Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study)

NCT ID: NCT01789216

Last Updated: 2021-02-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

450 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-07-31

Study Completion Date

2018-12-31

Brief Summary

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The purpose of this study is to definitively resolve questions regarding the use of multimodal pharmacologic pain management for orthopedic trauma patients in the context of a multicenter, randomized clinical trial.

Also, as a significant proportion of this population develops chronic post traumatic osteoarthritis (PTOA), a sub-objective of this study is to examine the etiology and incidence of chronic pain and PTOA in this population.

Detailed Description

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In this study, will test whether adjunctive analgesic therapy during the pre and peri-operative period, in addition to standard of care pain management, can improve overall pain control and pain related outcomes without increasing analgesic related side effects.

Patients will be randomized into three treatment groups. The intervention will begin within 48 hours of admission and continue for up to the time of definitive fixation.

Group 1: standard pain management, plus intravenous and oral placebo for up to 48 hours following definitive fixation.

Group 2: standard pain management, plus intravenous NSAIDs (ketorolac) and oral placebo for up to 48 hours following definitive fixation.

Group 3: standard pain management, plus intravenous placebo and oral pregabalin for up to 48 hours following definitive fixation.

Specific Aim 1: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus peri-operative NSAIDs (Group 2 - meloxicam + ketorolac) in the treatment of severe limb fractures.

Hypothesis 1a: When compared to patients who received standard of care pain management, patients treated with NSAIDs will: (1) have reduced post operative opioid utilization; (2) report reduced levels of persistent pain; and (3) have noninferior rates of surgery for nonunion.

Hypothesis 1b: When compared to patients who received standard of care pain management, patients treated with NSAIDs will benefit from (1) improved post operative pain control; (2) improved pre operative pain control; (3) reduced lengths of stay; (4) reduced pain interference; (5) improved functional outcomes; (6) lower levels of depression and post-traumatic stress disorder (PTSD); (7) improved overall health status; and (8) have noninferior rates of analgesic treatment related side effects.

Specific Aim 2: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus pre and peri-operative pregabalin (Group 3) in the treatment of severe limb fractures.

Hypothesis2a : When compared to patients who received standard of care pain management, patients treated with pregabalin will: (1) have reduced post operative opioid utilization; (2) report reduced levels of persistent pain; and (3) have noninferior rates of surgery for nonunion.

Hypothesis 2b: When compared to patients who received standard of care pain management, patients treated with pregabalin will benefit from (1) improved post operative pain control; (2) improved pre operative pain control; (3) reduced lengths of stay; (4) reduced pain interference; (5) improved functional outcomes; (6) lower levels of depression and post-traumatic stress disorder (PTSD); (7) improved overall health status; and (8) have noninferior rates of analgesic treatment related side effects.

Specific Aim 3: Estimate the incremental cost effectiveness of each adjunctive analgesic therapy relative to standard of care analgesic therapy in the treatment of severe limb fractures. Costs will be estimated from both the health care provider perspective and the societal perspective. The time horizon for cost-effectiveness analysis will be based on the actual period of observation. Incremental cost-effectiveness ratios will be calculated for: (a) study group 2 (NSAIDS - meloxicam + ketorolac) relative to standard of care; and (b) study group 3 (pregabalin) relative to standard of care. For purpose of cost-effectiveness analysis, the effect will be measured as unit change in specific outcome metrics at up to 15 months (or longer period as available) compared to baseline. The following cost-effectiveness metrics, all relative to standard of care, will be reported:

1. incremental cost per unit change in the Brief Pain Inventory
2. incremental cost per unit change in the Short Muscular Function Assessment (SFMA)
3. incremental cost per unit change in health state preference ("utility") as derived from the VR-12.

PTOA Pilot Study: Additional funding was received from NIH to conduct a pilot, observational study of post-traumatic osteoarthritis (PTOA), leveraging current resources of the Pain study. PTOA is an important outcome in the population to be enrolled in the Pain study. The aims of the PTOA Study are to: (1) measure the incidence of PTOA and chronic pain for up to 24 months following fracture reduction surgery and (2) quantify the extent to which fracture severity and post-reduction contact stress are related to the development of PTOA. Accomplishment of these aims will require (1) for all patients with ankle fractures in the Pain study: complete a PTOA survey at 12 months and at any subsequent visits that are conducted as part of standard of care and provide access to all standard of care imaging studies completed during the study period and (2) for a subset of 60 pilon fracture patients enrolled in the Pain study for whom post-operative CT scans are not standard of care, obtain additional consent for completion of a study-funded post-operative CT scan and 24 month radiographic study

Conditions

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Orthopaedic Fractures

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Placebo

Standard pain management + perioperative intravenous placebo \& oral placebo.

Control group will receive an oral dose of placebo up to two hours prior to surgery and twice daily for up to 48 hours following any surgery, in addition to an intravenous dose of placebo up to two hours prior to surgery and every 6 hours for up to 48 hours following surgery. All study medications will be in addition to standard of care pain medication.

\*Previous preoperative protocol was removed due to difficulty of medication adherence and limited importance of preoperative regimen to the intervention overall.

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

NSAID

Standard pain management + perioperative intravenous ketorolac \& oral placebo.

The NSAID group will receive 30 mg of intravenous (IV) ketorolac (Ketorolac 30 mg/ml dose vial, NDC 00409-3795-01; manufacturer: Hospira) administered up to two hours prior to the procedure and every 6 hours for up to 48 hours following the procedure. In addition, as part of the perioperative protocol, patients will receive an oral dose of placebo up to two hours prior to the procedure and every 12 hours for up to 48 hours following the procedure.

\*Previous preoperative protocol was removed due to difficulty of medication adherence and limited importance of preoperative regimen to the intervention overall.

Group Type ACTIVE_COMPARATOR

NSAID

Intervention Type DRUG

Gabapentinoid

Standard pain management + perioperative intravenous placebo \& oral pregabalin.

The Pregabalin group will receive an oral bolus dose of 300 mg of pregabalin up to two hours prior to the procedure and a 75 mg dose every 12 hours for up to 48 hours following the procedure. In addition, as part of the perioperative protocol, patients will receive an IV dose of placebo up to two hours prior to the procedure and every 6 hours for up to 48 hours following the procedure.

\*Previous preoperative protocol was removed due to difficulty of medication adherence and limited importance of preoperative regimen to the intervention overall.

Group Type ACTIVE_COMPARATOR

Gabapentinoids

Intervention Type DRUG

Interventions

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NSAID

Intervention Type DRUG

Gabapentinoids

Intervention Type DRUG

placebo

Intervention Type DRUG

Other Intervention Names

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Meloxicam/Mobic (NDC 68382-000-01; manufacturer: Zydus; encapsulated in size AA empty capsule shells, backfilled with Avicel by Fisher Clinical Services (Bristol) LLC) Ketorolac/Toradol (NDC 00409-3795-01; manufacturer: Hospira) Pregablin/Lyrica (NDC 00071-1014-68; manufacturer: Pfizer; encapsulated in size AA empty capsule shells, backfilled with Avicel by Fisher Clinical Services (Bristol) LLC,; Lyrica, NDC 00071-1018-68; manufacturer: Pfizer; encapsulated in size AA empty capsule shells, backfilled with Avicel by Fisher Clinical Services (Bristol) LLC)

Eligibility Criteria

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Inclusion Criteria

1. Patients with one of the following types of injuries:

1. Unilateral, Grade I \&II open or closed pilon (distal tibial plafond), calcaneus, talus fractures and Lisfranc dislocations requiring operative treatment with fixation; or
2. Unilateral, open (type I, II, or IIIA) ankle fractures with associated dislocation on presentation (OTA 44B3 or 44C) requiring operative treatment with fixation; or
3. Unilateral, open or closed distal and proximal humerus (OTA 11A-C and OTA 13 A-C); or
4. Open femoral shaft fracture (OTA 32 A-C; Gustilo Type I-IIIC) or open or closed supracondylar femur fractures (OTA 33 A-C); or
5. Open or closed tibial plateau or shaft fractures (OTA 42 A-C or 43 A-C)
6. Any combination of the above injuries which are surgically treated as a whole
2. Patients who present to the admitting hospital acutely or clinic following an initial assessment in the Emergency Department, for care up to 10 days following initial injury.
3. Patients 18-80 years old inclusive.
4. Patients who are English or Spanish competent.
5. Treating physicians agree that none of the study drugs are indicated for standard of care treatment for this patient.
6. Patients able to be followed at the METRC facility for at least 12 months following injury.

Exclusion Criteria

1. Patients unable to provide informed consent.
2. Patients with chronic pain being presently treated with opioid or gabapentinoid prescription or any other alternative therapy.
3. Patients who are current IVDA
4. Patients with bilateral or ipsilateral injuries requiring surgery
5. Patients with other orthopedic or non-orthopedic injuries requiring operative intervention
6. Patients with severe osteopenia.
7. Patients who are skeletally immature (defined as less than 18 years of age or no radiographic evidence of epiphyseal closure).
8. Patients who are expected to have a post-surgical stay less than 24 hours.
9. Patients with a history of allergy to any drugs in the study.
10. Patients unable to swallow oral medications or without adequately functioning GI tract.
11. Patients with a history of gastrointestinal bleeds or gastric perforation.
12. Patients with a history of stroke or heart attack.
13. Patients currently receiving an aspirin or NSAID regimen (exception: low dose (81 mg) aspirin. See section 6.5) Patients with any bleeding disorders.
14. Patients with severe renal failure. Patients with moderate renal failure may participate in the study at a modified dose. See Section 9.6.
15. Patients undergoing daily treatment with systemic glucocorticoids before surgery.
16. Patients using angiotensin-converting enzyme (ACE) inhibitors, who may be at increased risk of developing angioedema with pregabalin.
17. Patients likely to have severe problems maintaining follow-up, including patients diagnosed with a severe psychiatric conditions, patients who live too far outside the hospital's catchment area, patients who are incarcerated and patients who have unstable housing situations.
18. Patients who experienced a loss of consciousness consistent with a clinical diagnosis of a closed head injury, or concern of a cerebrovascular bleed secondary to traumatic brain injury.
19. Patients with a GCS \<15
20. Patient speaks neither English nor Spanish.
21. Patients who are pregnant or lactating at time of screening
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Major Extremity Trauma Research Consortium

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Renan Castillo, PhD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins Bloomberg School of Public Health

Lawrence Marsh, MD

Role: PRINCIPAL_INVESTIGATOR

University of Iowa Hospitals & Clinics

Katherine Frey, RN, MPH, MS

Role: STUDY_DIRECTOR

Johns Hopkins Bloomberg School of Public Health

Locations

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University of Miami Ryder Trauma Center

Miami, Florida, United States

Site Status

St. Mary's Medical Center

West Palm Beach, Florida, United States

Site Status

Eskenazi Health

Indianapolis, Indiana, United States

Site Status

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States

Site Status

Louisiana State University Health Sciences Center

Shreveport, Louisiana, United States

Site Status

Johns Hopkins University

Baltimore, Maryland, United States

Site Status

University of Maryland, R Adams Cowley Shock Trauma Center

Baltimore, Maryland, United States

Site Status

Boston Medical Center

Boston, Massachusetts, United States

Site Status

Hennepin County Medical Center

Minneapolis, Minnesota, United States

Site Status

Carolinas Medical Center

Charlotte, North Carolina, United States

Site Status

MetroHealth Medical Center

Cleveland, Ohio, United States

Site Status

Penn State University M.S. Hershey Medical Center

Hershey, Pennsylvania, United States

Site Status

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Site Status

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Site Status

UT Health: The University of Texas Health Science Center at Houston Medical School

Houston, Texas, United States

Site Status

Naval Medical Center Portsmouth

Portsmouth, Virginia, United States

Site Status

Countries

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United States

Other Identifiers

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W81XWH1020090

Identifier Type: -

Identifier Source: org_study_id

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