Vitamin D and n-3 Polyunsaturated Fatty Acids (PUFAs) to Prevent Chronic Pain Following Major Thermal Burn Injury

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to develop a safe, effective, and readily available treatment that will prevent chronic pain following Major Thermal Burn Injury (MThBI). Burn survivors are prone to develop chronic pain and there is an urgent unmet need for preventative treatments. The preventative treatments proposed for this study, Omega-3 Fatty Acids (O3FA) and Vitamin D have been selected given effectiveness across a range of painful musculoskeletal disorders and their wide availability and low cost. This study is a 2x2 factorial, double-blind, placebo-controlled randomized controlled trial test for the effectiveness of O3FA and Vitamin D to prevent chronic pain development. Burn survivors will be enrolled who have experienced thermal burns that cover less than 30% total body surface area that are severe enough to warrant surgical management, which represents the most common burn injury characteristics. Patients will be enrolled within 72 hours of their burn, and randomized via 1:1:1:1 allocation to receive placebo, O3FA, Vitamin D or both. The investigators will obtain blood samples on enrollment and at 6 weeks to assist in elucidating key mechanisms by which O3FA and Vitamin D reduce chronic pain following MThBI. Chronic pain severity, assessed with a 0-10 numeric rating scale at 6 weeks, 3 months, 6 months and 1 year will be entered into a repeated-measures model. Model estimated contrasts will serve as the primary outcome.

Detailed Description
-----------------
Patients will be screened daily. Patients who meet eligibility criteria will be approached for participation. Patients interested in participating will proceed through informed consent. Once informed consent is obtained, an initial questionnaire will be administered, a blood draw will be performed to assess for baseline Vitamin D/O3FA concentration and immune profile. Then patients will be randomized into one of 4 treatment arms in 1:1:1:1 allocation. Patients will receive study drug for 6 weeks following burn injury. Adverse event monitoring will occur daily while inpatient and weekly once discharged from the hospital through 6 weeks. Patient compliance with the study drug will be assessed via patient-reported reported missing doses, pill counts at the end of the study, and a 6-week blood draw in which Vitamin D/O3FA levels and immune profile will be assessed. Patient-reported outcomes will be collected via follow-up survey at 6 weeks, 3 months, 6 months, and 1 year following burn injury.s, and 1 year following burn injury.

Official Title
-----------------
Pilot, Double-blind, Randomized Controlled, Multi-center Study of the Effects of Fish Oil and Vitamin D in the Prevention of Chronic Pain Following Major Thermal Burn Injury

Conditions
-----------------
Chronic Pain Following Thermal Burn Injury

Intervention / Treatment
-----------------
* Drug: Omega-3 fatty acids (fish oil)
* Drug: Vitamin D3 (cholecalciferol)
* Drug: Vitamin D3 (cholecalciferol) placebo
* Drug: Omega-3 fatty acid placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥ 18 years and ≤ 65 years of age Admitted to burn center within 72 hours of thermal burn injury Estimated Total Body Surface area (TBSA) ≤ 30% Surgical team has plans for surgical management of the burn wound (e.g. xenograft and/or autograft). Patients experience a thermal burn injury, not an electrical or chemical burn. Has a telephone to receive follow-up calls. Able to speak and read English Resides within 150 miles of study site Alert and oriented Willing to take study medication for 6 weeks following enrollment Subjects are capable of giving informed consent. Predicted probability of chronic pain ≥ 0.3 when demographic parameters are entered into a logistic regression model developed from a previous cohort. (Initial pain score entered into this model will be based on the highest pain severity over the initial 24 hours of hospital admission). European American or African American Exclusion Criteria: Unwilling to take study drug Allergy to fish oil or corn/soybean oil. Patient taking clopidogrel (Plavix) Patient taking warfarin or dabigatran. Substantial comorbid injury (e.g. long bone fracture) Pregnancy/Breastfeeding Prisoner status Chronic daily opioid use prior to burn (>20 mg oral daily morphine equivalents). Active psychosis, suicidal ideation, or homicidal ideation Requires an escharotomy or fasciotomy for the treatment of burn injury. Has a disorder of pain processing or diminished capacity to perceive pain (congenital insensitivity to pain) Known Child-Pugh liver disease severity classification B or C. Known chronic kidney disease stage 4 or higher (GFR≤29). Known Hemophilia A/B Known bleeding dyscrasia History of an inability to tolerate fish oil or corn/soybean oil. Severe gastroesophageal reflux disease No other history or condition that would, in the investigator's judgment, indicate that the patient would very likely be non-compliant with the study or unsuitable for the study (e.g. might interfere with the study, confound interpretation, or endanger patient). Intubated and sedated at time of enrollment. Hypersensitivity to Vitamin D3, ergocalciferol, calcitriol, alfacalcidol, calcipotriol Hypercalcemia (if not already completed, this will be assessed by clinical labs with albumin correction prior to enrollment). Hypervitaminosis Sarcoidosis Hyperphosphatemia Arteriosclerosis Active myocardial ischemia Frequent antacid use (calcium carbonate, cimetidine) Cholestyramine or Colestipol use Taking Vitamin D supplements in excess of 800 IU daily. Taking >1g of fish oil per day.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2x2 Factorial design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: n-3 PUFA (O3FA) + Vitamin D3<br>4g fish oil in 4 softgels (n-3 PUFA/O3FA) + 2000 IU Vitamin D3 in 1 capsule | Drug: Omega-3 fatty acids (fish oil)<br>* 4 capsules comprising approximately 2 grams of Eicosapentaenoic acid/Docosahexaenoic acid (EPA/DHA) in a 3:2 ratio (this will require a total dose of 4 grams of fish oil). This will be administered daily, by mouth for 6 weeks<br>* Other names: n-3 fatty acids;Drug: Vitamin D3 (cholecalciferol)<br>* 1 capsule containing 2000 IU of Vitamin D3. This will be administered daily, by mouth for 6 weeks following enrollment.<br>* Other names: Vitamin D3;|
| Experimental: n-3 PUFA (O3FA) Placebo + Vitamin D3<br>4g of corn/soy oil blend in 4 softgels + 2000 IU Vitamin D3 in 1 capsule | Drug: Vitamin D3 (cholecalciferol)<br>* 1 capsule containing 2000 IU of Vitamin D3. This will be administered daily, by mouth for 6 weeks following enrollment.<br>* Other names: Vitamin D3;Drug: Omega-3 fatty acid placebo<br>* 4g of corn/soy oil blend in 4 softgels. This will be administered daily, by mouth for 6 weeks following enrollment.<br>* Other names: PUFA Matching Placebo;|
| Experimental: n-3 PUFAs (O3FA) + Vitamin D3 Placebo<br>4g fish oil in 4 softgels (n-3 PUFA/O3FA) + Vitamin D3 matching Placebo, an inert white powder placebo in 1 capsule | Drug: Omega-3 fatty acids (fish oil)<br>* 4 capsules comprising approximately 2 grams of Eicosapentaenoic acid/Docosahexaenoic acid (EPA/DHA) in a 3:2 ratio (this will require a total dose of 4 grams of fish oil). This will be administered daily, by mouth for 6 weeks<br>* Other names: n-3 fatty acids;Drug: Vitamin D3 (cholecalciferol) placebo<br>* 1 capsule containing inert substance. This will be administered daily, by mouth for 6 weeks following enrollment.<br>* Other names: Vitamin D3 Matching Placebo;|
| Placebo Comparator: n-3 PUFA (O3FA) Placebo + Vitamin D3 Placebo<br>4g n-3 PUFA/O3FA Matching Placebo, a corn/soy oil blend in 4 softgels + inert white powder Vitamin D3 matching placebo in 1 capsule | Drug: Vitamin D3 (cholecalciferol) placebo<br>* 1 capsule containing inert substance. This will be administered daily, by mouth for 6 weeks following enrollment.<br>* Other names: Vitamin D3 Matching Placebo;Drug: Omega-3 fatty acid placebo<br>* 4g of corn/soy oil blend in 4 softgels. This will be administered daily, by mouth for 6 weeks following enrollment.<br>* Other names: PUFA Matching Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative Review of Treatment-Related Adverse Events | A primary objective of this pilot study is to ensure safety of both treatments as well as combined. A qualitative review of treatment-related adverse events will be performed and a determination about the degree of relatedness of each adverse event with the intervention using CTCAE criteria will be made as CTCAE criteria assesses relatedness to therapy. Investigator reviewing the details of each adverse event rated the likelihood of relatedness to the study drug on a scale: (unrelated, unlikely, possible, probably, definitely). | 6 weeks following burn injury | 
| Percent of Participants Who Are Compliant With Follow-up (Feasibility) | The primary objective of this pilot study is to ensure that the investigators are able to make follow-up assessments on a majority of participants. The percent of participants who are compliant with follow-up will be determined 6 weeks following major thermal burn injury. Feasibility is defined as >80% of enrolled participants at 6 weeks following Major Thermal Burn Injury (MThBI). | 6 weeks following burn injury | 
| By Group Efficacy Estimates Over Year Following Thermal Burn Injury | Estimates of efficacy will be obtained via repeated measures analysis of pain severity over the 1 year following injury using mixed effects models. Pain will be assessed using a 0-10 numeric rating scale with 0 indicating no pain and 10 indicating pain as severe as you can imagine. Higher scores represent worse outcome. These values (collected in identical fashion over 1 year following burn injury) will be entered into a linear mixed model, and overall effect estimates (beta coefficients) among groups will be determined. Final model was a piece-wise linear mixed model, with a cut-point at 6 weeks. Mixed models were adjusted for age, sex, race, initial pain severity. Every 1 unit change in beta coefficient represents a 1 unit change in pain severity on the 0-10 numeric rating scale. | Over 1 year following MThBI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sex Differences in Treatment Response Based on Pain Scores | Examines existence of gender-based treatment response differences in pain severity measured by a 0-10 numeric rating scale where 0 is no pain and 10 is the most severe pain. Higher scores reflect greater pain (poor outcome). | 6 weeks following burn injury | 
| General Mental Health as Measured by the Short Form (SF)-12 General Mental Health Component Scores | Assessment of mental health will be determined by the short form (SF)-12 mental component score. The short form SF-12 Health Survey is a 12-item participant completed questionnaire to measure general health. It includes a mental component score (MCS): ranging from 0 to 100 points. Low values represent a poor health state and high values represent a good mental health. | 6 weeks following burn injury | 
| General Physical Health by Treatment Group Measured by the SF-12 General Physical Health Component Scores | Assessment of physical health will be determined by the SF-12 physical component score. The SF-12 Health Survey is a 12 item participant completed questionnaire to measure general health. It includes a physical component score (PCS): ranging from 0 to 100 points. Low values represent a poor physical health and high values represent a good physical health. | 6 weeks following burn injury | 
| Pain Interference by Treatment Group Measured by the Brief Pain Inventory | The degree to which pain interferes with important life function will be determined by the Brief Pain Inventory. This is a validated, self-reported scale that measures the severity of pain based on the average pain experienced and assesses impact of pain across 7 domains of life function (e.g., enjoyment of life, relationships, normal work). The total severity scores range from 0 (no interference) to 70 (maximum interference). Higher scores reflect greater pain interference. | 6 weeks following burn injury | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
burn injury, thermal burn injury, omega 3 fatty acids, vitamin D, fish oil, chronic pain, chronic pain due to trauma