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.
