therefore propose the following:
Specific Aims:
Specific Aim 1: Determine whether a 7-week course of daily brivaracetam reduces below-level neuropathic pain in SCI. The objective of this aim is to assess efficacy of a 7-week course of brivaracetam to reduce neuropathic pain in men and women with SCI. We will assess change in pain intensity and related outcomes, including mood, satisfaction with life, and community integration. We will monitor drug adverse events and tolerability.
Specific Aim 2: Determine whether a 7-week course of daily brivaracetam increases parietal operculum brain connectivity. The objective of this exploratory aim is to assess the effect of a 7-week course of brivaracetam treatment on parietal operculum activation and connectivity in SCI. We will assess changes in cortical activity of related pain perception regions and networks in the brain in response to brivaracetam treatment compared to placebo using rsfMRI and pain-related task-based fMRI. To achieve this aim, we will test the working hypothesis that brivaracetam increases parietal operculum activation and connectivity compared to placebo, using rsfMRI, task-based fMRI, and a validated image processing protocol. We will also examine changes in network connectivity and brain activity in the insula, because of its concurrent reported importance for neuropathic pain in SCI. We will assess the association between functional connectivity of the parietal operculum and the insula and change in pain intensity in response to brivaracetam treatment.
Specific Aim 3: Determine whether baseline microRNA-485 levels are associated with response to brivaracetam treatment. The objective of this exploratory aim is to assess microRNA expression as a potential predictive biomarker of response to brivaracetam treatment. To achieve this, we will test the working hypothesis that baseline circulating miR-485 levels predict change in pain intensity in response to brivaracetam treatment. To test this, we will use Next-Generation sequencing. We will assess miR-485 levels at baseline and after a three-month treatment course.
Significance of Research Question/Purpose:
There is currently no effective pharmacological treatment for severe neuropathic pain in SCI. Identification of an oral medication that is effective, safe, and well tolerated would represent a major improvement in the clinical approach to neuropathic pain in SCI. Additionally, there are no validated predictive biomarkers of response to pharmacological therapy in neuropathic pain after SCI. This work is innovative as it seeks to develop a new, mechanism-based pharmacological intervention for neuropathic pain in SCI. Additionally, this project seeks to identify novel biomarkers of neuropathic pain and response to therapy. Development of a reliable, easy to measure biomarker that distinguishes responders from non-responders would dramatically improve clinical care for this condition. Successful completion of this work will rapidly lead to larger clinical trials testing drug efficacy and validating novel predictive biomarkers of treatment response.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental group | Experimental | Drug dosage will be individually titrated for each participant with a goal of 100mg BID according to the following dose escalation protocol that we use clinically: 50mg BID for 1 week followed by 100mg BID for 28 days as tolerated. Participants will be allowed to reduce the dose of brivaracetam if they experience unacceptable side effects defined as increased somnolence according to routine clinical practice with other drugs in this class used for pain. Drug discontinuation at study completion will be done according to the following protocol we use clinically that will be initiated for 2 weeks: reduction to 50mg BID for 1 week followed by 50mg daily for 1 week. |
|
| Control group | Placebo Comparator | Participants with severe neuropathic pain will receive placebo drug |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| brivaracetam | Drug | Drug dosage will be individually titrated for each participant with a goal of 100mg BID according to the following dose escalation protocol that we use clinically: 50mg BID for 1 week followed by 100mg BID for 28 days as tolerated. Participants will be allowed to reduce the dose of brivaracetam if they experience unacceptable side effects defined as increased somnolence according to routine clinical practice with other drugs in this class used for pain. Drug discontinuation at study completion will be done according to the following protocol we use clinically that will be initiated for 2 weeks: reduction to 50mg BID for 1 week followed by 50mg daily for 1 week. |
| Measure | Description | Time Frame |
|---|---|---|
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Average Worst Neuropathic Pain Intensity | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Average Worst Neuropathic Pain Intensity assesses the average worst neuropathic pain intensity in the last week using a 0-10 numerical rating scale where higher scores represent greater pain intensity. Change in pain intensity will be evaluated by comparing baseline intensity with 7-week post intervention intensity. | 7 Weeks Post Intervention |
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Neuropathic Pain | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Neuropathic Pain assesses the average of the three worst neuropathic pain intensities in the last week using a 0-10 numerical rating scale where higher scores represent greater pain intensity. Change in average pain intensity will be evaluated by comparing baseline average intensity with 7-week post intervention average intensity. | 7 Weeks Post Intervention |
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Intensity Averaged Over All Pain Sites | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Intensity Averaged over all Pain Sites assesses the average pain intensities over all pain sites in the last week using a 0-10 numerical rating scale where higher scores represent greater pain intensity. Change in average pain intensity for all pain sites will be evaluated by comparing baseline average intensity with 7-week post intervention average intensity over all pain sites. | 7 Weeks Post Intervention |
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Day-to-Day Pain Interference | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Day-to-Day Pain Interference assesses interference of the worst neuropathic pain with daily activities in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in pain interference on daily activities will be evaluated by comparing baseline interference with 7-week post intervention interference. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ricardo Battaglino, PhD | University of Minnesota | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Minnesota | Minneapolis | Minnesota | 55455 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental Group | Participants with severe neuropathic pain will receive brivaracetam treatment brivaracetam: Drug dosage will be individually titrated for each participant with a goal of 100mg BID according to the following dose escalation protocol that we use clinically: 50mg BID for 1 week followed by 100mg BID for 28 days as tolerated. Participants will be allowed to reduce the dose of brivaracetam if they experience unacceptable side effects defined as increased somnolence according to routine clinical practice with other drugs in this class used for pain. Drug discontinuation at study completion will be done according to the following protocol we use clinically that will be initiated for 2 weeks: reduction to 50mg BID for 1 week followed by 50mg daily for 1 week. |
| FG001 | Control Group | Participants with severe neuropathic pain will receive placebo drug Placebo: Participants will receive placebo drug |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Baseline characteristics are only available for n=43 who proceeded to data collection after consenting, and before stopping/removed from the study. n=1 participant was found to not have met protocol eligibility after consenting and thus, did not complete any study activities.
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental Group | Participants with severe neuropathic pain will receive brivaracetam treatment brivaracetam: Drug dosage will be individually titrated for each participant with a goal of 100mg BID according to the following dose escalation protocol that we use clinically: 50mg BID for 1 week followed by 100mg BID for 28 days as tolerated. Participants will be allowed to reduce the dose of brivaracetam if they experience unacceptable side effects defined as increased somnolence according to routine clinical practice with other drugs in this class used for pain. Drug discontinuation at study completion will be done according to the following protocol we use clinically that will be initiated for 2 weeks: reduction to 50mg BID for 1 week followed by 50mg daily for 1 week. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Average Worst Neuropathic Pain Intensity | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Average Worst Neuropathic Pain Intensity assesses the average worst neuropathic pain intensity in the last week using a 0-10 numerical rating scale where higher scores represent greater pain intensity. Change in pain intensity will be evaluated by comparing baseline intensity with 7-week post intervention intensity. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
7 weeks post-intervention
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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 | Experimental Group | Participants with severe neuropathic pain will receive brivaracetam treatment brivaracetam: Drug dosage will be individually titrated for each participant with a goal of 100mg BID according to the following dose escalation protocol that we use clinically: 50mg BID for 1 week followed by 100mg BID for 28 days as tolerated. Participants will be allowed to reduce the dose of brivaracetam if they experience unacceptable side effects defined as increased somnolence according to routine clinical practice with other drugs in this class used for pain. Drug discontinuation at study completion will be done according to the following protocol we use clinically that will be initiated for 2 weeks: reduction to 50mg BID for 1 week followed by 50mg daily for 1 week. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bowel/ GI | Gastrointestinal disorders | Non-systematic Assessment |
The clinical trial allowed for in-person or fully remote participation; and when participating fully remote, in-person data collection were allowed not to be collected (e.g. MRI scan, blood banking for microRNA). Therefore, the clinical trial did not have sufficient paired data collected to analyze MRI or microRNA outcomes.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Angela Philippus | University of Minnesota | (612) 626-5399 | phili272@umn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 15, 2024 | Dec 11, 2025 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 15, 2024 | Oct 22, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D013119 | Spinal Cord Injuries |
| D009437 | Neuralgia |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020196 | Trauma, Nervous System |
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| ID | Term |
|---|---|
| C482793 | brivaracetam |
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| Placebo | Drug | Participants will receive placebo drug |
|
| 7 Weeks Post Intervention |
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference With Mood | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference with Mood assesses the interference of the worst neuropathic pain on mood in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in pain interference on mood will be evaluated by comparing baseline interference with 7-week post intervention interference. | 7 Weeks Post Intervention |
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference With Sleep | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference with Sleep assesses the interference of the worst neuropathic pain on sleep in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in pain interference on sleep will be evaluated by comparing baseline interference with 7-week post intervention interference. | 7 Weeks Post Intervention |
| The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Pain Interference | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Pain Interference assesses the average overall interference of the worst neuropathic pain (average interference of daily activities, mood, and sleep) in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in overall interference will be evaluated by comparing baseline overall interference with 7-week post intervention overall interference. | 7 Weeks Post Intervention |
| Change in Operculum Brain Connectivity | assess changes in cortical activity of related pain perception regions and networks in the brain in response to brivaracetam treatment compared to placebo using rsfMRI and pain- related task-based fMRI. Although MRI data were acquired, the predefined functional connectivity analysis pipeline was not completed; therefore, no operculum connectivity outcomes were generated or analyzed for this study. | 7 weeks |
| microRNA-485 Levels | use Next-Generation sequencing to assess miR-485 levels | baseline |
| microRNA-485 Levels | use Next-Generation sequencing to assess miR-485 levels | 7 weeks |
| Withdrawal by Subject |
|
| BG001 | Control Group | Participants with severe neuropathic pain will receive placebo drug Placebo: Participants will receive placebo drug |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Control Group | Participants with severe neuropathic pain will receive placebo drug Placebo: Participants will receive placebo drug |
|
|
| Primary | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Neuropathic Pain | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Neuropathic Pain assesses the average of the three worst neuropathic pain intensities in the last week using a 0-10 numerical rating scale where higher scores represent greater pain intensity. Change in average pain intensity will be evaluated by comparing baseline average intensity with 7-week post intervention average intensity. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
|
|
| Primary | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Intensity Averaged Over All Pain Sites | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Intensity Averaged over all Pain Sites assesses the average pain intensities over all pain sites in the last week using a 0-10 numerical rating scale where higher scores represent greater pain intensity. Change in average pain intensity for all pain sites will be evaluated by comparing baseline average intensity with 7-week post intervention average intensity over all pain sites. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
|
|
| Primary | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Day-to-Day Pain Interference | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Day-to-Day Pain Interference assesses interference of the worst neuropathic pain with daily activities in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in pain interference on daily activities will be evaluated by comparing baseline interference with 7-week post intervention interference. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
|
|
| Primary | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference With Mood | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference with Mood assesses the interference of the worst neuropathic pain on mood in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in pain interference on mood will be evaluated by comparing baseline interference with 7-week post intervention interference. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
|
|
| Primary | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference With Sleep | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference with Sleep assesses the interference of the worst neuropathic pain on sleep in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in pain interference on sleep will be evaluated by comparing baseline interference with 7-week post intervention interference. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
|
|
| Primary | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Pain Interference | The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Pain Interference assesses the average overall interference of the worst neuropathic pain (average interference of daily activities, mood, and sleep) in the last week using a 0-10 numerical rating scale where higher scores represent greater pain interference. Change in overall interference will be evaluated by comparing baseline overall interference with 7-week post intervention overall interference. | Posted | Mean | Standard Deviation | points | 7 Weeks Post Intervention |
|
|
|
| Primary | Change in Operculum Brain Connectivity | assess changes in cortical activity of related pain perception regions and networks in the brain in response to brivaracetam treatment compared to placebo using rsfMRI and pain- related task-based fMRI. Although MRI data were acquired, the predefined functional connectivity analysis pipeline was not completed; therefore, no operculum connectivity outcomes were generated or analyzed for this study. | The clinical trial allowed for in-person or fully remote participation; and when participating fully remote, in-person data collection were allowed not to be collected (e.g. MRI scan, blood banking for microRNA). Therefore, the clinical trial did not have sufficient paired data collected to analyze MRI or microRNA outcomes. For the MRI data, no change can be determined with only 1 timepoint. Data do not exist for a change analysis. | Posted | 7 weeks |
|
|
| Primary | microRNA-485 Levels | use Next-Generation sequencing to assess miR-485 levels | This outcome measure was prespecified at study registration, but the laboratory analysis required to generate miRNA data was not conducted. As a result, no data exist to summarize or report for this outcome. Samples failed pre-analytical quality control required for miRNA extraction and PCR quantification; therefore, miRNA assays were not performed and no miRNA data were generated | Posted | baseline |
|
|
| Primary | microRNA-485 Levels | use Next-Generation sequencing to assess miR-485 levels | This outcome measure was prespecified at study registration, but the laboratory analysis required to generate miRNA data was not conducted. As a result, no data exist to summarize or report for this outcome. Samples failed pre-analytical quality control required for miRNA extraction and PCR quantification; therefore, miRNA assays were not performed and no miRNA data were generated | Posted | 7 weeks |
|
|
| 0 |
| 21 |
| 0 |
| 21 |
| 15 |
| 21 |
| EG001 | Control Group | Participants with severe neuropathic pain will receive placebo drug Placebo: Participants will receive placebo drug | 0 | 19 | 0 | 19 | 9 | 19 |
| Capsule Size Intolerance | Product Issues | Non-systematic Assessment |
|
| Drowsiness/ Fatigue | General disorders | Non-systematic Assessment |
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| Headache | Nervous system disorders | Non-systematic Assessment |
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| Pain | Nervous system disorders | Non-systematic Assessment |
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| Mood | Psychiatric disorders | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Spasticity | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| D014947 | Wounds and Injuries |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |