Clinical trial NCT06453447: Prednisone for CRPS in Distal Radius Fracture
Official title: Prednisone for the Early Treatment of Complex Regional Pain Syndrome After Distal Radius Fracture - a Pilot Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Complex Regional Pain Syndromes
Distal Radius Fractures
Keywords: wrist fracture
pain
orthopaedic surgery
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Canadian Orthopaedic Foundation
First posted: 2024-06-11
Enrollment: 40
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Wrist fractures are the most prevalent adult fracture. Complex regional pain syndrome (CRPS) is a common complication that can occur, leading to permanent disability and is costly to the patient and healthcare system. In addition, amidst the opioid epidemic, the risk of increased opioid use in patients with CRPS prompts the need to find viable treatment strategies. This study aims to evaluate an anti-inflammatory medication, prednisone, in the early treatment of CRPS. Patients with wrist fractures who undergo surgical treatment will be randomized to receiving placebo vs prednisone for 2 weeks. Clinical assessments in the follow up period will be compared.

Detailed description: Purpose:

Distal radius fractures are the most prevalent adult fracture, accounting for 17.5% of all fractures. Complex regional pain syndrome (CRPS) is a common complication that can occur in this population, with a reported incidence of up to 32%. CRPS can lead to permanent disability and is costly to the patient and to the healthcare system, with an estimated cumulative outpatient and pain prescription cost of $42,026 over 8 years after diagnosis. In addition, amidst the opioid epidemic, the risk of increased opioid use in patients with CRPS prompts the need to find viable treatment strategies.

While there have been various proposed treatment modalities, evidence from randomized studies is lacking. Several small studies (retrospective and prospective case series) have shown potential efficacy of glucocorticoids for the treatment of CRPS. To our knowledge, there are no randomized controlled trials that evaluate treatment of CRPS in distal radius fractures with glucocorticoids.

The purpose of this pilot study is to evaluate a short course of oral prednisone as potential treatment for patients identified as developing early signs of CRPS after sustaining a distal radius fracture that was treated operatively. We will examine feasibility metrics including patient recruitment rate, adherence to allocation and protocol, withdrawal from study, and follow-through, in order to inform design of a definitive clinical trial. We will also assess the resolution of CRPS, post-operative opioid use, and any adverse events in patients who sustain a distal radius fracture after receiving prednisone vs placebo for 2 weeks post-operatively, with 6 months follow up post injury.

Hypothesis:

We hypothesize that the proposed pilot trial will demonstrate feasibility of a future definitive trial.

In addition, we hypothesize that there will be higher rates of CRPS resolution, lower amounts of opioid consumption, and no increased adverse effects, and better clinical outcomes in patients who receive prednisone treatment compared to those who received placebo. However, formal hypothesis testing will not be performed for this pilot trial.

Justification:

Developing CRPS after sustaining a distal radius fracture can lead to devastating outcomes, including permanent disability, opioid dependency, and the inability to return to work. In addition, diagnosing CRPS can be a prolonged process due to the range of vague symptoms on presentation, which can lead to delay in treatment and worsening of outcomes. Patients with CRPS may require more follow-up and referrals, which further burdens the healthcare system.

The pathogenesis of CRPS is complex and not fully known; evidence suggests nervous system sensitisation, autonomic dysfunction, and inflammatory changes. There are numerous treatment options for CRPS, though little high-quality evidence supports their efficacy. These include but are not limited to oral anti-depressants, parenteral lidocaine and corticosteroids, surgical treatment with compressed nerve release, counselling, and occupational and physical therapy. Vitamin C has been proposed as effective prophylaxis for CRPS in distal radius fractures but data have been conflicting, with the most recent randomized controlled trial (RCT) in 2014 by Ekrol et al. showing no difference in functional outcomes or rate of CRPS in patients with distal radius fractures given Vitamin C versus placebo.

Given the prevalence of distal radius fractures in adults, a relatively high CRPS incidence in this population, and no established efficacious treatment options, more research is needed to determine evidence-based and effective treatment options for this destructive condition. Studies have identified that using glucocorticoids can potentially be effective and safe for treating patients with CRPS, possibly due to the anti-inflammatory properties of glucocorticoids. One retrospective study of patients undergoing surgery for terrible triad elbow (complex elbow fracture dislocation) injuries demonstrated improved elbow range of motion for patients receiving intraoperative dexamethasone and 6-day oral course of methylprednisolone compared to patients who did not, with no increased postoperative infection. Furthermore, the anti-inflammatory nature of glucocorticoids deserves investigation for its potential to decrease opioid consumption after distal radius surgery.

A variety of doses and duration of glucocorticoids have been used in studies to manage CRPS, with a recent review article by Kwak et al showing starting doses between 30 mg to 100 mg of prednisolone. Although glucocorticoids are known to be associated with adverse effects, most are only seen with long term therapy. In addition, studies have shown that a short-course of glucocorticoids (less than 3 to 4 weeks), irrespective of dose, do not require a tapering regimen and is not associated with increased risk of adrenal insufficiency. While osteoporosis and fracture non-union are known adverse events of long-term glucocorticoid use, this has not been demonstrated in literature for short-term use. Moreover, given the risk of non-union in distal radius fractures is exceedingly rare (0.2%), this calls for less concern for using glucocorticoids in this population.

Therefore, evaluating prednisone, a relatively cheap, accessible, and safe oral medication when used for a short duration, as an anti-inflammatory and potential early treatment agent for CRPS in distal radius fractures in this pilot study may have implications for the complication profile and functional outcome for this common fracture.

Research Design:

This will be a pilot double-blind randomized control trial in patients who sustain a distal radius fracture treated operatively with a volar locked plate and identified as at risk of developing CRPS. Follow up will be 6 months, involving 4 study visits that correspond to standard post-operative clinic visits.

Statistical Analysis:

A power analysis assuming incidence of 20% CRPS and absolute risk reduction (ARR) of 10% with prophylaxis yielded a sample size of 199 patients per arm, with 80% power and significance level (α) of 0.05 (performed using online sample size calculator at clincalc.com/stats/samplesize.aspx). Incidence and ARR were estimated based on previous RCTs assessing Vitamin C as prophylaxis for CRPS in distal radius fractures. We aim to recruit 10% for this pilot study, with 20 per arm (placebo vs prednisone), for a total of 40 patients.

The CONSORT guidelines for reporting of randomized pilot and feasibility trial will be followed for the analysis and reporting of results. An intention-to-treat analysis will be utilized.

Primary Outcomes: Descriptive statistics, reported as count and percentage, will be used to summarize the feasibility outcomes (95% CI). Table 2 presents the traffic lights criteria for each outcome of the pilot study. Green indicates feasible, red indicates not feasible, and yellow indicates likely feasible but will require adjustments to the protocol. (please see attached protocol)

Secondary and Tertiary Outcomes: Chi-square (or Fisher's Exact) test will be used to compare the proportion of CRPS between groups. Either Mann-Whitney U test or two-sample t test will be used for the other quantitative outcomes depending on the variable distribution. Multivariable regression analysis will be conducted to test for associations between the intervention and each outcome, controlling for differences in patient characteristics. All P values will be 2-sided and statistical significance will be set at P \< 0.05. For this pilot trial, formal hypothesis testing will not be performed as it is underpowered.

Eligibility criteria: Inclusion Criteria:

1. Patient is aged 19 years or older;
2. Patient has a unilateral, closed, distal radius fracture confirmed by radiographs;
3. The fracture is acute, within 14 days of injury;
4. Patient undergoes open reduction internal fixation with volar locking plate;
5. Patient is identified as at risk of developing CRPS with 2 or more of the following:

   1. Pain score on visual analogue scale (VAS) greater than or equal to 5/10 within 1 week of injury and beyond;
   2. Centre of Epidemiologic Studies Depression (CES-D) score on presentation is greater than or equal to 16;
   3. Patient identifies as female;
6. Patient is identified as developing signs of CRPS based on the Budapest CRPS Criteria;
7. Patient provides informed consent.

Exclusion Criteria:

1. Patient has previously fractured ipsilateral wrist;
2. Patient has neurovascular injury associated with distal radius fracture;
3. Patient has associated extremity or polytrauma injuries that would interfere with rehabilitation and outcome measurements, in the opinion of the investigator;
4. Patient has allergy to prednisone or placebo ingredients;
5. Patient has contraindication to prednisone or placebo ingredients;
6. Patient already takes a glucocorticoid medication;
7. Patient has active bacterial, viral, or fungal infection;
8. Patient is diagnosed with diabetes;
9. Patient is pregnant, planning on becoming pregnant, or breastfeeding;
10. Patient is anticipated to have difficulty completing study follow up, in the opinion of the investigator.

Primary outcomes:
measure: Proportion of patient recruitment
timeFrame: 6 months
measure: Proportion of patient adherence to treatment allocation and protocol - determined by patient self-reporting
timeFrame: 6 months
measure: Proportion of patients with missing data from secondary and tertiary outcomes
timeFrame: 6 months
measure: Proportion of patient consent withdrawal from the study
timeFrame: 6 months
measure: Proportion of complete patient follow up at 6 months
timeFrame: 6 months
Secondary outcomes:
measure: Resolution of CRPS
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
measure: Total opioid consumption
timeFrame: 2 weeks
measure: Adverse effects
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
Other outcomes:
measure: Visual analogue scale (VAS) pain score
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
measure: Centre of Epidemiologic Studies Depression (CES-D) score
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
measure: Short Form-36 item (SF-36) questionnaire
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
measure: Passive wrist range of motion (ROM)
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
measure: The disabilities of the arm, shoulder, and hand (DASH) questionnaire
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
measure: The Brief Resiliency Scale (BRS) questionnaire
timeFrame: 2 weeks, 6 weeks, 3 months, 6 months
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: David Stockton, MD, MASc, FRCSC
role: PRINCIPAL_INVESTIGATOR
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