Valproic Acid for the Prevention of Post-Amputation Pain

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.

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