Brivaracetam to Reduce Neuropathic Pain in Chronic SCI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Average Worst Neuropathic Pain Intensity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18 years of age or older
- •Injured for > 3 months
- •Completed inpatient rehabilitation and living in the community
- •Chronic sublesional neuropathic pain defined as persistent pain (VAS grade 3-10) for three months or more
- •For people of child-bearing potential: currently practicing an effective form of two types of birth control (defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly).
排除标准
- •Progressive myelopathy secondary to posttraumatic cord tethering or syringomyelia
- •Active use of drugs known to interact with brivaracetam: rifampin, carbamazepine, sodium oxybate, buprenorphine, propoxyphene, levetiracetam, and phenytoin.
- •Brain injury or cognitive impairment limiting the ability to follow directions or provide informed consent
- •Pregnancy or lactation
- •Epilepsy or active treatment for seizure disorder
- •Past or current suicidality
- •Active treatment for psychiatric disease
- •Drug addiction
- •Moderate or heavy alcohol intake (up to four alcoholic drinks for men and three for women in any single day, and a maximum of 14 drinks for men and 7 drinks for women per week)
- •Hepatic cirrhosis, Child-Pugh grades A, B, and C
- •Impaired renal function (GFR<60ml/minute)
- •Contraindications to brivaracetam or pyrrolidine derivatives including allergy
- •Active clinically significant disease (e.g., renal, hepatic, neurological, cardiovascular, pulmonary, endocrine, psychiatric, hematologic, urologic, or other acute or chronic illness) that, in the opinion of the investigator, would make the patient an unsuitable candidate for this trial.
- •History of malabsorption or other gastrointestinal (GI) disease that may significantly alter the absorption of brivaracetam
- •Use of any investigational drug 30 days prior to enrollment in this study
- •Enrollment in another clinical trial.
研究组 & 干预措施
Experimental group
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.
干预措施: brivaracetam (Drug)
Control group
Participants with severe neuropathic pain will receive placebo drug
干预措施: Placebo (Drug)
结局指标
主要结局
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Average Worst Neuropathic Pain Intensity
时间窗: 7 Weeks Post Intervention
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.
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Neuropathic Pain
时间窗: 7 Weeks Post Intervention
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.
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Intensity Averaged Over All Pain Sites
时间窗: 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 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.
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Day-to-Day Pain Interference
时间窗: 7 Weeks Post Intervention
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.
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference With Mood
时间窗: 7 Weeks Post Intervention
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.
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Pain Interference With Sleep
时间窗: 7 Weeks Post Intervention
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.
The International Spinal Cord Injury Pain Data Set (ISCIPBDS) (Version 2.0) - Change in Composite Pain Interference
时间窗: 7 Weeks Post Intervention
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.
Change in Operculum Brain Connectivity
时间窗: 7 weeks
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.
microRNA-485 Levels
时间窗: baseline
use Next-Generation sequencing to assess miR-485 levels
microRNA-485 Levels
时间窗: 7 weeks
use Next-Generation sequencing to assess miR-485 levels
次要结局
未报告次要终点