Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults

NCT02145949 | Completed Phase 2 Results DMC

• 2 other identifiers: 12272013.024R01AG046401
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 2

Brief Summary

As a function of the growing population of older adults, an estimated 3.48 million total knee arthroplasty (TKA) procedures will be performed annually in the U.S. by 2030. Despite the near-universal success of this surgery in mitigating chronic knee pain, TKA is not successful in restoring long-term physical function in older adults, primarily because of quadriceps muscle atrophy, which explains 77% of the strength deficits. Overall, strength and functional mobility in TKA patients is 30-50% below age-matched healthy controls. Functional tasks such as stair-climbing remain a clinical problem for 75% of patients following TKA. Muscle atrophy occurs in both operative and non-operative legs, and is essentially permanent for older patients because of their impaired ability to increase muscle mass. The purpose of this clinical research is to determine the effects of essential amino acid (EAA) supplementation on muscle mass, strength, and functional mobility following TKA in older adults. Based on strong preliminary data, the investigators hypothesize that twice-daily ingestion of 23 g of EAA for 1 wk before through 6 wk after TKA will increase basal rates of muscle protein synthesis via inactivation of catabolic signaling, and up-regulation of anabolic and cyto-protective proteins. The investigators further hypothesize that short-term atrophy prevention and accelerated return of functional mobility will lead to longer-term structural and functional adaptations, and improved quality of life in older TKA patients vs. Placebo. Identifying the mechanisms up-regulated by EAA treatment that preserve muscle volume and mobility will have a major impact on rehabilitation science. This study will accomplish two specific aims: (1) determine if EAA elevates basal rates of muscle protein synthesis by up-regulating anabolic pathways and cyto-protective proteins, and inactivating catabolic pathways in the short term vs. Placebo and (2) determine if short-term prevention of atrophy, weakness, and functional mobility leads to positive changes in muscle cell structure and function, and improved quality of life in the longer term vs. Placebo. This work is significant because it advances knowledge of the molecular and cellular changes occurring during muscle atrophy (Placebo) and atrophy prevention (EAA) in a clinical setting using a treatment that is broadly applicable, is well tolerated, and can be implemented immediately.

Conditions

Muscle Atrophy; Quality of Life

Keywords

aging; clinical; translational; functional mobility; total knee arthroplasty

Outcome Measures

Primary Outcomes (4)

• MRI Quadriceps Involved Leg

  MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra to measure muscle volume in Arbitrary Units (AU). Low values = low volume. High values = higher volume. Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region. MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra (UO Lewis Center for Neuroimaging). Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region.

  6 weeks after baseline

• MRI Quadriceps Contralateral Leg

  MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra to measure muscle volume in Arbitrary Units (AU). Low values = low volume. High values = higher volume. Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region. MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra (UO Lewis Center for Neuroimaging). Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region.

  6 weeks after baseline

• MRI Hamstrings Involved Leg

  MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra to measure muscle volume in Arbitrary Units (AU). Low values = low volume. High values = higher volume. Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region. MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra (UO Lewis Center for Neuroimaging). Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region.

  6 weeks after baseline

• MRI Hamstrings Contralateral Leg

  MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra to measure muscle volume in Arbitrary Units (AU). Low values = low volume. High values = higher volume. Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region. MRI of the bilateral lower extremities was performed utilizing a Siemens 3T Skyra (UO Lewis Center for Neuroimaging). Dixon pulse sequence optimized for imaging near metal implants was used to capture T1-weighted, water, and fat images of the mid-thigh region.

  6 weeks after baseline

Secondary Outcomes (16)

• Daily Physical Activity

  6 weeks after baseline

• Handgrip Strength

  6 weeks after baseline

• Short Physical Performance Battery

  6 weeks after baseline

• Timed Up and Go

  6 weeks after baseline

• 4-Meter Walk

  6 weeks after baseline

Study Arms (2)

Essential Amino Acids (EAA)

EXPERIMENTAL

Aim 1: Twice-daily ingestion of 20 g of EAA for 1 wk before through 6 wk after TKA. Supplement composition for the EAAs: histidine, 2.2 g (11% of total); isoleucine, 2.0 g (10%); leucine, 3.6 g (18%); lysine, 3.2 g (16%); methionine, 0.6 g (3%); phenylalanine, 3.2 g (16%); threonine, 2.8 g (14%); and valine, 2.4 g (12%). Aim 2: Twice-daily ingestion of 23 g of EAA for 1 wk before through 6 wk after TKA. Supplement composition for the EAAs: histidine, 1.28 g (5% of total); isoleucine, 1.8 g (8%); leucine, 7.4 g (32%); lysine, 3.6 g (15%); methionine, 1.76 g (8%); phenylalanine, 3.1 g (13%); threonine, 1.9 g (8%); valine, 2.08 g (9%); and tryptophan, 0.5 g (2%).

Drug: Essential Amino Acids (EAA)

Placebo (Alanine)

PLACEBO COMPARATOR

Aim 1: Twice-daily ingestion of 20 g of Alanine (Non-essential amino acid) for 1 wk before through 6 wk after TKA. The placebo supplement consists of 20 g (100%) alanine. Aim 2: Twice-daily ingestion of 23 g of Alanine (Non-essential amino acid) for 1 wk before through 6 wk after TKA. The placebo supplement consists of 23 g (100%) alanine.

Drug: Placebo (Alanine)

Interventions

Essential Amino Acids (EAA) DRUG

Twice daily ingestion of 20 or 23 grams of EAA for 7 days leading up to surgery and continuing for 6 weeks after surgery \[surgery = primary total knee arthroplasty\]

Also known as: L-Histidine, L-Isoleucine, L-Leucine, L-Lysine monohydrochloride, L-Methionine, L-Phenylalanine, L-Threonine, L-Valine, L-Tryptophan

Essential Amino Acids (EAA)

Placebo (Alanine) DRUG

Twice daily ingestion of 20 or 23 grams Placebo (alanine) for 7 days leading up to surgery and continuing for 6 weeks after surgery \[surgery = primary total knee arthroplasty\]

Also known as: L-Alanine, A4349 (Non-essential amino acid)

Placebo (Alanine)

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: between 50-80 years.
• Primary TKA surgery.

You may not qualify if:

• Previous TKA and/or total hip arthroplasty surgery (older subjects).
• Dementia or related mental issues that may potentially put the subject at risk as determined by the surgeon.
• Untreated endocrine disease (Hypo/Hyperthyroidism, Addison's or Cushing's syndrome, etc.).
• Significant heart, liver, kidney, blood, or respiratory disease.
• Peripheral vascular disease.
• Active cancer.
• Recent (within 6 months) treatment with anabolic steroids.
• Alcohol or drug abuse.
• Inability to have MRI

Sponsors & Collaborators

• University of Oregon: lead
• Slocum Center for Orthopedics and Sports Medicine: collaborator
• Slocum Research & Education Foundation: collaborator
• Oregon Research Institute: collaborator
• Oregon Health and Science University: collaborator
• University of Arkansas: collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (2)

University of Oregon

Eugene, Oregon, 97401-1240, United States

Location

Slocum Center for Orthopedics and Sports Medicine

Eugene, Oregon, 97401, United States

Location

Related Publications (4)

• Dreyer HC, Owen EC, Strycker LA, Smolkowski K, Muyskens JB, Kirkpatrick TK, Christie AD, Kuehl KS, Lantz BA, Shah SN, Mohler CG, Jewett BA. Essential Amino Acid Supplementation Mitigates Muscle Atrophy After Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial. JB JS Open Access. 2018 Jun 4;3(2):e0006. doi: 10.2106/JBJS.OA.18.00006. eCollection 2018 Jun 28.

  PMID: 30280129 RESULT

• Muyskens JB, Foote DM, Bigot NJ, Strycker LA, Smolkowski K, Kirkpatrick TK, Lantz BA, Shah SN, Mohler CG, Jewett BA, Owen EC, Dreyer HC. Cellular and morphological changes with EAA supplementation before and after total knee arthroplasty. J Appl Physiol (1985). 2019 Aug 1;127(2):531-545. doi: 10.1152/japplphysiol.00869.2018. Epub 2019 Jul 25.

  PMID: 31343947 RESULT

• Muyskens JB, Hocker AD, Turnbull DW, Shah SN, Lantz BA, Jewett BA, Dreyer HC. Transcriptional profiling and muscle cross-section analysis reveal signs of ischemia reperfusion injury following total knee arthroplasty with tourniquet. Physiol Rep. 2016 Jan;4(1):e12671. doi: 10.14814/phy2.12671.

  PMID: 26733251 RESULT

• Dreyer HC. Tourniquet Use During Knee Replacement Surgery May Contribute to Muscle Atrophy in Older Adults. Exerc Sport Sci Rev. 2016 Apr;44(2):61-70. doi: 10.1249/JES.0000000000000076.

  PMID: 26829246 RESULT

Related Links

• Muscle Physiology Lab at the University of Oregon

MeSH Terms

Conditions

Muscular Atrophy

Interventions

Amino Acids, Essential; Histidine; Isoleucine; Leucine; Methionine; Phenylalanine; Threonine; Valine; Tryptophan; Alanine

Condition Hierarchy (Ancestors)

Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Cyclic; Amino Acids, Branched-Chain; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids, Neutral; Amino Acids, Aromatic

Results Point of Contact

• Title: Dr. Hans Dreyer
• Organization: University of Oregon

hcdreyer@uoregon.edu

541-346-3902

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: May 19, 2014
• First Posted: May 23, 2014
• Study Start: December 1, 2014
• Primary Completion: February 1, 2020
• Study Completion: February 1, 2020
• Last Updated: July 23, 2024
• Results First Posted: July 23, 2024

Record last verified: 2024-07

Locations

US (2)