Optimal Treatment of Acute Skeletal Muscle Injury

February 15, 2024 updated by: Monika Lucia Bayer, Bispebjerg Hospital

Optimal Treatment of Inflammation Following Acute Skeletal Muscle Injury

Acute muscle strain injuries occur both during sports, in leisure time activities and during manual occupation and represent a major clinical challenge and has societal economic costs. The recovery time is long and a substantial injury recurrence is observed. Despite current best evidence rehabilitation with early mechanical loading, a significant loss of muscle mass, fatty infiltration and formation of scar tissue is reported.

Animal models and human in vitro experiments suggest that inflammation is vital in the early period after an injury, however an inhibition of inflammatory processes is beneficial for healing.

We investigate here whether a pharmacological inhibition of inflammatory pathways in the 2nd week following a muscle strain injury will provide a better clinical outcome and an advantageous cellular profile than rehabilitative training alone would.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Injuries in skeletal muscle occur in sports, under recreational activities and during manual occupational work, and it represents both a significant clinical challenge and a burden for the individual in the form of long-term functional disability and pain, and for society causing a major economic cost (Ekstrand 2011). Traumatic muscle strain injuries occur most often in the hamstring and the calf region, are caused by high-force movements and most often result in a partial defect at the muscle-tendon (aponeurosis) interface (Tidball 1993, 2017). A major clinical challenge is that the recovery after a traumatic muscle strain injury is often long and in addition to this, substantial injury recurrence is observed. Several studies estimate that 80% of re-injuries occur at the site of the original injury (Wangensteen 2016).

It is known that early mechanical loading is important for shortening the period until pain-free return-to-sport (Bayer 2017). Whereas that study supports the role for mechanical loading in tissue repair and clinical recovery in the form of pain-free return to sports, early loading did not prevent muscle strength reduction and a significant loss of muscle mass in the injured muscle group, indicating that the recovery of the injured region is incomplete (Bayer 2018).

Experimental muscle injury precipitates an inflammatory response in the damaged tissue, which includes sequential infiltration of many cells and the release of inflammatory cytokines and growth factors (Chazaud 2016). Further, a study with human muscle cells and tissue after experimentally induced muscle injury found that a pro-inflammatory phase characterized by M1-macrophages was obligatory needed in the first 7 days after injury in order to initiate the healing process, manifested as proliferation capacity of the myogenic precursor cells (MPC) (Saclier 2013). It can be argued thus that a blockade of this proinflammatory phase would inhibit the healing process. In contrast, to advance the healing process after this initial pro-inflammatory phase, a switch to more anti-inflammatory activity - M2-macrophage activity - was needed in the later phase (7-14 days) to ensure differentiation of the MPC and thus a continued regeneration of tissue (Saclier2013). It is therefore possible that this anti-inflammatory stage is vital and that continued inflammation would cause an overall suboptimal healing response. Recently, a long-lasting inflammatory response after a muscle strain injury was reported. Based on analysis of injury exudates, very high levels of several pro-inflammatory factors were observed (Bayer 2019). Persistent presence of inflammation is linked to the development of fibrotic tissue changes in the long run (Wynn 2016) and importantly, fibrotic changes have been described following strain injuries (Bayer 2021, Silder 2008). Also, as prolonged elevated TNF-α (tumor necrosis factor-α) is known as an activator of the Nuclear Factor NF-κB pathway, this could cause stimulation of muscle atrophy related genes (Cohen 2015). It appears therefore clinically relevant to ensure that the pro-inflammatory phase following strain injuries is initially undisturbed, but the continuous pro-inflammatory phase is blunted to reduce the formation of fibrosis.

The aim of the present study is to test the hypothesis that an inhibition of inflammation, combined with the best standard training regimen in the later phase of recovery after injury (day 7-14) will provide a more optimal tissue recovery after injury than training alone will do.

The overall hypothesis is that administration of NSAID in the second week after an acute muscle strain injury in otherwise healthy humans, will be beneficial for tissue healing, characterized by an improved cellular composition allowing for less scar formation in the regeneration phase.

Participants will undergo a basic physical examination, including ultrasonographic scanning of the injured muscle site and fulfill questionnaire regarding previous injury history and present activities as well as symptoms.

Participants are then randomized to either placebo or NSAID treatment (Bonyl/ Naproxen 500 mg x 2 per day for 7 days) starting on day 7 and continued until day 14 post injury.

When participants are free of pain during movement including repeated explosive movements, the duration of the injury onset until full recovery is recorded (time to return to sports). Each participant will be followed by questionnaires for one year to record potential re-injuries.

Biopsies will be taken in week 1 post injury, before the pharmacological intervention, and in week 3 post injury, after the pharmacological intervention.

Biopsies will be analyzed by single nuclei RNA sequencing. Bioinformatics will be applied to investigate the distribution and number of cells in the injured muscle. Each biopsy will be compared to the control muscle (the same muscle as the injured one on the healthy, contralateral leg).

The biopsies will be obtained with a semi-automatic equipment that is routinely used to sample tendon tissue and tissue from chronic scar area in muscle (Bard Monopty) with a diameter of 1,6 mm a length of 10 mm.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Sports-active individuals with an acute muscle train injury in either the hamstrings or calf muscle caused by an explosive movement (during sprinting, jumping etc)
  • Age older than 18 years

Exclusion Criteria:

  • Lack of hypoechoic/ hyperechoic area on ultrasound
  • Diabetes type I and II
  • Connective tissue disorders, rheumatism or any other chronic disease affecting the musculoskeletal system
  • Anticoagulant medication
  • Needle phobia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Anti-inflammatory medicine
Week 2 after muscle strain injury Naproxen 500mg 2x daily
Drug: Naproxen 500 Mg
Attenuating the sub-acute inflammatory processes to monitor potential beneficial tissue healing following a muscle strain injury
Other Names:
  • Anti-inflammatory Agents, Non-steroidal
Procedure: Rehabilitation
Rehabilitation after muscle strain injury
Other Names:
  • Physical therapy to stimulate tissue healing
Placebo Comparator: Placebo
Week 2 after muscle strain injury Placebo pill, no active compounds 2x daily
Procedure: Rehabilitation
Rehabilitation after muscle strain injury
Other Names:
  • Physical therapy to stimulate tissue healing
Drug: Placebo
Sub-acute inflammatory processes not attenuated. Group will be treated as control to monitor tissue healing following a muscle strain injury without pharmacological intervention.
Other Names:
  • inert pills

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect of anti-inflammatory medicine on cellular profile in skeletal muscle
Time Frame: 12 months
Single-nuclei RNA sequencing (seq) of muscle tissue after a strain injury. Single nuclei RNA seq will be performed on biopsies obtained in week 1 after the strain injury. The cellular profile will be compared to the contralateral healthy muscle. Another biopsy, in both the injured and contralateral healthy muscle will be taken in week 3 post injury to investigate the effect of one week of Naproxen treatment versus inert placebo pills on the cellular profile measured with single nuclei RNA seq.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional outcome performance
Time Frame: Up to 12 months
Return-to-Sport. The time from onset of injury until the participants full and pain-free return to sport will be recorded.
Up to 12 months
Functional outcome re-injury rate
Time Frame: 12 months
The number of re-injuries, participants sustain within 12 months after the initial strain injury will be recorded.
12 months
Functional outcome Patient Related Outcome Measures (PROM)
Time Frame: 12 months
Participants will be asked to fill in a strain injury specific questionnaire as a "Patient related outcome measures ("PROM"). The questionnaire has 5 sub-categories including pain, symptoms, soreness, function during daily activities and sports and quality of life.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Bispebjerg Hospital

Investigators

  • Study Director: Michael L Kjaer, DMSCi, Bispebjerg Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

February 15, 2024

Primary Completion (Estimated)

July 31, 2025

Study Completion (Estimated)

December 31, 2029

Study Registration Dates

First Submitted

January 30, 2024

First Submitted That Met QC Criteria

February 15, 2024

First Posted (Estimated)

February 23, 2024

Study Record Updates

Last Update Posted (Estimated)

February 23, 2024

Last Update Submitted That Met QC Criteria

February 15, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-22038917

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Inflammation

Clinical Trials on Naproxen 500 Mg

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Canada

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe