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Alterations in Muscle After Total Knee Arthroplasty

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02281877
Recruitment Status : Suspended (On hold due to COVID-19 outbreak)
First Posted : November 4, 2014
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

Tracking Information
First Submitted Date  ICMJE October 7, 2014
First Posted Date  ICMJE November 4, 2014
Last Update Posted Date June 2, 2020
Study Start Date  ICMJE October 2014
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2014)
Catabolic gene expression [ Time Frame: Change in gene expression from immediately pre surgery to 2 weeks after surgery ]
Standard procedures including total RNA isolation, cDNA synthesis, cRNA labeling, microarray hybridization and image acquisition will be performed. Protein content (translation of MAFbx, MuRF1, myostatin) will be analyzed. Total RNA (500 ng) will be reverse transcribed with the iScript cDNA synthesis kit (Bio-Rad, Hercules, CA), and quantitative PCR will be performed using primer sets for genes of interest, reference genes and iQ SYBR Supermix (Bio-Rad) following manufacturer's protocols.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 27, 2017)
  • Changes in quadriceps strength [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Isometric quadriceps strength will be using a doublet interpolation test performed by research assistants blinded to participants' treatment randomization. Briefly, patients will be seated and stabilized in a HUMAC NORM (Computer Sports Medicine Incorporated, Stoughton, MA) dynamometer with their knee flexed to 60 degrees. After proper warm up, patients will be asked to perform a maximum voluntary isometric contraction of their quadriceps while receiving verbal reinforcement.
  • Changes in quadriceps size [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Peripheral Quantitative Computed Tomography scans of the distal femur will be used to assess the changes in quadriceps muscle morphology quantitatively. The maximal cross-sectional area of the quadriceps will be determined prior to TKA and ~14 days after TKA by manually placing the scanner at a line marked on the vastus lateralis one third of the distance between the greater trochanter and the lateral epicondyle of the femur. The pQCT software will analyze the image and calculate muscle cross-sectional area. A previous investigation by Cramer, et al. validated the pQCT to measurement of muscle cross-sectional area by comparison to MRI and (R2 values of 0.979 and 0.983). In addition, the use of the pQCT to measure muscle cross sectional area had high test-retest reliability, with ICC values of 0.996 and 0.998.
  • Changes in quadriceps activation [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Isometric quadriceps activation testing will be using a doublet interpolation test performed by research assistants blinded to participants' treatment randomization. Briefly, patients will be seated and stabilized in a HUMAC NORM (Computer Sports Medicine Incorporated, Stoughton, MA) dynamometer with their knee flexed to 60 degrees. After proper warm up, patients will be asked to perform a maximum voluntary isometric contraction of their quadriceps while receiving verbal reinforcement. During the contraction, a 2 pulse, 600 µs duration/pulse, supramaximal 100Hz stimulus will be delivered to the muscle to assess whether the subject is indeed maximally contracting the quadriceps muscle and again at rest.
  • Functional Performance Measures (4 meter walk test, timed up and go, stair climbing test) [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    The timed Stair Climbing Test (SCT) places a high demand on the quadriceps and therefore measures a higher level of function and, therefore, minimizes the possibility of a ceiling effect. The SCT has been shown to significantly correlate to the Timed Up and Go (TUG). The TUG measures the time it takes a patient to rise from an arm chair (seat height of 46 cm), walk 3 m, turn and return to sitting in the same chair without physical assistance.25 This test has excellent inter-rater (ICC=0.99) and intra-rater reliability (ICC=0.99), as measured in a group of 60 functionally disabled older adults (mean age 80 years).25 The 4 meter Walk Test (4mWT) will be assessed at the fastest safe speed for each participant.
  • Anabolic Gene Expression [ Time Frame: Immediately pre surgery to 2 weeks after surgery ]
    Standard procedures including total RNA isolation, cDNA synthesis, cRNA labeling, microarray hybridization and image acquisition will be performed. Protein content (translation of mTOR, myogenin, and MyoD) will be analyzed. Total RNA (500 ng) will be reverse transcribed with the iScript cDNA synthesis kit (Bio-Rad, Hercules, CA), and quantitative PCR will be performed using primer sets for genes of interest, reference genes and iQ SYBR Supermix (Bio-Rad) following manufacturer's protocols.
  • Muscle Fiber Cross-Sectional Area [ Time Frame: Immediately pre surgery to 2 weeks after surgery ]
    Cross sectional area of individual myofibrils taken from the vastus lateralis muscle using immunohistochemical staining and microscopy to determine change in cross sectional area comparing one hour before surgery to two weeks after surgery
  • Changes in neural cell adhesion molecule (NCAM) concentration [ Time Frame: Preop and 2 weeks postop ]
    NCAM will be assessed by immunohistochemistry with anti-CD56/NCAM antibody (555514; BD Biosciences, San Jose, CA), followed by goat anti-mouse AF555 (A-21127, ThermoFisher). NCAM is a multifunctional cell-surface protein that has been shown to be associated with muscle regeneration, through its roles in neurite outgrowth and synaptic plasticity. NCAM immunohistochemistry will be able to assess 1) denervation status, 2) skeletal muscle response to an intervention, and 3) the capacity for skeletal muscle to improve.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2014)
  • Changes in quadriceps strength [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Isometric quadriceps strength will be using a doublet interpolation test performed by research assistants blinded to participants' treatment randomization. Briefly, patients will be seated and stabilized in a HUMAC NORM (Computer Sports Medicine Incorporated, Stoughton, MA) dynamometer with their knee flexed to 60 degrees. After proper warm up, patients will be asked to perform a maximum voluntary isometric contraction of their quadriceps while receiving verbal reinforcement.
  • Changes in quadriceps size [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Peripheral Quantitative Computed Tomography scans of the distal femur will be used to assess the changes in quadriceps muscle morphology quantitatively. The maximal cross-sectional area of the quadriceps will be determined prior to TKA and ~14 days after TKA by manually placing the scanner at a line marked on the vastus lateralis one third of the distance between the greater trochanter and the lateral epicondyle of the femur. The pQCT software will analyze the image and calculate muscle cross-sectional area. A previous investigation by Cramer, et al. validated the pQCT to measurement of muscle cross-sectional area by comparison to MRI and (R2 values of 0.979 and 0.983). In addition, the use of the pQCT to measure muscle cross sectional area had high test-retest reliability, with ICC values of 0.996 and 0.998.
  • Changes in quadriceps activation [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    Isometric quadriceps activation testing will be using a doublet interpolation test performed by research assistants blinded to participants' treatment randomization. Briefly, patients will be seated and stabilized in a HUMAC NORM (Computer Sports Medicine Incorporated, Stoughton, MA) dynamometer with their knee flexed to 60 degrees. After proper warm up, patients will be asked to perform a maximum voluntary isometric contraction of their quadriceps while receiving verbal reinforcement. During the contraction, a 2 pulse, 600 µs duration/pulse, supramaximal 100Hz stimulus will be delivered to the muscle to assess whether the subject is indeed maximally contracting the quadriceps muscle and again at rest.
  • Functional Performance Measures (4 meter walk test, timed up and go, stair climbing test) [ Time Frame: 3 days Pre operative and 2 weeks post operative ]
    The timed Stair Climbing Test (SCT) places a high demand on the quadriceps and therefore measures a higher level of function and, therefore, minimizes the possibility of a ceiling effect. The SCT has been shown to significantly correlate to the Timed Up and Go (TUG). The TUG measures the time it takes a patient to rise from an arm chair (seat height of 46 cm), walk 3 m, turn and return to sitting in the same chair without physical assistance.25 This test has excellent inter-rater (ICC=0.99) and intra-rater reliability (ICC=0.99), as measured in a group of 60 functionally disabled older adults (mean age 80 years).25 The 4 meter Walk Test (4mWT) will be assessed at the fastest safe speed for each participant.
  • Anabolic Gene Expression [ Time Frame: Immediately pre surgery to 2 weeks after surgery ]
    Standard procedures including total RNA isolation, cDNA synthesis, cRNA labeling, microarray hybridization and image acquisition will be performed. Protein content (translation of mTOR, myogenin, and MyoD) will be analyzed. Total RNA (500 ng) will be reverse transcribed with the iScript cDNA synthesis kit (Bio-Rad, Hercules, CA), and quantitative PCR will be performed using primer sets for genes of interest, reference genes and iQ SYBR Supermix (Bio-Rad) following manufacturer's protocols.
  • Muscle Fiber Cross-Sectional Area [ Time Frame: Immediately pre surgery to 2 weeks after surgery ]
    Cross sectional area of individual myofibrils taken from the vastus lateralis muscle using immunohistochemical staining and microscopy to determine change in cross sectional area comparing one hour before surgery to two weeks after surgery
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alterations in Muscle After Total Knee Arthroplasty
Official Title  ICMJE Alterations in Skeletal Muscle Gene Expression Following Total Knee Arthroplasty
Brief Summary The overall goals of this work are: 1) to elucidate alterations in gene expression and downstream protein synthesis 2 weeks after Total Knee Arthroplasty (TKA) to better explain quadriceps muscle atrophy after TKA and 2) understand the mechanisms responsible for improved maintenance of muscle strength with Neuromuscular Electrical Stimulation (NMES) utilization. Furthermore, this investigation seeks to expand previous findings regarding attenuation of strength and functional performance deficits with NMES application to better understand how altered gene expression influences muscle function.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Condition  ICMJE Knee Osteoarthritis
Intervention  ICMJE
  • Procedure: Neuromuscular electrical stimulation (NMES)
    5x/week, 2x/day, for 45 minutes/session
  • Behavioral: Standard Rehabilitation Protocol
    Standard physical therapy after TKA
Study Arms  ICMJE
  • Experimental: Neuromuscular Electrical Stimulation

    Neuromuscular Electrical Stimulation (NMES) 48 hours after TKA, 5x/week, 2x/day, for 45 minutes/session.

    Standard Rehabilitation Protocol

    Interventions:
    • Procedure: Neuromuscular electrical stimulation (NMES)
    • Behavioral: Standard Rehabilitation Protocol
  • Active Comparator: Control
    Standard Rehabilitation Protocol
    Intervention: Behavioral: Standard Rehabilitation Protocol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: October 30, 2014)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2020
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 50 to 75 years of age
  • Scheduled for unilateral TKA at University of Colorado Hospital
  • Diagnosed with osteoarthritis
  • Cognitive status that allows patients to consistently comprehend and repeat back directions regarding the details of the study

Exclusion Criteria:

  • Neurological, vascular or cardiac problems that significantly limit function
  • BMI > 35
  • Testosterone supplementation
  • Pregnancy
  • Anticoagulant therapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02281877
Other Study ID Numbers  ICMJE 14-0905
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Victor Cheuy, PhD University of Colorado, Denver
PRS Account University of Colorado, Denver
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP