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Valproic Acid for the Prevention of Post-Amputation Pain

Information source: Duke University
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pain, Phantom; Pain, Neuropathic

Intervention: Valproic Acid (Drug); Cherry Syrup (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
Thomas E Buchheit, MD, Principal Investigator, Affiliation: Duke University

Overall contact:
Dionne R Apedjihoun, MS, Phone: 919-286-0411, Ext: 7372

Summary

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: Efficacy of Valproic Acid in reducing the Incidence of chronic neuropathic and post-amputation pain.

Secondary outcome:

Neuropathic limb or post-amputation pain, and the incidence of pain sub-types

Effect on analgesic requirement

Qualitative characterization of pain sub-types

Detailed description: 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 420 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 378 evaluable patients (189 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. 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-month evaluation point, and the chronic pain will be defined as an average pain score of 3 points or greater on the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS). Secondary endpoints will include the numeric scores from the S-LANSS, Brief Pain Inventory (BPI), Defense and Veterans Pain Rating Scale (DVPRS) and the change in these scores from baseline to 3 months, as well as the incidence of neuropathic limb or post-amputation pain at 1 and 6 months after surgery. 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 effect of treatment on the primary endpoint and post-amputation pain by adjusting for potential prognostic variables including baseline pain level, study site and type of surgery. Two-sample t-tests will be used to assess treatment difference in changes of mean pain scales from baseline. In addition, linear regression will be used to assess the effect of treatment on changes in 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. 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 Durham Veterans Administration Medical Center (VAMC) and Walter Reed National Military Medical Center (WRNMMC) respectively.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

- End-stage renal disease requiring dialysis or Chronic Kidney Disease with creatinine

of 2. 5mg/Dl and above

- Contraindication to, or refusal of, regional anesthesia catheter

- BMI > 50

Locations and Contacts

Dionne R Apedjihoun, MS, Phone: 919-286-0411, Ext: 7372

Walter Reed National Military Medical Center, Bethesda, Maryland 20814, United States; Recruiting
Mary McDuffie, RN, Phone: 301-816-4722, Email: mmcduffie@dvpmi.org
Chester T Buckenmaier III, MD, Principal Investigator
Lisa L Bleckner, MD, Sub-Investigator

Duham VA Medical Center, Durham, North Carolina 27705, United States; Recruiting
Dionne R Apedjihoun, MS, Phone: 919-286-0411, Ext: 7372, Email: dionne.apedjihoun@dm.duke.edu
Mary M Kirkley, Phone: 919-681-1170, Email: Mary.kirkley@duke.edu
Thomas E Buchheit, MD, Principal Investigator
Andrew D Shaw, MD, Sub-Investigator
Thomas Van de Ven, MD, Sub-Investigator
Juliann Hobbs, MD, Sub-Investigator
Karthik Raghunathan, MD, Sub-Investigator
Srinivas Pyati, MD, Sub-Investigator
Cynthia K Shortell, MD, Sub-Investigator

Additional Information

Related publications:

Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD009183. doi: 10.1002/14651858.CD009183.pub2. Review.

Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, Kim JM, Park DK, Kun Lee S, Kim M, Roh JK. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis. 2007 May;26(2):464-72. Epub 2007 Feb 23.

Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation. J Biol Chem. 2003 Jul 25;278(30):27586-92. Epub 2003 May 14.

Zhang Z, Cai YQ, Zou F, Bie B, Pan ZZ. Epigenetic suppression of GAD65 expression mediates persistent pain. Nat Med. 2011 Oct 9;17(11):1448-55. doi: 10.1038/nm.2442.

Reiber GE, McFarland LV, Hubbard S, Maynard C, Blough DK, Gambel JM, Smith DG. Servicemembers and veterans with major traumatic limb loss from Vietnam war and OIF/OEF conflicts: survey methods, participants, and summary findings. J Rehabil Res Dev. 2010;47(4):275-97.

Starting date: December 2013
Last updated: August 3, 2015

Page last updated: August 20, 2015

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