Valproic Acid for the Prevention of Post-Amputation Pain

Study Overview
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Brief Summary
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The objectives of this study are, to test the effectiveness of Valproic Acid (VPA) in the prevention of chronic neuropathic and post-amputation pain, as well as to further define the underlying inflammatory and epigenetic mechanisms that lead to the development of such chronic pain. HYPOTHESES AND QUESTIONS Hypothesis 1: The use of oral valproic acid in combination with regional anesthesia in surgical limb-injury patients will decrease the incidence of chronic nerve injury and post-amputation pain. Goal 1: In a blinded, randomized placebo-controlled, multi-center clinical trial, investigators will determine if oral VPA added to regional anesthesia and standard perioperative management will reduce the incidence of nerve injury and post-amputation pain when compared with regional anesthesia alone. Hypothesis 2: The transition from acute to chronic pain is mediated via epigenetic mechanisms (differential DNA methylation) in genes involved in nociception. Goal 2: Investigators will analyze the DNA methylation patterns of patients with different types of neuropathic and post-amputation pain and determine if they are altered by VPA.

Detailed Description
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RESEARCH DESIGN This study will be a prospective, randomized, double-blinded, placebo-controlled trial to test the efficacy of valproic acid (VPA) in reducing the incidence of chronic neuropathic and post-amputation pain following amputation, stump revision, and surgery for limb injury with neurologic damage. Patients randomized to the Control arm of the trial, will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and a placebo. Patients randomized to the Intervention arm of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for either 6 days post-operatively or until the time of discharge. METHODOLOGY The enrollment goal for the study (from all sites) will be 224 patients. Subjects will be recruited from the surgical clinics and the anesthesia pre-operative clinic. Outcomes for patients in the intervention arm will be compared with those managed with the current institutional standards of care including regional anesthesia catheter infusions. The study team anticipates a 10% drop-out rate at 3 months secondary to death and loss to follow up. Thus 202 evaluable patients (101 patients in each arm) at 3 months after surgery will be included in this study. After screening and enrollment, the study medication (VPA or placebo) will be administered. Research blood samples will be collected preoperatively, postoperatively (at the completion of study drug administration, and at the Amputation Clinic follow-up for expression analysis. The third and final blood draw will be taken at the 3 month follow up. If patient is unavailable the research team will make accommodations to collect blood sample at the 6 month follow up or at a time of maximal patient convenience, not to exceed 18 months from study enrollment. All samples will be de-identified and subsequently studied in our laboratory and core facilities at Duke. Study specific questionnaires will be administered during the hospital stay, at 1 month (via mail), at 3 months (in clinic) and at 6 months (in clinic when possible). RANDOMIZATION AND TREATMENT Randomization will be stratified by site and by surgical etiology. At the time of enrollment, subjects will be assigned to one of three surgical categories on the randomization assignment log: amputation, stump revision, or surgery for limb injury with neurologic damage. Prior to surgery, the Investigational Drug Pharmacist will dispense the study medication in liquid form and the container will be labeled study drug with no indication of the liquid contents. The pharmacist will be the only person aware of the treatment allocation. At the end of the trial, once endpoint adjudication has been completed for all study subjects, the study data and treatment allocation will be un-blinded. Initial drug administration will be performed prior to induction of anesthesia on the day of surgery. Subsequent doses will be administered at the bedside by the ICU or floor nurse depending on patient location. Participants will complete study drug administration unless they withdraw their consent or either their treating physician or the principal investigator believes it would be dangerous to continue valproic acid. If the subject withdraws during the administration of VPA, they will continue with their current medical regimen without alteration. DATA ANALYSIS PLAN The primary endpoint is the incidence of chronic pain at the 3 months or time of final adjudication evaluation point, and the chronic pain will be defined as an S-LANSS average pain score of 3 points or greater. Secondary endpoints will include the numeric scores from forms BPI, S-LANSS, and DVPRS and the change in these scores from baseline to 3 months or time of final adjudication, as well as the incidence of neuropathic limb or post-amputation pain at enrollment and 3 months or time of final adjudication. Frequency and percentage of the categorical variables in above endpoints will be reported by treatment arm and by assessed time. Mean, standard deviation and range of the mean scales of the above forms, as well as the changes of mean scales from baseline will be computed by arm and by assessed time. Two-sample chi-square tests will be used to assess the treatment difference of the primary endpoint and post-amputation pain (or neuropathic pain) at each time. Logistic regression will be applied to investigate the treatment difference on the primary endpoint and post-amputation pain by adjusting for potential prognostic variables including baseline pain level, study site, type of surgery, diabetes, and intervening therapies. Similar analyses will be carried out in study sub-groups of site, surgery type, and diabetic status. Two sample t-tests will be used to assess treatment difference in changes of mean scales from baseline. In addition, linear regression will be used to assess the treatment difference on changes of mean scales from baseline by adjusting for covariants. P values of less than 0.05 will be considered to indicate statistical significance. Intent-to-treat analysis will be performed. Sensitivity analyses will also be carried out by excluding patients who drop out before 3 month post-surgery. If the dropout rate is larger than 10% and if there is evidence that the missing mechanism is not MCAR (missing completely at random) but MAR (missing at random), multiple imputation will be conducted. RASS will be used during hospitalization to define any changes in sedation between study groups during drug administration. Analysis of clinical study data will be carried out with a de-identified download from REDCap. All of these data shared with the Duke Center for Human Genetics (CHG) will be fully stripped of all 18 Health Insurance Portability and Accountability Act (HIPAA)identifiers (ID). Private health information of study participants will be respected and all data analysis will be done in blinded fashion, such that individuals will not be identifiable from the final analysis dataset. Each patient will be allocated a study ID number when they sign a consent form, and thereafter will be referred to by that number. Investigators will have secure password protected access to REDCap in order to enter data. The dataset and biorepository will be fully de-identified once the dataset is complete and locked. Research blood samples are tracked and stored within our existing Laboratory Inventory Management System. All specimens are identified by barcode and are not identifiable except via a coding table held securely at Duke University Medical Center (DUMC), Durham Veterans Administration Medical Center (VAMC) and Walter Reed National Military Medical Center (WRNMMC) respectively.

Official Title
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Regional Anesthesia and Valproate Sodium for the Prevention of Chronic Post-Amputation Pain

Conditions
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Pain, Phantom, Pain, Neuropathic

Intervention / Treatment
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* Drug: Valproic Acid
* Other: Cherry Syrup


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female active duty military personnel or veterans, age 18 years and older. Patient is scheduled to undergo amputation, stump revision, or surgery for a limb injury with neurologic damage. Patient able to provide written informed consent prior to any study procedures. Exclusion Criteria: Severe Traumatic Brain Injury (Diagnosis of traumatic brain injury resulting in documented, permanent or prolonged cognitive deficits that would preclude participation in the study) Significant cognitive deficits or dementia of any cause as noted in Computerized Patient Record System(CPRS). Patient has a designated Legally Authorized Representative Substantial hearing loss without alternative means of communication. Patient has documented spinal cord injury with permanent or persistent deficits Patient is under age 18 or a legal Minor Current pregnancy or lactation Cirrhosis with evidence of decompensation: coagulopathy International Normalized Ratio (INR) >1.3, thrombocytopenia with platelets <100,000, ascites or hepatic encephalopathy Therapy with valproic acid or other valproates, coumadin, chlorpromazine and olanzapine at the time of surgery and study drug administration Current diagnosis of seizure disorder requiring anti-epileptic medication Current therapy with tricyclic antidepressants (eg: amitriptyline, nortriptyline, imipramine, desipramine) at doses greater than 50mg/day Currently taking zidovudine Current diagnosis of malaria requiring anti-malaria medication (such as mefloquine and chloroquine) Currently taking monoamine oxide inhibitors (MAOI) Allergy to valproates or valproic acid Contraindication to, or refusal of, regional anesthesia catheter BMI > 50

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cherry syrup<br>Cherry Syrup: Patients randomized to the Control arm of the trial will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and the placebo. | Other: Cherry Syrup<br>* Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid 250mg preoperatively, and then three times per day for 6 days post-operatively.<br>|
| Experimental: Valproic Acid<br>Intervention arm patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management, and valproic acid. | Drug: Valproic Acid<br>* Intervention patients will receive standard regional anesthesia catheters (either peripheral nerve or epidural catheter), anesthetic management and oral valproic acid 250mg preoperatively, then three times per day for either 6 days post-operatively or until discharge from the hospital.<br>* Other names: Depacon, Depakene, Depakote, Stavzor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Chronic Post-amputation Pain | The primary endpoint is the incidence of chronic pain after surgery. The study team will use the average pain score over the past week as noted on the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) for the assessment of pain, and define chronic pain as a score greater than or equal to 3. | 3 months or time of final adjudication assessment, up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Pain Sub-types | The incidence of neuropathic limb or post-amputation pain sub-types as defined by adjudication classification at each assessment time point. | Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months) | 
| Effect on Analgesic Requirement | The effect of study drug on perioperative analgesic consumption and corresponding analysis of pain/sedation scales. Outcome defined as total opioid consumption (mg) during each 24-hour periods following surgery. | Assessments during hospitalization (0-24 hours and 24-48 hours post-surgery) | 
| Brief Pain Inventory (BPI) Short Form Score | The BPI short form is a multidimensional patient-completed measure that assesses the sensory component of pain intensity. We will analyze the change in average pain score question (ranges 0-10) and the sum of the 7 interference questions (total range 0-70) from baseline. Higher score indicates greater pain and interference. | Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months) | 
| Change in Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (S-LANSS) | The S-LANSS is a self-reported version of the Leeds Assessment of Neuropathic Symptoms and Signs pain scale. It aims to differentiate neuropathic pain from somatic or nociceptive pain. We will analyze the change in numeric average pain score during the past week (range from 0-10) from baseline. Higher scores indicate greater pain. | Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months) | 
| Defense and Veterans Pain Rating Scale (DVPRS) Score | The DVPRS is a pain assessment tool developed by the military in an effort to improve reliability and interpretability of pain assessment in the military population. It has been found to be an effective and valid tool in this population. We will analyze the change in numeric pain response (range 0-10) and the sum of the four supplemental questions (range 0-40) from baseline. Higher scores indicate greater pain and functional limitations. | Assessments at enrollment and 3 months or time of final adjudication assessment (up to 6 months) | 
| Richmond Agitation-Sedation Scale (RASS) | The RASS is a commonly used, valid and reliable assessment tool for use in hospitalized patients. Validity testing reveals good inter-rater reliability among medical, surgical, and intensive care units. We will analyze the numeric score at each assessment (range -5 (unarousable) to 4 (combative)). | during hospitalization (0-24 hours and 24-48 hours post-surgery) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amputation, Post-amputation Pain, Neuropathic pain, Valproic Acid, Anesthesia, Conduction, Neuralgia, stump