Conditions: Muscle Atrophy Quality of Life
Keywords: aging clinical translational functional mobility total knee arthroplasty
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

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.

Detailed description:
The investigative team has completed recent studies showing that essential amino acid (EAA) supplementation attenuates quadriceps atrophy and accelerates the return of functional mobility following TKA. For patients on EAA, quadriceps atrophy was only -6% and -3% in the operative and non-operative quadriceps, respectively, 6 wks after TKA, but -18% and -10%, respectively, in patients on Placebo, a threefold difference. Of clinical relevance, the patients on EAA were able to maintain strength and demonstrated an accelerated return of functional mobility vs. Placebo 6 wks post-TKA. Positive changes at the cellular level are likely responsible for the reduction in muscle loss and preservation of strength, and to explain the acceleration of the return of functional mobility. As such, we hypothesize that twice-daily ingestion of 23 g of EAA from 1 wk before to 6 wks after TKA will increase basal rates of muscle protein synthesis via inactivation of catabolic signaling (FoxO3a), and up-regulation of anabolic and cyto-protective proteins. We also propose that short-term atrophy prevention and accelerated return of functional mobility will translate into long-term (6 mo and 1 yr post-TKA) structural and functional adaptations, leading to improved quality of life in TKA patients with EAA supplementation vs. Placebo.

The study will use a two-arm parallel design to determine the effect of EAA supplementation on post-TKA muscle cell structure and function, and quality of life in the shorter term (6 months post-TKA) and long term (1 yr post-TKA) vs. Placebo. Subjects will be 80 older male and female adults having primary TKA at the Slocum Center for Orthopedics and Sports Medicine, Eugene, Oregon. Slocum study staff will pre-screen/identify potential subjects for recruitment based on inclusion/exclusion criteria. Eligible patients will be invited to join the study. After the completion of informed consent procedures, participants will be assigned a unique patient identification number, and randomly assigned to either EAA or Placebo on a 1:1 allocation ratio, with blinding of treatment condition to subject and research staff/statisticians collecting data. Twice-daily ingestion of 23 g of supplement will begin 7 days prior to TKA and end at 6 wks post. EAA subjects will receive EAA and Placebo subjects will receive the non-essential amino acid Alinine. Subjects will document compliance with the supplement protocol in a log book and will return empty vials. Subjects will be followed for 1 yr.

Key research questions are: (a) Does EAA prevent shorter-term (6 wks post-TKA) bilateral muscle atrophy, preserve quadriceps strength, and accelerate the return of functional mobility vs. Placebo? (b) Are there shorter-term sex differences on outcome measures? (c) Will EAA increase longer-term (6 mo post-TKA) quadriceps strength and functional mobility vs. Placebo? (d) Does EAA improve long-term (1 yr post-TKA) functional mobility and measures of quality of life vs. Placebo? (e) Are there long-term sex differences in functional mobility or measures of quality of life? Assessment points will be at 6 wks, 4 wks, and 1 wk prior to surgery, and 1 wk, 2 wks, 6 wks, 6 mos, and 1 yr post-TKA. At different assessment points, we will collect demographic, medical (e.g., length of hospital stay, tourniquet use), physiological (e.g., muscle biopsy, MRI, DEXA, strength; blood tests), pharmacologic, functional mobility, physical activity (accelerometer), psychometric (e.g., quality of life; Veterans RAND 12-item Health Survey \[VR-12\]), food intake (3-day diary), physical therapy, and perceived pain data. The following schedule of assessments will be followed: no more than 6 mo pre-TKA (enrollment and screening), 6 wks pre-TKA (screening, surveys, DEXA scan, MRI test, physical activity and food recording), 4 weeks pre-TKA (blood draw, strength and functional mobility testing, muscle and fat biopsy); 1 wk pre-TKA and in hospital (physical activity and food recording); 1 wk post-TKA (physical activity and food recording); 2 wks post-TKA (blood draw, physical activity and food recording); 6 wks post-TKA (blood draw, MRI test, strength and functional mobility testing, physical activity and food recording, muscle and fat biopsy); 3 mos post-TKA (surveys, strength and functional mobility testing, physical activity and food recording); 6 mos post-TKA (surveys, DEXA scan, MRI test, strength and functional mobility testing, physical activity and food recording, muscle and fat biopsy), and 1 yr (surveys, DEXA scan, MRI test, strength and functional mobility testing, physical activity and food recording, muscle and fat biopsy).

Data will be collected from a variety of sources, including surveys, electronic medical records, medical and functional tests, and staff reports. Data will be entered and double-verified in password-protected spreadsheets sand databases stored behind a firewall. Any electronic medical records data captured will use secure data transfer and HIPAA-compliant protocols approved by the University of Oregon IRB. Staff reports will be forwarded directly to project data managers. All personal data will be identified by numbers rather than names. Interim reports of project results will be made to the Data and Safety Monitoring Board.

Power analyses indicated that a sample size of 80 subjects would be sufficient to detect anticipated effects on primary outcomes: operative leg quadriceps volume (MRI), non-operative leg quadriceps volume (MRI), isometric strength, Get Up And Go test, stair climb up test, stair climb down test, and six-minute walk test. The mean effect size across these outcomes, based on baseline- to 6-week percent change in pilot data) was d = 1.01, reflecting large effects. For a sample size of 30/group, this study can detect ESs of d \> .79 with 85% power, and the minimally detectable ES drops to 0.68 or 0.52 with pretest covariates of r = .50 or .75. Every effort will be made to reduce attrition and obtain data on all participants at all assessment points. However, attrition is expected. Because this study will have power to detect anticipated physiological and functional effects with 30 subjects per condition, we will enroll 80 total subjects (40/condition) to account for possible attrition.

The EAA intervention is designed to attenuate muscle loss, improve functional outcomes, and enhance quality of life. Data analyses will focus on shorter-term, longer-term results, and change over time. Preliminary analyses will employ descriptive statistics to understand the nature of the data and ensure that data distributions are appropriate for the statistical tests employed. Chi-square tests and analyses of variance, as appropriate, will be conducted to evaluate the equivalence of continuing participants vs. dropouts on demographic, medical history, and recent levels of dependent variables.

We will conduct random coefficients analysis (RCA) to model muscle and functional mobility across time, as well as covariates that could affect outcomes, such as age, sex, physical activity, and dietary intake. RCA models trajectories from assessments nested within subjects; test of condition are represented by the interaction between a time factor and treatment condition. The RCA avoids the many pitfalls associated with traditional repeated measures ANOVA: It adjusts for within-individual dependence or autocorrelation in the data, can model nonlinear growth, does not require fixed spacing among assessments, and accommodates missing values over time. By using any available data across time, the RCA will limit the effects of missing data, reducing bias and increasing power. Based on our preliminary data, we estimate that we will be able to collect \>92% of all data points.

Expected study outcomes are as follows:

1. With successful completion of this research, we expect to demonstrate that EAA prevents muscle atrophy bilaterally, as our preliminary data suggest. To date, it is not known if EAA can prevent atrophy.
2. We expect to show that atrophy prevention will lead to strength gains and accelerated return of functional mobility. We further expect to show that EAA may have positive effects on central activation deficits, as our preliminary data suggest that strength is increased by 6 wks with EAA. To date, it is not known if preserving muscle following TKA will increase strength and augment the return of functional mobility.
3. We expect to document that EAA will increase muscle cell size (CSA) bilaterally, in the vastus lateralis of the operative and non-operative quadriceps. It is not known if atrophy prevention and early return of functional mobility will stimulate positive gains in muscle cell structure.
4. We expect to demonstrate that EAA increases mitochondrial mass bilaterally and increases mitochondrial respiration at rest. By sampling from the non-operative (control leg) and operative leg, we expect to show that EAA normalizes mitochondrial function over time (6 mo and/or 1 yr post-TKA). It is not known if early gains in functional mobility will positively impact muscle cell function.
5. We expect to show that quality of life (as measured by instruments such as VR-12) will be significantly increased with EAA. It is not known to what extent the above positive gains will have on longer-term (6 mo and 1 yr) quality of life.

We expect each of the above to stimulate and be transformative. EAA supplements are inexpensive ($800/patient or $16/day), are well tolerated, and can be implemented immediately.

Arms:
arm 1: 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%). arm 2: 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.

Interventions: intervention 1: Essential Amino Acids (EAA) intervention 2: Placebo (Alanine)
Intervention descriptions: intervention 1: Twice daily ingestion of 20 or 23 grams of EAA for 7 days leading up to surgery and continuing for 6 weeks after surgery \[surgery = primary total knee arthroplasty\] intervention 2: Twice daily ingestion of 20 or 23 grams Placebo (alanine) for 7 days leading up to surgery and continuing for 6 weeks after surgery \[surgery = primary total knee arthroplasty\]

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
 
College of Arts and Sciences 
DEPARTMENT OF HUMAN PHYSIOLOGY 
1240 University of Oregon, Eugene OR 97403-1240  
T (541) 346-4107 F (541) 346-2841  
An equal-opportunity, affirmative-action institution committed to cultural diversity and compliance with the Americans with Disabilities Act 
 
 
 
 
Study Title: Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults 
 
 
NCT number: NCT02145949 
 
 
Date of the document: January 26, 2019. 
 


 
 
 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS ● RESEARCH COMPLIANCE SERVICES 
 
677 E. 12
th Ave., Suite 500, 5237 University of Oregon, Eugene OR 97401-5237 
 
T 541-346-2510  F 541-346-5138  http://rcs.uoregon.edu 
 
 
An equal-opportunity, affirmative-action institution committed to cultural diversity and compliance with the Americans with Disabilities Act 
DATE:  
January 26, 2019 
IRB Protocol Number:  12272013.024 
 
TO:     
Hans Dreyer, Principal Investigator 
 
Department of Human Physiology 
 
RE: 
Protocol entitled, “Mechanistic approach to preventing atrophy and restoring 
function in older adults” 
 
Notice of IRB Review and Approval 
Amendment Review 
The amendment submitted on January 04, 2019 for the project identified above has been 
reviewed and approved by the Committee for Protection of Human Subjects (CPHS), the 
University of Oregon Institutional Review Board (IRB).  The IRB has approved the changes 
to the research as described in the attached materials. As a reminder, it is your 
responsibility to submit any proposed changes for IRB review and approval prior to 
implementation. 
 
Amendment Description: 
 
Separated inclusion and exclusion criteria for patients who are eligible and 
interested in having biopsies vs. patients who are ineligible due to timeline or are not 
within the biopsy window. 
 
Revised the pre-operative study timeline from -6 weeks (+/- 2 weeks) to -8 weeks to –
1 week. 
 
Revised the informed consent to reflect the timeline requirements and option to 
participate in biopsies, as well as the option to participate in the study in the 
timeline for biopsies is too short (<4 weeks from date of surgery). 
 
Revised the Research Plan and consent form accordingly. 
 
For this research, the following determinations have been made: 
 
This research was previously determined to be greater than minimal risk and 
requires full board review. 
 
This amendment was determined to be a minor change to previously approved 
research and was reviewed in accordance with expedited review procedures as per 
Title 45 CFR 46.110 under the pre-2018 Common Rule. 
Approval period: January 26, 2019 - November 06, 2019 
 
If you anticipate the research will continue beyond the IRB approval period, you must 
submit a Continuing Review Application to request continued approval at least 45-days 
prior to the expiration date. Without continued approval, the protocol will expire on 
November 06, 2019 and human subject research activities must cease.  A closure report 
must be submitted once human subject research activities are complete.  Failure to maintain 
current approval or properly close the protocol constitutes non-compliance.   
You are responsible for adhering to the Investigator Agreement submitted with the initial 
application for IRB review.  The responsibilities of the agreement are reiterated at the end of 


 
 
 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS ● RESEARCH COMPLIANCE SERVICES 
 
677 E. 12
th Ave., Suite 500, 5237 University of Oregon, Eugene OR 97401-5237 
 
T 541-346-2510  F 541-346-5138  http://rcs.uoregon.edu 
 
 
An equal-opportunity, affirmative-action institution committed to cultural diversity and compliance with the Americans with Disabilities Act 
this letter below.  You are responsible for conduct of the research and must maintain 
oversight of all research personnel to ensure compliance with the IRB approved protocol. 
The University of Oregon and Research Compliance Services appreciate your commitment 
to the ethical and responsible conduct of research with human subjects.   
Sincerely, 
 
Daniel Berman 
Research Compliance Administrator 
 
CC: 
Tessa Kirkpatrick, Erin Owen 


 
 
 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS ● RESEARCH COMPLIANCE SERVICES 
 
677 E. 12
th Ave., Suite 500, 5237 University of Oregon, Eugene OR 97401-5237 
 
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An equal-opportunity, affirmative-action institution committed to cultural diversity and compliance with the Americans with Disabilities Act 
 
INVESTIGATOR AGREEMENT 
Principal Investigator and Faculty Advisor Responsibilities 
A. Conduct of the Research 
1. 
I accept responsibility for the ethical conduct of this research and protection of participants 
as set forth in the Belmont Report, Declaration of Helsinki, the Nuremberg Code, the 
Common Rule, and the ethical principles of my discipline. 
2. 
I accept responsibility for the conduct of this research ensuring this research is conducted 
according to 
a. 
sound research design and methods;  
b. 
the IRB approved protocol including the informed consent process;  
c. 
the applicable terms of the grant, contract and/or signed funding agreements; and 
d. 
applicable laws and regulations, including those for protecting the rights, safety, 
and welfare of human subjects.  
3. 
I certify that I am or my faculty advisor is sufficiently qualified by education, training, 
and/or experience to assume responsibility for the proper conduct of this research. I accept 
responsibility for ensuring that members of this research team, including study staff and 
trainees, are appropriately qualified, trained and supervised.  
4. 
I accept responsibility to personally conduct and/or directly supervise this research. I certify 
that I have sufficient time and resources to properly conduct and/or supervise this research 
for which I am responsible. 
B. Ensuring and Maintaining Compliance 
1. 
I will comply with relevant regulatory and institutional requirements, including those 
relating to conflicts of interest, responsible conduct of research and research misconduct.  
2. 
I understand it is my responsibility to ensure that any research personnel, including myself, 
responsible for the design, conduct, and reporting of research declare any potential conflicts 
of interests related to the research and to maintain current records. I will ensure changes in 
conflicts of interest are promptly disclosed to the IRB.  
3. 
I will ensure that informed consent is obtained as approved by the IRB and a copy is 
provided to participants, unless the IRB waives these requirements.  
4. 
I will obtain initial IRB approval prior to implementing human subject research activities as 
well as prior approval for any amendments to this research.  
5. 
I will conduct this research within the approval period issued by the IRB. I agree to submit a 
request for continuing review of this research at least 45 days in advance of the expiration 
date.  
6. 
I will submit a closure report form prior to protocol expiration or within 45 days of 
completion of all activities involving human subjects or identifiable participant data. 
7. 
I will maintain approval, as applicable, with collaborative entities including approvals from 
other countries or jurisdictions. 
8. 
I will promptly report to the IRB (no later than seven days of discovery) any instances of 
noncompliance with the approved protocol or requirements of the IRB and any 
unanticipated problems.  


 
 
 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS ● RESEARCH COMPLIANCE SERVICES 
 
677 E. 12
th Ave., Suite 500, 5237 University of Oregon, Eugene OR 97401-5237 
 
T 541-346-2510  F 541-346-5138  http://rcs.uoregon.edu 
 
 
An equal-opportunity, affirmative-action institution committed to cultural diversity and compliance with the Americans with Disabilities Act 
INVESTIGATOR AGREEMENT 
Principal Investigator and Faculty Advisor Responsibilities 
9. 
I will assist in the facilitation of any monitoring and/or auditing of study activities and/or 
records as required by the IRB, funding entities, sponsors, and any federal and state 
regulatory agencies.  
C. Investigator Records, Reports and Documentation 
1. 
I will maintain research records, all protocol materials, and any other documents associated 
with this research (e.g., research plan, signed consent forms, and IRB correspondence). 
2. 
I will maintain records for at least three years after this research ends, or for the length of 
time specified in applicable regulations or institutional or sponsor requirements, whichever 
is longer. I will take measures to prevent accidental or premature destruction of these 
documents. 
3. 
I will ensure the safe and secure storage of this research data (whether in paper or electronic 
formats) and for protecting the confidentiality of the data in accordance with the approved 
protocol. 
4. 
I will submit written reports to the IRB and permit inspection of the research records as 
required by the IRB.  
 


 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS 
RESEARCH COMPLIANCE SERVICES 
 
AMENDMENT 
APPLICATION 
 
 
Application - Amendment 
V – 04/20/2018 
 
Page 1 of 5 
Instructions: Use this application to request IRB review of proposed changes to previously approved expedited or full board 
research. You must obtain IRB approval prior to implementing any change(s) in your research.  This application can also be used to 
request a study previously reviewed under the pre-2018 Common Rule regulations be considered for transition to oversight under the 
2018 Common Rule. Submit this application and all applicable research materials solicited in the checklist at the end of the form to 
ResearchCompliance@uoregon.edu. Save this form before proceeding. 
 
PART I: STUDY AND INVESTIGATOR INFORMATION 
Principal  
Investigator (PI): 
Hans C. Dreyer, PhD, PT  
Today’s 
Date: 
1/4/2019 
 
Faculty Advisor 
      
 
Protocol 
number: 
12272013.024  
Study Title: 
Mechanistic approach to preventing atrophy and restoring function in older adults 
 
Research Status (check one) 
 
 Project not yet started (no subjects being recruited) 
 
 Currently in progress (subjects being recruited)  
 
 Closed to new subject entry (long term follow-up only or data analysis)  
PART II: PROPOSED CHANGES TO PREVIOUSLY APPROVED RESEARCH 
1. 
Give a brief description of the proposed change(s). 
Separation of inclusion and exclusion criteria for patients who are eligible and interested in having biopsies vs. patients 
who are ineligible due to timeline, or are not within biopsy window. We have separated the inclusion/exclusion criteria 
into two categories: Biopsy participant and non-biopsy participant.  
 
The pre-operative study timeline has been updated from -6 weeks (+/- 2 weeks) to -8 weeks to -1week to account for 
the ability of patients to enroll before supplement ingestion as long as there is enough time to complete pre-operative 
study activities, including completion of biopsies at least 4 weeks prior to date of surgery.  
 
Changes to the informed consent document reflect the timeline requirements and option to participate in biopsies, as 
well as option to participate in the study if the timeline for the biopsies is too short (< 4 weeks from date of surgery).  
 
Last, the final consent page in the informed consent document has separated two of the existing bullets into two 
separate bullets for clarity.   
2. 
Describe the rationale for the change(s). 
The current protocol allows for patient to opt in or out of biopsies. However, the inclusion and exclusion criteria are 
structured to account for risks associated with biopies. We have divided out the inclusion and exclusion criteria to 
Purpose:  This application is designed to help facilitate review of changes to an existing protocol and to assure compliance of the 
federal regulations as set forth in 45 CFR Part 46. 
 
Research Compliance 
Services 
 
RECEIVED 
January 04, 2019
"APPROVED"
Research 
Compliance Services
01/26/2019-11/06/2019


 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS 
RESEARCH COMPLIANCE SERVICES 
 
AMENDMENT 
APPLICATION 
 
 
Application - Amendment 
V – 04/20/2018 
 
Page 2 of 5 
reflect patients who are opting in and/or eligible for biopsy consideration versus patients who opt out, or due to 
timeline, are not eligible for biopsies.  
 
Timeline: Patients who are less than 4 weeks from the date of surgery are not eligible for biopsies, but could be 
included in study and not undergo any biopsies.  
 
Biopsy risk: Patients who are timeline eligible (more than 4 weeks from date of surgery) and opt to have biopsies 
performed, need to be evaluated for bleeding risk associated with taking an oral blood thinner medication. The current 
exclusion criteria excludes patients taking oral blood thinners. Patients who choose not to participate in the biopsies or 
who are not within study window for biospies (ineligible for biospies due to proximity to the date of surgery) can still 
enroll in the study, but do not need to be evaluated for bleeding risk secondary to taking oral blood thinners.  
3. 
Are you making changes to your previously established project period at this time?  
 Yes 
 No 
Provide anticipated end date for human 
subject research activities (month and year):  
      
PART III: RESEARCH PERSONNEL 
If you are you making any changes to research personnel at this time (e.g., adding research staff, changing PI, etc.), list the 
individuals below and attach an updated Research Personnel Form highlighting those individuals. 
 No changes to Research Personnel; proceed to Part IV below. 
  Research Personnel Form is attached; the following individuals have been added and/or updated:  
 
      
 
It is the responsibility of the Principal Investigator (PI) to ensure that any research personnel, including the PI, responsible for 
the design, conduct, and reporting of research complete the Human Subjects Conflict of Interest (COI) form. 
 
The PI must keep completed copies of all Human Subject COI forms for their records. 
 
The PI must submit with this application Human Subject COI forms only for  
o 
New research personnel who have identified a real, perceived, or potential conflict of interest on their form; and 
o 
Existing personnel who have identified a change to a real, perceived, or potential conflict of interest on their form. 
 No conflicts are identified. 
 Yes, conflicts and/or changes are identified and Human Subject COI form(s) are attached for the following individuals: 
 
      
PART IV: RESEARCH RISK 
1. 
Based on the proposed change(s), are there any new or altered risks?  
 
 Yes 
 No 
Explain in the text box below:  
 
Patients participating in biospies cannot be taking oral blood thinners to participate; patients not having biopsies 
may be taking oral blood thinners at the time of enrollment, as the risk from taking oral blood thinners is the risk of 
bleeding from biopsies.  
 
Research Compliance 
Services 
 
RECEIVED 
January 04, 2019
"APPROVED"
Research 
Compliance Services
01/26/2019-11/06/2019


 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS 
RESEARCH COMPLIANCE SERVICES 
 
AMENDMENT 
APPLICATION 
 
 
Application - Amendment 
V – 04/20/2018 
 
Page 3 of 5 
2. 
In your opinion, how do the proposed change(s) impact the overall risk profile for the previously approved research 
(select one of the following): 
 
 Increase 
 Decrease 
 Remain the same 
 
Provide rationale and justification with support for your response. 
 
Addressed in response to Part IV, question 1.  
3. 
Is the proposed amendment a result of an unanticipated problem or adverse event? 
 
 Yes 
 No 
If “Yes”, explain in the text box below 
 
      
4. 
As a result of the proposed change(s), has a Data and Safety Monitoring Plan (DSMP) been created for this research? 
This is typically required by a sponsor or regulatory agency (e.g., FDA). 
 
 Yes 
 No 
If “Yes," attach a copy of the DSMP and address in the Research Plan. 
5. 
As a result of the proposed change(s), has a Data Safety Monitoring Board or Committee (DSMB/DSMC) been 
established for this research? This is typically required by a sponsor or regulatory agency (e.g., FDA). 
 
 Yes 
 No 
If “Yes," attach a copy of the DSMB/DSMC information and address in the Research Plan. 
PART V: COLLABORATIONS 
1. 
As a result of the proposed change(s), will the research be conducted with institutions, or at site(s)/organization(s) other 
than University of Oregon (e.g., public schools, tribes, non-profit organizations, companies, hospitals, universities, etc.)? 
 
 Yes 
 No 
If “Yes”, explain and attach applicable permission and/or approval documentation:  
 
      
PART VI: MATERIALS 
1. 
New and revised materials must be submitted with this application. Revisions to any previously approved protocol 
materials must be submitted with proposed changes clearly indicated (e.g., using track changes).  
Check material type below and indicate if this is new or revised. 
 
Material Type 
New 
Revised 
Title(s)/Comments/Other 
 
 
Form - Personnel 
 
 
      
 
 
Form - Conflict of Interest 
 
 
      
 
 
Form - Funding 
 
 
      
 
 
Research Plan 
 
 
      
 
 
 
Incl. 
n/a 
 
 
 
 
 
 
 
 
 
Appendix A - Drugs 
 
 
      
 
 
 
 
 
Appendix B - Medical Devices 
 
 
      
 
 
 
 
 
Appendix C - Ionizing Radiation 
 
 
      
 
 
 
 
 
Appendix D - HIPAA 
 
 
      
 
 
 
 
 
Appendix E - Genetic Materials 
 
 
      
 
 
Recruitment Materials 
 
 
      
 
Research Compliance 
Services 
 
RECEIVED 
January 04, 2019
"APPROVED"
Research 
Compliance Services
01/26/2019-11/06/2019


 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS 
RESEARCH COMPLIANCE SERVICES 
 
AMENDMENT 
APPLICATION 
 
 
Application - Amendment 
V – 04/20/2018 
 
Page 4 of 5 
 
Material Type 
New 
Revised 
Title(s)/Comments/Other 
 
 
Consent/ Assent Materials 
 
 
      
 
 
Debriefing Materials 
 
 
 
 
 
Data Collection Materials/Instruments 
 
 
      
 
 
Data Safety Monitoring Plan 
 
 
 
 
 
Data Safety Monitoring Board/Committee Information 
 
 
      
 
 
Permissions/ Support Letters/ Outside IRB Approval 
 
 
      
 
 
For funded/sponsored Research: Human Subjects portion 
of grant Proposal 
 
 
      
 
 
Other (specify) 
 
 
      
 
 
Other (specify) 
 
 
      
 
 
Other (specify) 
 
 
      
2. 
As a result of the proposed changes, will any of the previously approved protocol materials no longer be used? 
 
 Yes 
 No 
If “Yes”, list materials below 
 
Material Name/Type/Title/Comments 
 
 
      
 
 
      
 
 
      
 
 
      
 
 
      
 
 
      
 
[Remainder of page intentionally left blank; acknowledgements and signature page to follow.] 
 
 
 
Research Compliance 
Services 
 
RECEIVED 
January 04, 2019
"APPROVED"
Research 
Compliance Services
01/26/2019-11/06/2019


 
COMMITTEE FOR THE PROTECTION OF HUMAN SUBJECTS 
RESEARCH COMPLIANCE SERVICES 
 
AMENDMENT 
APPLICATION 
 
 
Application - Amendment 
V – 04/20/2018 
 
Page 5 of 5 
PART VII: INVESTIGATOR AND FACULTY ADVISOR SIGNATURES 
 
By signing below I certify that I will conduct this research as approved by the University of Oregon CPHS (IRB) and in accordance 
with the Investigator Agreement. 
 
I understand that any changes listed above may not be implemented in the human subjects research until this amendment has 
been approved by the CPHS (IRB). 
 
Hans C. Dreyer, PhD, PT 
 
January 4, 2019 
 
Principal Investigator Signature 
Date  
 
Electronic signatures acceptable. The name of the Principal Investigator may be typed in the signature line. 
 
If the person emailing this application is not the Principal Investigator, the Principal Investigator must be copied on this 
application submission. 
REQUIRED FOR STUDENT RESEARCH  
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UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
November 2018 
 
 
 
MECHANISTIC APPROACH TO 
PREVENTING ATROPHY AND 
RESTORING FUNCTION IN 
OLDER ADULTS 
National Institute on Aging: R01AG046401-01A1 
PRINCIPAL INVESTIGATOR 
Hans C. Dreyer, PhD, PT 
Co-Investigators 
Brian A. Jewett, MD 
Brick A. Lantz, MD 
Craig G. Mohler, MD 
Steven N. Shah, MD 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 1  
Contents 
PROJECT SUMMARY ...........................................................................................................................3 
INTRODUCTION AND BACKGROUND ...................................................................................................4 
Preliminary Studies. .................................................................................................................................. 5 
Biochemistry. ........................................................................................................................................ 5 
Physiology. ............................................................................................................................................ 6 
Contribution to Scientific Knowledge. ....................................................................................................... 7 
Hypothesis. ................................................................................................................................................ 8 
SPECIFIC AIMS ....................................................................................................................................8 
METHODS, MATERIALS AND ANALYSIS ................................................................................................. 10 
Study Design. ........................................................................................................................................... 10 
Investigational Supplement. ................................................................................................................... 10 
Study Aim #1 (Biochemistry). ................................................................................................................... 11 
Randomization Assignments. .............................................................................................................. 11 
Primary Biochemical Outcome Measures. .......................................................................................... 12 
Secondary Outcome Measures. .......................................................................................................... 13 
Covariate Measures. ........................................................................................................................... 16 
Blood Draws. ....................................................................................................................................... 17 
Physical Therapy (PT). ......................................................................................................................... 18 
Aim #1 Study Activities Timeline. ........................................................................................................ 18 
Specific Aim #2 (Physiology). ................................................................................................................... 20 
Randomization Assignments. .............................................................................................................. 20 
Changes to Study-Related Activities. .................................................................................................. 20 
New or Altered Study Procedures or Measures for Participants Enrolled in Aim #2. ........................ 20 
Primary Physiological Outcome Measures. ........................................................................................ 21 
Secondary Physiological Outcome Measures. .................................................................................... 21 
Covariate Measures. ........................................................................................................................... 21 
Aim #2 Study Activities Timeline. ........................................................................................................ 21 
Participant Withdrawal. .......................................................................................................................... 22 
Study Stopping Criteria ....................................................................................................................... 22 
Data Collection. ....................................................................................................................................... 24 
Sources of Materials. .............................................................................................................................. 24 
Data Analysis........................................................................................................................................... 25 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 2  
 
Potential Limitations. .............................................................................................................................. 26 
RESEARCH POPULATION & RECRUITMENT METHODS ........................................................................ 27 
Target Population. .................................................................................................................................. 27 
Inclusion & Exclusion Criteria. ................................................................................................................. 28 
Research Sites. ........................................................................................................................................ 30 
Participant Recruitment. ......................................................................................................................... 31 
Primary Recruitment Approaches. ...................................................................................................... 31 
Secondary Recruitment Approaches. ................................................................................................. 32 
Informed Consent Process. ...................................................................................................................... 35 
Enrollment & Randomization. ................................................................................................................. 35 
Participant Compensation....................................................................................................................... 35 
PROVISIONS FOR PARTICIPANT AND DATA CONFIDENTIALITY. .......................................................... 36 
POTENTIAL RESEARCH RISKS OR DISCOMFORTS TO PATIENTS ........................................................... 37 
Risks. ....................................................................................................................................................... 37 
Adequacy of Protection Against Risks. .................................................................................................... 39 
Data Safety Monitoring Plan................................................................................................................... 41 
POTENTIAL RESEARCH BENEFITS TO PARTICIPANTS ........................................................................... 42 
INVESTIGATOR EXPERIENCE ............................................................................................................. 43 
WORKS CITED .................................................................................................................................. 47 
APPENDIX 1: DATA SPECIFICATIONS TABLE ....................................................................................... 56 
APPENDIX 2: STUDY LOGS ................................................................................................................ 61 
APPENDIX 3: PATIENT-REPORTED QUESTIONNAIRES ......................................................................... 75 
Social Readjustments Rating Scale – Life Events Questionnaire (Administered on paper) ..................... 75 
KOOS KNEE SURVEY (Administered on paper) ........................................................................................ 76 
PHQ-9 Questionnaire (Administered on paper) ...................................................................................... 81 
Oxford Knee Score (Administered Electronically via iPad) ...................................................................... 82 
VR-12 (Administered Electronically via iPad) .......................................................................................... 83 
Patient Activation Measure (Administered Electronically via iPad) ........................................................ 85 
Visual Analogue Pain Scale (Administered Electronically via iPad) ........................................................ 86 
APPENDIX 4: PATIENT INFORMATION FLIER ...................................................................................... 88 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 3  
PROJECT SUMMARY 
As a function of our 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, which is considered a high fall-risk 
activity, 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 their ability to 
increase muscle mass is significantly impaired. Thus, safe and effective treatments to prevent muscle 
loss and preserve strength are urgently needed and clinically meaningful, as they have the potential to 
significantly impact the quality of life for millions of older adults.  
 
The purpose of the proposed 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. Our 
hypothesis, based on strong preliminary data, is that twice-daily ingestion of 20 g of EAA (Aim 1) and 23 
g of EAA (Aim 2) for one week before through six weeks after TKA will increase basal rates of muscle 
protein synthesis via inactivation of catabolic signaling, and up-regulation of anabolic and cyto-
protective proteins. We 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. The rationale for the proposed research is that effective 
treatments to prevent muscle atrophy after increasingly common TKA surgery will result in short- and 
longer-term muscle cell adaptations that boost functional mobility and quality of life. Identifying the 
mechanisms up-regulated by EAA treatment that preserve muscle volume and mobility will have a major 
impact on rehabilitation science.  
 
The proposed research will empirically test our hypotheses by accomplishing 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. The proposed 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.
 
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5-year Clinical Trial: Essential Amino Acid Supplementation & TKA 
PI: Hans C. Dreyer, PhD, PT 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
November 2018 
INTRODUCTION AND BACKGROUND 
In the coming decades, the demand for primary total knee arthroplasty (TKA) in the U.S. is projected to 
increase 673% to 3.4 million surgeries performed annually. TKA surgery is primarily performed on older 
adults and results in significant muscle atrophy in the operative and non-operative thigh (quadriceps 
and hamstrings), which compromises balance, impairs functional mobility, and dramatically increases 
the risk of falls and related injuries. For older adults, muscle atrophy occurring during periods of 
inactivity or following surgery may be more difficult to recover.  
 
Age-associated muscle dysfunction results from reduced muscle mass, strength, and functional capacity 
(i.e., sarcopenia) (38). Sarcopenia occurs with normal healthy aging and is associated with an elevated 
risk for falls, physical disability, and loss of independence (105, 106). Estimated healthcare costs due to 
sarcopenia in the U.S. in 2000 was $18.5 billion (60). Reducing the prevalence of sarcopenia by 10% can 
save $1.1 billion/year in healthcare costs (60). While sarcopenia progresses at a rate of 1%/year in 
healthy older males and females, surgeries such as hip and knee replacement, will accelerate sarcopenia 
(99). The projected increase (nearly 7-fold) in the number of TKA to be performed annually in the U.S. in 
the coming decades will place a significant burden on our healthcare infrastructure, Medicare and 
Medicaid. The studies in this research plan are significant because they specifically address a major 
clinical barrier by mitigating post-operative muscle loss that translates directly into improved strength 
and functional mobility in older adults. Accelerating functional mobility will help to alleviate a significant 
economic burden by reducing recovery time, shortening time in clinical care, and halting the 
acceleration of sarcopenia. 
 
While evidence exists linking EAA to anabolic and catabolic regulation of muscle cell metabolism in 
healthy subjects (87-89), there is a dearth of experimental data investigating mechanistic adaptations 
that prevent muscle atrophy and restore function in TKA patients. It is known that EAA stimulates an 
acute anabolic response in muscle by activating the mTORC1 pathway and increasing fractional rates of 
protein synthesis (i.e., FSR) (50), and that chronic EAA supplementation elevates fasting rates of muscle 
protein synthesis in older healthy adults (29). However, studies conducted in healthy populations tell us 
very little about how muscle cell metabolism is altered following major surgery and if EAA 
supplementation causes an increase in basal rates of muscle protein synthesis and/or attenuate 
breakdown. Further, mechanisms linking atrophy prevention with positive functional adaptations in a 
clinical setting are lacking.  
 
Recent reports demonstrate that changes in fat oxidation in human primary myocytes parallel whole 
body metabolism of the donor (115). In other words, primary cells isolated from human subjects, which 
were allowed to expand and become myocytes and subjected to experiments to measure metabolism, 
revealed that myocyte metabolism were similar to host metabolism. This suggests that normally 
dormant satellite cells (primary cells) residing in muscle tissue recapitulate the metabolic characteristics 
of that tissue bed. Further, others have shown that satellite cells from older animals have reduced 
regenerative capacity as compared to young animals (25), however, when the blood from young mice is 
mixed with blood of older mice (heterochronic parabiosis) regenerative capacity in older muscles is 
restored (19, 26). In addition, altering defective signaling pathways in older satellite cells has the ability 
to normalize their regenerative response to injury (21, 25, 26). While these reports show that the 
satellite cell microenvironment plays an important role in regeneration a recent report from the Blau lab 
demonstrate that satellite cells from aged animals have inherent defects in their ability to respond 
appropriately to muscle tissue injury (27). From these reports we may conclude that satellite cells have 
metabolic and regenerative characteristics that relate back to the health status and age of the donor. 
Furthermore, these are important consideration to take into account when interpreting results from 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 5  
clinical trials evaluating the response(s) of muscle tissue(s), and, more importantly, functional mobility, 
in older adults.  
 
Recent experiments performed on C2C12 myotubes have demonstrated that following incubation with 
essential amino acids (EAA) anabolic pathways are upregulated (9), which is similar to the anabolic 
response measured in muscle cells obtained from healthy young adults after in bolus ingestion (50). 
Interestingly, we have shown that older adults demonstrate a diminished anabolic response to EAA 
ingestion relative to younger subjects (41) that is dose dependent (28) and appears to be sensitive to 
Leucine concentration (63). Interestingly, a recent report from Farup and colleagues (45) showed that 
subjects supplemented with Whey protein before and after an eccentric contraction protocol 
demonstrated significantly greater expansion of their satellite cell pool vs. placebo subjects, which is 
important because Whey supplement has higher concentrations of EAAs and is absorbed quickly relative 
to intact protein (steak) (95-97). Thus, it appears that EAA supplementation may be acting on muscle 
tissue by positively influencing satellite cells as well as muscle protein anabolism and/or catabolism. 
Lastly, recent work from Joshi and colleagues (61) provide methods for assessment of in vitro model of 
ischemia using myotubes that may be used to isolate pathways that are up and/or downregulated 
response to ischemia-reperfusion injury. Assimilated, the above information suggest that primary cells 
isolated from humans of different ages (young vs. old) and varying health status (metabolic) may, under 
certain experimental conditions, provide valuable insight into donor muscle response(s).  
 
Preventing muscle atrophy and weakness is clinically significant because it leads to immediate and 
tangible improvements in functional mobility in the short term, which may lead to positive changes in 
longer-term muscle cell structural and functional adaptations that will improve quality of life for older 
patients following TKA. Quadriceps weakness inhibits balance (84), reduces functional mobility (20, 82), 
and increases the risk of falls (83). Muscle atrophy increases the prevalence of physical disability (103) 
and accelerates the progression of sarcopenia (99). Tests of functional mobility consistently 
demonstrate marginal improvements following TKA surgery (47, 92, 123). Functional tasks such as stair-
climbing, which is considered a high fall-risk activity, remains a clinical problem for 75% of patients 
following TKA (92). A recent report suggests that early post-operative function may predict the speed of 
functional recovery and the overall success of rehabilitation (64). Evidence suggests that acute weakness 
in the non-operative limb following TKA is related to poorer functional outcomes in the long-term (126), 
and maintaining greater muscle volume in the operative leg is essential to maximize muscle strength 
(79, 80) and attenuate the acceleration of sarcopenia (99). Studies show that, after a peak in functional 
recovery at 6 months, there is an acceleration of functional decline due to quadriceps weakness that 
outpaces normal ‘aging’ that is not attributable to lack of range of motion or pain (81, 82, 98, 125). 
Reports suggest a link between mitochondrial dysfunction and aging (2), which is exacerbated by 
inactivity (5). Preserving muscle volume and cellular function is essential to improve strength and 
accelerate functional mobility, which we hypothesize will lead to positive structural and functional 
adaptations in muscle cells at 6 months post-TKA (79, 80). 
 
Preliminary Studies.  
Biochemistry. Recent studies in the Dreyer Laboratory have generated exciting preliminary results 
showing essential amino acid (EAA) supplementation attenuates quadriceps atrophy and accelerates the 
return of functional mobility following TKA (37). For patients on EAA, quadriceps atrophy was only -6% & 
-3% in the operative and non-operative quadriceps, respectively, six weeks after TKA but -18% & -10%, 
respectively, in patients on Placebo (a 3-fold difference). Of clinical relevance, these patients on EAA 
were able to maintain strength and demonstrated an accelerated return of functional mobility vs. 
Placebo, 6 wk post-TKA. At the cellular level, our preliminary results show that EAA supplementation 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 6  
down-regulated catabolic signaling (FoxO3a) and up-regulated amino acid transporter (SLC36A2), 
regulated in development and DNA damage response (REDD1) and activating transcription factor 4 
(ATF4) expression vs. Placebo. While studies by others have linked these molecules with the insulin like 
growth factor (IGF-I) and vascular endothelial growth factor (VEGF) (i.e., angiogenesis) pathways, 
whether they are directly stimulated by EAA supplementation in a clinical population remains unknown. 
We interpret these positive changes at the cellular level to be responsible for the reduction in muscle 
loss and, preservation of strength, and explain the acceleration of the return of functional mobility. 
 
Our preliminary fractional synthesis data (FSR) show that older adults respond appropriately to acute 
ingestion of 20 g of EAA (i.e., similar response to young healthy controls). We also have preliminary FSR 
data showing that basal rates of muscle protein synthesis are similar between TKA patients (0.0563 ± 
0.008%/hour) and older healthy control subjects (0.0566 ± 0.008%/hour). What is not known is what 
effect TKA has on muscle protein synthesis and breakdown in response to chronic EAA supplementation 
(for 1 week prior to, and for 6 weeks post-TKA). We have extensive experience with stable isotope tracer 
methods to determine fractional synthesis rates (FSR), a direct measure of muscle protein synthesis (31-
35, 39-41, 50, 113, 114). However, in order to determine mechanisms, and link cellular changes in 
anabolic and catabolic pathways with atrophy (Placebo) and atrophy prevention (EAA) we must also 
quantify muscle protein breakdown.  
 
Our preliminary results show that EAA phosphorylates (inactivates) a primary regulator of muscle 
protein catabolism (FoxO3a). As well, EAA supplementation stimulated the expression of the anabolic 
amino acid transporter, which has gained attention due to its ability to act as both a transporter and 
signaling protein linked to the IGF-I signaling pathway (54, 102). Interestingly, we also measured an up-
regulation of the transcription factor ATF4, which has been shown to stimulate the expression of amino 
acid transporters and promote protein anabolism (76). In vivo and in vitro experiments have shown that 
IGF-I treatment increased REDD1 expression in muscle (49), and recent studies have shown that REDD1 
confers cyto-protective effects by mitigating cell stress (22, 120). REDD1 is upregulated by ATF4 (49, 76, 
122). ATF4 is increased in the presence of insulin (4) and IGF-I (49), and plays an important role in 
mediating the effects of VEGF on cell growth and survival (3, 75, 93). Thus, ATF4 may be necessary for 
amino acid and protein anabolism (4). We have preliminary data showing that REDD1 expression is 
elevated with EAA. This is important because our preliminary results support mechanisms of action by 
which EAA up-regulate amino acid transporters via ATF4 that have implications for muscle protein 
metabolism (76). We interpret these results as supporting a mechanistic role in atrophy prevention. 
 
Physiology.  Immobilization following orthopedic surgery accelerates sarcopenia (99). For example, 
1%/year = normal sarcopenia progression, but in our TKA patients, sarcopenia was accelerated by +18 
and +10 years, in the operative and non-operative leg, respectively. However, in patients randomized to 
EAA, progression was only +6 and +3 years, respectively. Thus, EAA have the potential to mitigate early 
onset of sarcopenia. Preventing muscle atrophy bilaterally is clinically important, as early post-operative 
quadriceps weakness in the non-operative leg is directly linked to poorer long-term functional outcomes 
(126).   
 
Quadriceps weakness results from both muscle atrophy and neural activation deficits (80, 107). In the 
longer term however, strength deficits are due to persistent muscle atrophy, explaining 77% of the 
quadriceps strength deficits 1 year post-TKA (80). Our preliminary data show that EAA supplementation 
reduces strength loss and accelerates the return of functional mobility. Persistent quadriceps atrophy 
and weakness have profound effects on functional mobility and activities of daily living (13, 107, 119). It 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 7  
is well known that quadriceps mass and strength are strong predictors of functional mobility (i.e., timed 
up-and-go, stair-climb down [descent] ability and ambulation).  
We also have compelling preliminary data showing that Type II muscle cell cross-sectional area (CSA) is 
reduced (atrophied) compared to controls following TKA. We expect to show that CSA increase 
(normalize to that of the non-operative side) in the EAA group. As well, we have preliminary data from 
isolated muscle fiber bundle analysis of oxygen consumption (mitochondria respiration) from muscle 
cells from TKA subjects have lower (-61%) basal mitochondrial function (respiration) vs. age- and sex-
matched controls.  
 
 
Contribution to Scientific Knowledge. 
Muscle atrophy occurs in cancer cachexia (12), chronic heart failure (8), chronic obstructive pulmonary 
disease (70), HIV-AIDS (121, 124), renal failure (66), rheumatoid arthritis (71, 77), osteoarthritis (116), 
burn injury (18), following total hip and knee arthroplasty (58), ACL reconstruction (57), and during bed 
rest (94). Despite its widespread impact in clinical settings little progress has been made in devising ways 
to prevent muscle atrophy. As such, our R01 proposal is significant because it has broad clinical appeal 
as a high yield therapy to attenuate atrophy under a variety of clinical conditions (EAA are well 
tolerated, easily digested, and immediately available).  
 
The significance of this Research Plan also centers on our use of TKA as a model system for the study of 
muscle atrophy (Placebo) and atrophy prevention (EAA), which are due to an imbalance between 
anabolic and catabolic alterations at the molecular and cellular level. Our study will advance knowledge 
of the molecular and functional changes that are occurring during muscle atrophy and prevention in 
older males and females, and will identify additional novel targets for therapeutic interventions. 
 
Our study is innovative for several reasons. Foremost is our translational approach which will allow us to 
identify novel molecular regulators of muscle atrophy (Placebo) and atrophy prevention (EAA). Using 
isotopically labeled tracer methodologies we will quantify muscle protein synthesis and breakdown, and 
link those results with changes in muscle volume, strength and functional mobility. We will also 
determine the degree to which short-term preservation of muscle volume, strength and function 
translate into longer-term structural and functional (mitochondrial respiratory) adaptations at the 
cellular level. Our plan to explore potential sex differences in the age-related changes in muscle protein 
synthesis and breakdown following TKA and the mechanistic effects of EAA on muscle metabolism, 
atrophy, and mobility is exciting. Finally, this research plan brings together a clinical and translational 
research team to investigate the biochemistry and physiology of muscle atrophy and incorporates 
functional measures of mobility and quality of life in a unique and meaningful way.  
 
The primary innovation is our integration of cellular and molecular methods with measures of muscle 
protein synthesis and breakdown, volume, and functional mobility in order to better understand how 
muscle atrophy can be prevented in a clinical setting(s). Our protocol will be freely available to clinicians, 
therapists, and researchers interested in mitigating muscle atrophy, which may profoundly affect the 
medical/rehabilitation field as the use of EAA in atrophy prevention spreads and gains momentum. 
 
 
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5-year Clinical Trial: Essential Amino Acid Supplementation & TKA 
PI: Hans C. Dreyer, PhD, PT 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
November 2018 
Hypothesis.  
The working hypothesis, based on strong preliminary results, is that twice-daily ingestion of 20 g of EAA 
for 1 week before and 6 weeks after TKA, will increase basal rates of muscle protein synthesis via 
inactivation of catabolic signaling (FoxO3a), and up-regulation of anabolic (SLC36A2, IGF-I & VEGF) and 
cyto-protective proteins (ATF4 & REDD1). We further propose that short-term atrophy prevention and 
accelerated return of functional mobility will translate into long-term (6 months post-TKA) structural 
(cross-sectional area, CSA) and functional (mitochondrial respiration) adaptations, leading to improved 
quality of life in TKA patients vs. Placebo in older men and women. 
 
SPECIFIC AIMS 
To test our hypothesis our Research Plan proposes scientifically rigorous methods designed to achieve 
the following specific aims:  
 
 
Specific Aim #1 (Biochemistry):  Determine if EAA elevates basal rates of muscle protein 
synthesis by up-regulating anabolic pathways & cyto-protective proteins, and inactivating 
catabolic pathways in the short-term vs. Placebo. 
 
Identifying molecular pathways that are up-regulated by EAA are needed in order to uncover 
potential mechanisms of action. Successful completion of the proposed research will determine 
the degree to which EAA elevate basal rates of muscle protein synthesis and the extent to which 
these changes coincide with increases in anabolic (SLC36A2, IGF-I, & VEGF) and cyto-protective 
(ATF4 & REDD1) pathways. As well, completion of Aim 1 will allow us to determine changes in 
muscle protein breakdown in parallel with changes in catabolic (FoxO3a) proteins (Fig. 3). We 
expect these findings will provide mechanistic data on the effects of EAA on muscle cell 
metabolism and signaling that will help explain how muscle atrophy is prevented and functional 
mobility accelerated following TKA.  
 
To accomplish Specific Aim #1, subjects will be enrolled pre-operatively and asked to participate 
in a number of study-related activities designed to isolate the effect of EAA supplementation on 
muscle protein synthesis. Subjects will consume “heavy water” to aid in quantifying chronic 
muscle protein synthesis rates while consuming the study EAA supplement. Study specific blood 
draws, muscle imaging (via MRI) and muscle biopsies will be assessed at regular intervals. 
Patients will capture accelerometer data and complete three-day food diaries, as well as patient 
reported outcome measures designed to capture health-related quality of life, knee-specific 
functioning, pain and the degree to which the patient has an ability engage in total joint pre- 
and post-operative care. Finally, functional testing will capture patient strength and functional 
capabilities pre- and post-operatively.  
 
 
 
 
 
 
 
 
 
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5-year Clinical Trial: Essential Amino Acid Supplementation & TKA 
PI: Hans C. Dreyer, PhD, PT 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
November 2018 
The proposed research design will answer the following questions:  
1.1 Does EAA elevate or alter levels of muscle protein synthesis vs. Placebo?  
1.2 Does EAA decrease or alter levels of muscle protein breakdown vs. Placebo?  
1.3 Will EAA inactivate catabolic (FoxO3a) and up-regulate anabolic (SLC36A2, IGF-I, 
ATF4 and REDD1) pathways vs. Placebo? 
1.4 Does inhibition of angiogenic factors (IFG-1 & VEGF) inhibit a pro-angiogenic 
response? 
1.5 Does EAA influence markers of inflammation vs. Placebo?  
1.6 Does EAA influence markers of mitochondria function vs. Placebo?  
1.7 Does statin use influence cell respiration over time?  
1.8 Does EAA affect primary cell derived myocyte function over time?  
 
Specific Aim #2 (Physiology): Determine if short-term prevention of atrophy, weakness, and 
functional mobility leads to positive changes in muscle cell structure and function, and quality 
of life in the long term (6 months post-TKA) vs. Placebo. 
Successful completion of Aim 2 will identify a role for EAA supplementation in clinical settings 
using a mechanistic approach. Our approach is based on strong preliminary clinical data from 
older men and women following TKA demonstrating that EAA supplementation for 1 week prior 
to, and for 2 week post-TKA was effective in preventing significant muscle atrophy (37). 
However, our preliminary data suggest that in the EAA group, atrophy at 2 weeks post-TKA was 
half that at 6 weeks in the operative quadriceps and hamstrings. This potential ‘catch-up’ muscle 
loss was not observed in the non-operative leg within the EAA group but was identical to the 
change from 2 weeks to 6 weeks in the operative leg of the Placebo group. We interpret these 
data to support the need to supplement for 6 weeks post-TKA in order to maximally prevent 
bilateral muscle atrophy.  
 
The proposed research design will answer the following questions:  
2.1 Does EAA prevent short-term (7 wk post-TKA) bilateral muscle atrophy, preserve 
quadriceps strength, and accelerate the return of functional mobility vs. Placebo? 
2.2  Are there short-term sex differences on the above outcome measures? 
2.3  Will EAA increase long-term (6 mo post-TKA) quadriceps functional mobility vs. 
Placebo? 
2.4  Does EAA improve longer-term (6 mo post-TKA) functional mobility and measures of 
quality of life vs. Placebo? 
2.5  Are there long-term sex differences in functional mobility or measures of quality of 
life? 
2. 6 Does inhibition of angiogenic factors (IFG-1 & VEGF) inhibit a pro-angiogenic 
response?  
2.7 Does EAA influence markers of inflammation vs. Placebo?  
2.8 Does EAA influence markers of mitochondrial function vs. Placebo?  
2.9 Does statin use influence cell respiration over time?  
2.10 Does EAA affect primary cell derived myocyte function over time?  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 10  
Methods, Materials and Analysis  
 
Study Design. 
Prospective, randomized, blinded, controlled, two-arm, parallel clinical trial design with 1:1 allocation 
ratio to EAA versus Placebo. Staged enrollment is planned; we will complete Aim #1 before enrolling into 
Aim #2.  
 
Investigational Supplement.  
This trial is being conducted under IND#121601, with mandates to report results from Aim #1 to the 
Food and Drug Administration (FDA). The investigational supplement (or Placebo) will be ingested twice-
daily, at 10:00a and 2:00p for one week prior to TKA surgery.  
 
Aim 1 -Supplement will be compounded by Northwest Compounders, and ordered per standard 
of care for pharmaceutical ordering (fax or phone call) and dispensing. 
 
 
Aim 2 – Supplement will be supplied by MEND Nutrition, Inc. Supplement will come individual 
containers shipped directly to the Dreyer Lab. Containers will be distributed to patients by study 
coordinators. Patient will measure two (2) scoops per dose (twice daily). Scoop provided in each 
container.  
 
Aim 1 Supplement will be suspended on the day of surgery and resume on post-operative day #1. On 
post-operative days where subject participates in physical therapy, supplementation will occur within 
one hour of treatment (20 g of EAA or Placebo). The EAA supplement or Placebo composition is 
described in Table 1 below. Our preliminary study suggest the EAA supplementation is safe and no 
subjects withdrew due to problems with supplement ingestion (37).  
 
 
Aim 2 Supplement will be suspended on the day of surgery and resume on post-operative day #1. On 
post-operative days where subject participates in physical therapy, supplementation will occur within 
one hour of treatment (23.42 g of EAA or Placebo). The EAA supplement or Placebo composition 
provided by MEND Nutrition, Inc. is described in Table 2 below. Our preliminary study suggest the EAA 
supplementation is safe and no subjects withdrew due to problems with supplement ingestion (37). 
Supplement composition has changed due to new manufacturer/supplier of the supplement (MEND). To 
our knowledge there are no scientific or risk implications related to the change in proportions. 
 
Recent results from the Phillips group (128) demonstrated that free-living older males taking 5 grams 
of Leucine with each meal (3x/day for 3 days), placed on either a low- (RDA; 0.8g protein/kg/day) or high- 
(1.2g protein/kg/day) protein diet, had elevated basal and post-exercise myofibrillar protein synthesis vs. 
the same individuals on the same diets (low or high) without supplemental Leucine. Subjects on low-
protein and high-protein diets supplemented with 5g of Leucine were not different from one another in 
this study. The finding has direct implications for our patients who eat less after surgery (37). Data for the 
Phillips paper were obtained by using D20 and reflect the rates of myofibrillar synthesis over 3 days in 
individuals who consumed their normal meals and performed their usual level of activity. This suggests to 
us that using doses of Leucine closer to 15g/day may have a more profound effect in offsetting muscle 
autophagy, which can be stimulated by mTORC1, which is activated by Leucine (129).  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 11  
This will bring us close (13.6g/day) to the 15g/day used by the Phillips group. These more current 
findings justify modifying our protocol in order to maximize our ability to positively influence patient 
outcomes.  
 
Participant compliance will be assessed by two primary mechanisms: (1) log-book inspection which the 
subject will record each supplement ingestion time and (2) empty vial collection. Supplements will be 
randomly tested for quality control using HPLC to ensure no mixing of samples between groups. 
 
 
 
Table 1: Composition of investigational supplement (EAA) and Placebo – Aim 1.  
Composition 
% 
g 
Essential Amino Acid 
   Histidine 
11 
2.2 
   Isoleucine 
10 
2.0 
   Leucine 
18 
3.6 
   Lysine 
16 
3.2 
   Methionine 
3 
0.6 
   Phenylalanine 
16 
3.2 
   Threonine 
14 
2.8 
   Valine 
12 
2.4 
Placebo 
   Alanine 
100 
20 
 
 
Table 2: Composition of investigational supplement (EAA) and Placebo – Aim 2  
Composition 
% 
g 
Essential Amino Acid 
   Histidine 
5 
1.28 
   Isoleucine 
8 
1.8 
   Leucine 
32 
7.4 
   Lysine 
15 
3.6 
   Methionine 
8 
1.76 
   Phenylalanine 
13 
3.1 
   Threonine 
8 
1.9 
   Valine 
9 
2.08 
   Tryptophan 
2 
0.5 
Placebo 
   Alanine 
100 
23.42 
 
Study Aim #1 (Biochemistry).  
Aim #1: Determine if EAA elevates basal rates of muscle protein synthesis by up-regulating anabolic 
pathways & cyto-protective proteins, and inactivating catabolic pathways in the short-term vs. Placebo. 
Randomization Assignments. Aim #1 will consist of 2 groups (N=20/group through protocol 
completion; EAA vs. Placebo) that are identical in protocol design except for metabolic studies. 
Metabolic studies will partition the EAA group into 2 (post-TKA bilateral biopsy at 1 or 2 weeks after 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 12  
surgery) and Placebo group into 2 (post-TKA bilateral biopsy at 1 or 2 weeks after surgery). This will 
allow us to collapse data by group treatment group; questionnaire, activity, food-log, strength & 
activation, muscle volume and functional data (this equals N of 20 through protocol completion for EAA 
and N of 20 for Placebo through protocol completion; 20/group, enough for sex comparison), while 
enabling us to quantify changes over time in metabolism (D20) and at discrete time points after surgery 
(1 and 2 weeks post) between legs when 80% or more of muscle atrophy is occurring (37). 
 
Primary Biochemical Outcome Measures.  
To answer our study questions will be answered using an in vivo experimental design. The procedure 
schedule can be referenced in Figure 1 (page 17, following a description of all study-related 
procedures and measures for Aim #1).  
 
Deuterium Oxide Ingestion Followed by Muscle Biopsies. Deuterium oxide (D2O, i.e., heavy water) will 
be used to quantify chronic (days) muscle protein synthesis rates. D20 will be ingested (50 ml) three 
times per day for 7 days leading up to TKA. During TKA surgery, a single biopsy will be obtained in the OR 
from each leg. Beginning on POD#1 and continuing through week 1 or week 2, subjects will continue 
ingesting 50 ml of D2O twice daily. Bilateral biopsies obtained from each leg at 1 or 2 weeks post-TKA 
will be analyzed to determine muscle protein synthesis rates. All subjects will have a total of two 
biopsies from each leg, in a fasting state. This will allow us to determine the independent effects of 
supplementation on rates of muscle protein synthesis and breakdown (2H20) during the acute and sub-
acute period.  
 
Measures include structural (CSA of cell and extracellular matrix) and functional (mitochondrial 
respiration & inflammatory cell infiltration) determination. Muscle cell structure (CSA) and function 
(mitochondrial respiration) will be determined based on percent change from baseline and made 
relative to the non-operative leg (internal control). From muscle biopsies we will also isolate primary 
muscle cells (i.e., satellite cells).  
 
To perform the biopsies, a small incision about the size of this dash “---" approximately at mid-thigh, 
through which a needle about the size of this letter "O" will be advanced into the muscle and fat.  A 
piece of tissue will then be removed.  This will be done on each leg.  
 
The postoperative biopsies will be performed by the Principal Investigator (Dreyer). Dr. Dreyer has 
performed over 500 biopsies and he has performed over 200 tracer studies. The biopsies will be 
performed in his lab at the Center for Medical Education and Research, or at the Slocum Center, in the 
morning in a fasted state.  This procedure involves the taking of a small piece of tissue from the leg, 
containing both fat and muscle. The skin is cleaned and made sterile, and the skin and tissue below are 
injected with local anesthetic, lidocaine (numbing medicine), to eliminate pain.  Afterwards, the skin will 
be closed with a single stitch (Aim 1 only).  The stitch will be removed at the lab in about 7 days (plus or 
minus one day to accommodate participant schedule). 
 
 
During the surgery, the surgeon or one of his assistants will perform the biopsies. The patient will still be 
under anesthesia. The intraoperative biopsies will not have a stitch that requires removal. The site will 
be covered with a sterile dressing.  
 
Primary cell isolation. Primary cells isolation studies will be performed using standard methods that 
exist in our lab in order to conduct experiments on muscle cells that could not be perform on subjects 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 13  
Muscle cells may be manipulated in a laboratory environment, and much learned from the 
manipulation, in ways that are not possible in vivo. For example, we can block metabolic processes from 
happening and evaluate the impact on muscle tissue. This approach will have the added benefit of 
increasing the amount of muscle tissue we have to work with. However, this approach is not intended to 
develop perpetual cell lines. The myocytes are in cell culture, they have a finite life span and will expire 
within 2 to 4 weeks.  After the experiments on cells are completed they will be dead already or 
destroyed. 
 
 
Muscle Morphology. Morphology will be determined from tissue obtained using immunohistochemical 
techniques to examine differences in muscle fiber cross sectional area (CSA), and fiber type.  CSA will be 
determined using standard methods (7). Tissue sections will be cut at 10μm thickness in a Leica CM 1850 
UV cryostat maintained at -22ºC. Each tissue section will be mounted on Fisherbrand Superfrost®/Plus 
microscope slides (Fisher Scientific, USA). Digital images will be captured on a Leica DM4000 Epi-
Fluoroscent microscope and analyzed using MetaMorph Premier Software. 
 
Westerns. Specific cell signaling pathways probed will be stress response and anabolic and catabolic 
pathways. The PI has extensive laboratory experience and training in these methods, techniques and 
application of immunoblotting techniques (2, 3, 5-7, 10, 12). The phosphorylation status of each protein 
will be expressed relative to total protein after each is individually expressed relative to GAPDH or α-
Tubulin. Anti-rabbit IgG horseradish peroxidase-conjugated secondary antibody will be purchased from 
Amersham Bioscience. Western blot signals will be analyzed with a BioRad XRS Chemiluminescence 
imaging system, which detects ECL signals over 5 orders of magnitude, and its sensitivity range far 
exceeds that of conventional densitometry.  
 
Gene Expression:  RNA will be extracted from 15-20 mg of muscle tissue according to protocol 
(Molecular Research Center, Inc, Cincinnati, OH). High quality RNA will be determined using lab-on-chip 
microfluidic technology automated nucleic acid electrophoresis and analysis. Total RNA will be reverse 
transcribed into cDNA using the iScript cDNA Synthesis Kit (Bio Rad, Hercules, CA) on a C1000 Thermal 
Cycler (Bio Rad, Hercules, CA). Determination of relative mRNA expression will be performed using a 
CFX96 Real-Time System coupled to a C1000 Thermal Cycler (Bio Rad, Hercules, CA) and Genomics Core 
facility NextSeq 500 at the University of Oregon.   
 
Mitochondrial respiration. Oxidative phosphorylation rates in response to 50µM ADP will be 
determined in saponin permeabilized vastus lateralis biopsies (5-10 mg) using the two-channel high 
resolution respirometer (Oroboros Oxygraph; Innsbruck, Austria) with the saturating concentrations of 
the following substrate combinations [in mM]: pyruvate [5] + malate [5], palmitoylcarnitine [0.04] 
+ malate [5],  succinate [10] + 100 nM rotenone, or malate [5] + glutamate [10].  Respiration studies 
were performed at an initial oxygen concentration of 300 µM at 37C in MiR06 respiration buffer 
containing [in mM] EGTA [0.5], MgCl2·6 H2O [3], K-lactobionate [60], taurine [20], KH2PO4 [10], HEPES 
[20], sucrose [110], 1g/L BSA, 280U/ml catalase, pH 7.4 [with KOH].  
 
Mitochondrial dysfunction may introduce sample bias as well as negatively impact short and longer-
term function. To account for this, we propose to measure mitochondrial respiration using the Oroboros 
O2k respirometer, and normalize results statistically and use the non-operative leg as internal control.  
 
Secondary Outcome Measures. Study Aim #1 will allow the team to collect preliminary functional 
outcome data to better inform the long-term study (Aim #2).  The secondary outcome measures will be 
quantified using the following study activities and procedures:  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 14  
 
 
Muscle volume. The MRI unit is located at the Lewis Center for Neuroimaging (LCNI) on the 
University of Oregon campus. Should the MRI unit at LCNI be unavailable within study-specific 
assessment points (i.e. scheduling or mechanical issues), the MRI at the Slocum Center for 
Orthopedics will be utilized. In addition, patients in partnership with the study team, may elect 
to have all scans performed at the Slocum Center.  
 
All scans will be performed prior to strength & functional testing and a minimum of 24 hr post-
therapy. T1 & T2 weighted MR images will be used to quantify quadriceps volume vs. edema. 
MRI is safe for TKA patients (implants are non-ferrous) and is ideally suited for muscle volume 
quantitation. Capture protocols will be stored on the unit to ensure accurate image collection 
over the course of the study. MRIs will not be performed in a fasting state.  
 
MRIs performed at the Slocum Center will follow the standard operating procedures of Slocum 
MRI as per standard of care. Slocum MRI will carry out their own screening processes at the time 
of the scan. Research staff will alert MRI staff if the patient has any contraindicated implanted 
devices prior to the scan.  Slocum MRI will follow their standard operating procedures to ensure 
MRI safety.  
 
Because MRIs at the LCNI are strictly used for research purposes, study participants will 
complete the IRB-approved LCNI screening form in advance of their MRI procedure(s). Based on 
the screening form results if LCNI requires more information to comfortably scan our patients, 
LCNI will call the study coordinators. Information that may be requested by LCNI includes any of 
the following (more than one possible): 
1. Confirmation of MRI scan with implant in question has occurred previously 
2. Blinded operative notes of the implant in question 
3. Advance conversation with the patient at LCNI 
4. Communication /confirmation/conference with surgeon 
5. Identification of implant type 
 
If the patient requires any #2-5 above, a separate HIPAA authorization to communicate 
with LCNI will be completed. For patients who have pre-operative and post-operative research 
scans at the Slocum Center, data will be stored per standard of care; however, images will be 
transported through a secure VPN connection for analysis at the Dreyer Lab.  
 
It is important patient’s have pre-operative and post-operative scans on the same MRI machine. 
The study team will work with the patients and his/her care team to determine the MRI location 
to best serve the patient’s needs.  
 
 
Edema and fluid accumulation in the surgical versus nonsurgical thigh. From the biopsies, 
muscle samples will be weighed wet and then dried and weighed again. The difference between 
the two weights will be used to estimate fluid accumulation in the muscle tissue. Biopsies will be 
performed in a fasting state. 
 
 
Function. Standardized grip strength, standing balance, chair stand test, timed up-and-go (TUG), 
timed stair ascent and timed stair descent, 4 meter walk test and the 6 minute walk will be 
assessed. Grip strength will determine changes in each hand grip over time. Standing balance 
will measure changes over time in balance. The chair stand test measures the time it takes for 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 15  
the subject to stand and sit five times. TUG will measure the time (seconds) needed to stand 
from a chair, walk 3 meters, turn around, walk back and be seated again. Timed stair ascent (10 
steps) and descent will be recorded. The 4 meter walk will tell us how long it takes you to walk a 
short distance (4 meters) while the 6 minute walk will measure the distance you can walk over a 
longer distance (total distance in 6 minutes). We have experience with these functional 
measures. Each functional mobility measure will be performed on a single standardized chair 
(TUG) and stairs. Functional assessments will not be performed in a fasting state. Functional 
measurements may be performed at either the Dreyer Lab on the University of Oregon campus 
or the Slocum Center for Orthopedics & Sports Medicine.  
 
 
Strength & central activation deficit. Co-Investigator Dr. Anita Christie, PhD, will contribute her 
expertise to quantify pre- and post-operative changes in strength and quadriceps activation 
(24). Strength will be quantified using a Biodex +/- tests for central activation deficits (CAD). CAD 
contributes to early weakness following TKA, and Dr. Christie will quantify this progression 
between groups over time using previously published methods will be followed (23, 44, 62, 65, 
67, 112). Voluntary activation of the knee extensor muscles will be assessed through the 
painless method of supramaximal magnetic stimulation of the femoral nerve superimposed on 
the MVC (90). Central activation of the knee extensors will be calculated from the resulting force 
as follows: (MVC/(MVC + Stimulation)) x 100 (65). Nerve function will be determined using the 
latency of the M-wave in response to supramaximal magnetic stimulation of the femoral nerve 
(23, 44). Additionally, pre-post surgery measures of the area of the negative peak of the M-wave 
will be used to estimate motor neuron loss (67). Strength and central activation deficits will not 
be performed in a fasting state. Central activation is measured on the University of Oregon 
campus or at the Slocum Center. 
 
 
Patient-reported outcome measures.  Patients will be asked to complete questionnaires 
assessing self-reported quality of life, knee-specific functioning and pain.  
 
1. VR-12 - Consists of select items from the eight concepts of health in the SF-12, 
summarized in a physical component summary and a mental component summary. 
Useful in understanding health-related quality of life, and differences in disease burden. 
Administered at Slocum per standard of care via iPads. 
 
2. KOOS - Well-established standardized knee-specific functional outcomes tool. Used 
frequently in the literature to report degree of functional mobility and knee-related 
disability. WOMAC scores may be calculated from KOOS. Reviewers may expect 
KOOS/WOMAC data collection use in orthopedic clinical trials. Administered on paper 
for research purposes. 
 
3. Oxford Knee - Shorter knee-specific functional outcomes tool. Suggested to have 
superior validity, reliability and responsiveness compared to older knee-specific 
outcome tools. Well established for use in Europe, and has gained significant traction in 
the United States over the past few years. Reviewers may expect Oxford data collection 
use in orthopedic clinical trials. Administered at Slocum per standard of care via iPads. 
 
4. Visual Analogue Pain Scale (VAS) - Measures self-reported pain, which is associated 
with functional outcomes in orthopedic clinical trials. Administered at Slocum per 
standard of care via iPads. 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 16  
 
Covariate Measures.   
There are a number of study-related activities employed to allow the study statisticians to isolate the 
effect of EAA supplementation on primary and secondary outcome measures (described above).  
 
Accelerometer. All subjects will wear an ActiGraph (Pensacola, FL) GT3X accelerometer at 
various points throughout the study, including during inpatient and outpatient PT (see Study 
Timeline). Participants will be instructed to wear the device at all times except when showering, 
bathing, swimming, or sleeping. Accelerometry data will be downloaded to a computer using 
ActiLife v.6 software. Total daily energy expenditure (TDEE; kcal/day) will be estimated, and 
physical activity levels (PALs; TDEE/basal metabolic rate [BMR]) calculated to adjust for body 
size. Activity energy expenditure (AEE; kcal/day), calculated as TDEE-BMR, will be used to 
describe the caloric costs of physical activity. In addition, time spent in standard categories of 
activity (sedentary, moderate, vigorous) will be assessed. Our study coordinator will exchange 
accelerometers every week, which we have determined from our preliminary studies to 
maximize battery life and capture all activity data.  
 
 
3-day food log. All subjects will receive a thorough explanation of, and examples of, how to 
complete the 3-day food log.  In addition, food intake will be captured by study coordinators 
and/or hospital staff while the patient is admitted. Our study coordinator will interact with 
subjects in person and by phone to monitor compliance. In addition to monitoring food log 
compliance, the study coordinator will collect supplement containers to ensure compliance 
between groups. Carbohydrate, fat, and protein intake will be incorporated into our statistical 
analysis. A copy of the 3-day food log can be reviewed in Appendix 2.  
 
 
Patient-Reported Outcome Measures. Additional questionnaires will be collected for conditions 
that may impact our primary and secondary outcome measures.  
o PHQ-9 - Depression has been associated with orthopedic outcomes for total knee 
arthroplasty procedures. The presence and severity of depression may confound study 
results if not measured. Administered on paper for research purposes.  
 
o Life Events - Similar to the rationale for depression, significant life events may impact 
overall health status, thereby possibly confounding primary study endpoints. Capturing 
significant life events will allow for investigators to control for externalities that may 
otherwise go unmeasured in total knee outcome studies. Administered on paper for 
research purposes. 
 
o Patient Activation Measure (PAM) - Measures the degree to which patients have the 
confidence, knowledge and ability to manage health conditions, health needs and 
medical care. Patient Activation level has been associated with cost, utilization and 
health outcomes.  Administered at Slocum under a separate research protocol (data to 
be used for both studies). 
 
 
Patient Demographics, Medical History, Limited Social History, Medications. Please refer to 
Appendix 1 and the Data Specifications Table to review covariate measures collected for this 
protocol.  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 17  
Blood Draws.  
Table 2 describes the blood tests required to achieve study aims or, as requested by the Food and Drug 
Administration (FDA) under the IND requirements. Each subject will have daily AM fasting blood draws 
(18 ml). Standard of care includes blood draws at the pre-operative visit with the anesthesiologist and 
daily am blood (7 ml) draws while in the hospital. Should the pre-operative visit with anesthesia occur 
prior to study enrollment, the patient will be asked to have research-only labs drawn prior to initiating 
supplementation (Aim 1). Aim 2 preoperative blood draw will not overlap with standard of care. Some 
patients may require a blood draw on the day of surgery under standard of care (and required for 
research purposes), or additional labs (e.g. AM and PM) while in the hospital; however, the typical 
patient will have between four and five blood draws during the TKA course of treatment. At each 
standard of care blood draw, one or two tubes of blood are collected. For research purposes, to satisfy 
the FDA and research requests, four additional tubes of blood will be drawn (tests for: homocysteine, C - 
reactive protein, standard lipid panel, and ketone assay). While the subject is in the hospital, they will 
only have the additional tubes of blood drawn on the day of surgery and post op day two. In addition, 
we will collect two extra tube of blood for analyzing at the Dreyer Lab at each blood draw. One tube is a 
serum collection tube and the other a plasma collection tube. Both types of blood product are required 
to conduct the analysis described in the study procedures.) In total, at each study time-point (pre-admit, 
day of surgery, post op day two, and two and six weeks post-TKA), seven or eight tubes of blood are 
collected (routine care plus study bloods).  
For pre-admission blood work, the surgeon requires additional blood work to assess for blood clotting 
(PT/INR) and type and screen (i.e. blood type) per standard of care. Pre-admission blood work will not 
be performed in a fasting state. No ketone assay is collected at pre-admission, resulting in two tubes of 
blood per standard of care, plus five tubes of research-specific blood work.  
Through hospital discharge, labs collected overlap with standard of care time-points. Inpatient blood 
draws will be performed in a fasting state. There are two additional blood draws required that are for 
research purposes only: two weeks post-TKA (Aim 1) and six weeks post-TKA, which will also be 
performed in a fasting state. All eight tubes of blood collected at two weeks, and all seven tubes of 
blood collected at six weeks post-TKA are for research purposes only.  
Each blood tube collected is between 2.7mL and 7.0mL, depending on the blood test requirements. The 
amount of blood collected at each blood draw is between 28mL and 39mL (high estimate).  As 
reference, when a person donates blood, 500-550mL of blood are donated. Even with seven tubes of 
blood, the amount collected at each draw is approximately 8% of the amount required at a typical blood 
donation.  
Research blood will be kept on ice on the floor/unit for research staff pickup. 
A copy of the laboratory results collected for study-related procedures will be provided to the patient’s 
primary care provider. Transmission of results will occur under standard HIPAA protocols for clinic to 
clinic sharing of information (e.g. fax). The patient’s primary care provider may elect to follow-up on 
results to assure high quality care and care management.  Patients will authorize lab result sharing 
through the study-specific HIPAA Authorization for Research. 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 18  
Table 2. Study blood draws identifying timeline, type of blood test and requirements satisfied.  
 
Laboratory Test 
 
 (- 6 wk to -1 
wk less 1 
day)) 
 
Day of 
Surgery 
 
Inpatient 
 
2 weeks 
post-opβ 
(± 2 
days) 
6 weeks 
post-op 
(± 2 days) 
 
As needed 
for:  
Comprehensive Metabolic Panel 
X* 
X 
X 
X 
X 
FDA 
CBC, no differential 
X* 
X* 
X* 
X 
X 
Research 
Homocysteine 
X 
X 
X 
X 
X 
FDA 
C-Reactive Protein 
X 
X 
X 
X 
X 
FDA 
Standard Lipid Panel 
X 
X 
X 
X 
X 
Research 
KetoneAssay 
 
X 
X 
X 
 
Research 
7 ml K3 EDTA tube  
(extra blood)** 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Research  
5 mL SST tube (extra blood)** 
X 
X 
X 
X 
X 
Research 
*Overlaps with routine standard of care.  
**Collected to achieve primary biochemistry outcome measures.  
β Aim 1 time point only 
 
Physical Therapy (PT).  
Inpatient PT will be standardized for all patients as follows: Post-op day zero (POD#0). Subject will have 
same-day evaluation if the patient is stable and is transferred to the PT floor by 3:30 pm. POD#1: Patient 
will have an individual treatment between 9:00 am and 11:00 am and group therapy session at 1:30 pm. 
POD#2: Patient will have group therapy at 9:30 am and 1:30 pm, and individual treatment. POD#3: 9:30 
am exercise class followed by discharge if medically cleared. Supplement will be ingested within 1 hr 
after morning and afternoon therapy to maximize anabolic effect at each time point (32).  
Ms. Embree, PT, and Dr. Dreyer will facilitate standardization of outpatient PT at all locations; however, 
each patient is individually treated and subjects in EAA may respond/advance through therapy faster, 
potentially requiring fewer treatments, which would be a positive outcome. This will be accounted for 
statistically. All subjects will have 14 outpatient therapy visits as follows: Post-op days #5 and #7 for 
initial evaluation and first treatment. Thereafter PT will routinely see patients 3 times/week for 2 weeks 
and then 2 times/week for 4 weeks.  Physical therapists will be asked to complete a standardized 
assessment form to document the patient’s range of motion, leg circumference and types of exercises 
performed. The standardized PT data collection tool will be completed by the patient’s physical 
therapist at the first outpatient PT appointment and on the last day treated each week, beginning the 
week following discharge and ending at post-operative week #5.  
For Aim #2, the count of PT visits will be captured as well of date of discharge from formal therapy; 
however, community therapists will not be asked to complete a standardized assessment. Range of 
motion at standard of care six week and three month post-op appointment with their surgeon will be 
obtained.  
Aim #1 Study Activities Timeline.  
Patients may be enrolled up to six months prior to surgery, and remain on the protocol until 6 weeks ± 2 
days post-TKA (up to 7.5 months of total enrollment).  Figure 1 (next page) describes the schedule of 
study-related events, including evaluable time windows, under Study Aim #1.  
 
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5-year Clinical Trial: Essential Amino Acid Supplementation & TKA 
PI: Hans C. Dreyer, PhD, PT 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
November 2018 
 
 
Figure 1. Overview of Aim #1 timeline and all study activities, measures and procedures.
inpatient
daily EAA or Placebo
week -6 to -1 week (-1 day)
week -1
TKA
week 6
daily accelerometer 
recordings and 3-day 
food diary complete by 
6 wk visit (-5 wk start); 
function, MRI strength 
& activation
questionnaire blood 
draw
bilateral biopsy (OR), 
daily monitoring of food 
intake daily AM blood, 
food intake while in 
admitted
week 2
daily D20 
begins
3-day food 
diary
daily D20
week 1
Schedule of Events
Time
-6 mo
max
-6 wk to -
1 wk
(-1 day)B
-1 wk
(± 0 day) 
TKA
(Day 0)
1 wk
(± 2 days) 
2 wk
(± 2 days) 
5 wk
(± 2 
days) 
6 wk
(± 2 
days) 
Enrollment and Randomization1
X
Screening1
X
X
Questionnaires1
X
X
Blood Draw2
X
X
X
X
MRI3
X
X
X
Functional Mobiliy4
X
X
X
Strength & Central Activation4
X
X
3-day food log
X
X
in hosp.
X
X
X
AccelerometerA
X
< -accelerometer on at all times->
X
Daily Supplement Ingestion**
all start
—>
—>
—>
all stop
Daily Heavy Water Ingestion
all start
—>
half stop
half stop
*Bilateral Biopsy (muscle & fat)
all subjects
half of 
subjects4
half of 
subjects4
1 Performed at the Slocum Center for Orthopedics and Sports Medicine. 
2 Performed at PeaceHealth Labs at Sacred Heart Medical Center, RiverBend. Pre-operative bloods collected per standard of care. If pre-operative blood is 
collected prior to enrollment, study-specific bloods are drawn before initiating study medication (before – 1wk). Inpatient draws on day of surgery and post-
operative day two.
3 Performed at the the Lewis Center for Neuroimaging, University of Oregon.In case of scheduling, mechanical issues, or patient preference, MRIs may be 
performed at the Slocum Center for Orthopedics & Sports Medicine. Patients must have all study MRI scans on the same machine. 
4 Performed at the the Center for Medical Education and Research, University of Oregon or the Slocum Center. 
A Accelerometer ON daily during waking hours (off while sleeping and showers) including during inpatient hospitalization. Between -6wks to -2 wks wear for 7 
consecutive days;  -1 week before surgery through 2 weeks post-op, wear for 21 consecutive days; 6 weeks post-op, wear for 7 consecutive days. 
B All pre-operative functional assessments, labs, MRI, strength & central activation, baseline accelerometer and food log must be complete before the subject 
begins supplement ingestion. 
* All subjects will have a single biopsy from each leg in the OR during TKA, while half of subjects will have a single biopsy from each leg at 1 week post and the 
other half will have a single biopsy from each leg at 2 weeks post. All subjects will only have two biopsies per leg during the entire study. Muscle weight dry 
versus wet will be compared at 1 or 2 weeks post versus baseline (intraoperative). 
**Inpatient Research Protocol & Integration w ith Standard Patient Care: Protocol w hile subject is inpatient (IP) on orthopedic floor (estimate 2 to 3 days as IP); Daily AM fasting 
blood draw  by phlebotomist on POD 0 and POD 2. (leave blood on ice, research staff to pick up); Subject to don accelerometer at all times; Tw ice daily ingestion of supplement 
(subject and investigators are blinded to treatment group); Ingestion w ill occur 1 hour after daily physical therapy; Inpatient physical therapy to begin at 9 AM and 1 PM. Therapy per 
MD/PT standard Tx; Tw ice daily ingestion of deuterium oxide (D20); Daily food-log recordings (all nutrient intake) by subject. Research staff and nursing to remind subject to 
complete this task.
Informed 
consent, 
enrollment and 
screening
max 6 mo
before TKA
accelerometer on
bilateral biopsy*
3-day food diary, 
half stop D20
bilateral biopsy*
3-day food diary
daily D20 ends for 
half,
blood draw
function, MRI
Screening or re-verify screening if 
previously enrolled, administer 
questionnaires, start 7 day 
accelerometer collection, three-day 
food log., perform MRI
strength & activation, functional 
mobility, blood draw
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 20  
Specific Aim #2 (Physiology).  
Aim #2 - Determine if short-term prevention of atrophy, weakness, and functional mobility leads to 
positive changes in muscle cell structure and function, and quality of life in the long term (6 months 
post-TKA) vs. Placebo.  
Randomization Assignments.  
 
Aim #2, Trial #1 enrolled 19 patients before closing enrollment in June 2018. Please refer to the 
Event Form submitted on June 4, 2018 for additional details. Please refer to study protocol 
December 2017 for information on Aim #2, Trial #1 EAA proportions and protocols.  
 
 
Aim #2, Trial #2 (reflected throughout the protocol as “Aim 2”) will consist of 2 groups 
(N=40/group through protocol completion; EAA vs. Placebo) that are identical in protocol 
design.  Up to 160 patients will be consented to achieve 40 per group completion.   
Summary of Study-Related Activities.  
 
Patient questionnaires before and after surgery 
 
Functional mobility tests before and after surgery 
 
Accelerometer before surgery and after surgery 
 
Optional muscle biopsy before and after surgery 
Changes to Study-Related Activities.  
Omitted Procedures or Measures for Participants Enrolled in Aim #2  
 
No strength & central activation testing 
 
No consumption of heavy water (D20) 
 
No muscle biopsies at surgery, 1 week or 2 weeks post-TKA operation 
 
No blood draws  
 
No MRIs performed  
 
No Three day food diary 
 
Removal of 6 minute walk 
 
Removal of study questionnaires at 2 weeks post-TKA (functional testing remains)  
New or Altered Study Procedures or Measures for Participants Enrolled in Aim #2.  
 
New study assessment time points: 3 months & 6 months 
 
Optional (patient choice at enrollment) muscle biopsies at pre-op, 6weeks & 6 months 
post-TKA 
 
Option for patients with surgery dates less than 4 weeks prior to surgery to be enrolled 
in the functional testing arm only 
 
Option for patients who are taking Coumadin/Warfarin to be enrolled in the non-biopsy 
arm of the study 
 
Biopsies will be closed with suture and/or steri-strips 
 
Addition of the pain and catastrophizing questionnaire (covariate measure) 
 
The procedure schedule can be referenced in Figure 2 (page 23, following a description of all study-
related procedures and measures for Aim #2). 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 21  
Primary Physiological Outcome Measures. Consistent with the Secondary Outcome Measures 
described in Aim #1 (please refer to Aim #1) aside from the omitted and new/altered procedures noted 
above (see Changes to Study-Related Activities in this section), but followed over a longer period time (6 
months).  
Secondary Physiological Outcome Measures. Consistent with the Primary Outcome Measures 
described in Aim #1 (please refer to Aim #1) aside from the omitted and new/altered procedures noted 
above (see Changes to Study-Related Activities in this section). 
Covariate Measures. Consistent with the Covariate Measures described in Aim #1 (please refer to Aim 
#1 above), with the addition of the pain and catastrophizing scale (questionnaire) 
Aim #2 Study Activities Timeline. Participants will be enrolled for up to six months prior to surgery 
through 6 months post-operatively. Figure 2 (next page) describes the schedule of study-related events, 
including evaluable time windows, under Study Aim #2.  
 
EAA or Placebo
week -1
TKA
week 6
3 months
functional mobility,
daily accelerometer 
recordings 
completed prior to 
3 mo. visit (start 
week prior), 
questionnaires
6 months
daily accelerometer 
recordings complete 
by 6 mo visit (start 
week prior); bilateral 
biopsyB, 
functional mobility,
questionnaires
Overview of Aim #2 study timeline, activities, measures and procedures.
Schedule of Events
Time
-6 mo
max
-8 wks to 
-1 wks 
(+ 1 day)
-1
wk
(± 0 day)
TKA
(Day 0)
2
wk
(± 1 week)
6
wk
(± 1 week)
3
mo
(± 2 weeks)
6
mo
(± 2 weeks)
Enrollment
X
X
Screening
X
X
Questionnaires
X
X
X
X
Functional Mobility Test
X
X
X
X
X
Accelerometer 
XA
X
XA
XA
Supplement*
start
Stop
Bilateral Muscle BiopsyB
XB
X
X
Functional testing & biopsy: Performed at the Dreyer Lab, University of Oregon or the Slocum Center.
A Subjects will have the accelerometer ON daily during waking hours (off while sleeping and showers) for a 7 consecutive day period ending at this time point.
BOptional muscle biopsy as per patient choice; Biopsies must be completed a minimum of 4 weeks prior to TKA; patients who are enrolled between 
-4 weeks and -1 week (+ 1 day) will not be eligible to participate in the biopsy arm. 
*Twice daily ingestion of supplement (subject and investigators are blinded to treatment group); Ingestion will occur within1 hour after daily physical therapy.
supplement start 
-6 mo max
informed 
consent, 
enrollment 
and 
screening
-8 weeks to -1 week (+ 1 day) 
functional 
testing, 
questionnaires, 
stop ingestion of 
supplement. 
Bilateral muscle 
biopsyB; daily 
accelerometer 
Screening or re-verify 
screening if previously 
enrolled, administer 
questionnaires, start 7 day 
accelerometer collection, 
perform, functional 
mobility, biopsyB. 
Week 2
Functional 
testing only
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 22  
Participant Withdrawal.  
Participants will be withdrawn from the study by the PI or physician Co-Investigators if required to 
protect the subject’s well-being. Adverse events will be closely monitored and assessed for possible 
relationships to study treatment. Please refer to the Adverse Event form, located in Appendix 2. Clear 
study-stop criteria have been established:  
Study Stopping Criteria 
 
Criterion #1: Patient experiences a serious reportable adverse event (SRAE).  
1. Death; immediate individual stop.  
2. Life-Threatening; immediate individual level stop.  
3. Hospitalization (initial or prolonged) 
a. Where prolonged is defined as discharge on Post-Operative Day 4 (POD #4) or longer; 
use Criteria #2 to further assess for study stop.  
b. Where immediate subject withdrawal from study will occur at Post-Operative Day 6 
(POD #6) 
4. Disability or permanent damage; immediate individual stop.  
5. Required intervention to prevent permanent impairment; Use Criteria #2 to further assess.  
 
Criterion #2: The intensity of an adverse event warrants discontinuation at the individual level.  
 
For all adverse events (not limited to SRAEs), grading of severity is derived from the daily life 
consequences and need for additional treatments/interventions.  
 
Intensity of adverse events are defined as follows:  
 
Mild – Does not interfere with daily activity 
 
Moderate – Interferes with daily activity, no treatment required 
 
Severe – Prevents daily activity or requires treatment (see decision support below) 
 
Life Threatening – Supports stopping decision 
 
Please refer to Figure 3 (next page).  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 23  
Figure 3. Algorithm for individual-level study discontinuation, essential amino acid versus placebo in 
TKA.  
 
Criterion #3 – Risk/benefit criteria for individual-level study stop.   
Subjects with adverse events will be assessed for risk/benefit stopping criteria.  
 
Subject experiences clinically relevant deterioration in health (additional adverse events, vital 
signs, laboratory parameters) following the initial adverse event 
 
Subject demonstrates clinically relevant change in liver or renal parameters, as confirmed by a 
minimum of one additional repeat comprehensive metabolic panel, occurring no less than 12 
and no greater than 24 hours following initial report.  
 
Subject demonstrates clinically relevant change in vital signs if technical failure or human error 
can be excluded, supported by at least two clinically relevant measures. 
 
Criterion #4 – Cohort-level study stop.   
All serious adverse events will be reported to the DSMB and IRBs within 24 hours of any member of the 
study team becoming aware of the adverse event.  
 
The following will be assessed in consideration of complete trial discontinuation:  
1. The types of adverse events 
2. Individual-level adverse event frequency and intensity 
3. Ability to effectively monitor observed adverse events in current and future patients 
4. Reversibility of adverse events and possible outcomes 
5. The number of subjects who experience (a) the same adverse event and (b) any adverse events 
6. Medication assignment among subjects who experience (a) the same adverse event and (b) any 
adverse events 
 
Stopping Rules Adapted from: Sibille M, Patat A, Caplian H & Donazzolo Y. A safety grading scale to support dose escalation and 
define stopping rules for healthy subjects first entry into man studies. British J Clin Pharm 2010; 70(5): 736-748. 
 
 
 
Algorithm for individual-level study discontinuation. 
If grade is < Severe
Event occurrence 
If grade is ≥ Severe
Physician co-Investigator defines as:    
•
“Probably” related” or    
•
“Definitely related
DSMB un-blinds and 
reviews event
Continue per protocol
Study participant discontinues 
study medication and related 
procedures
Placebo
EAA
Continue with 
recruitment
Physician co-Investigator 
defines as: “Possibly 
related” or “Not related"
Investigator and study team 
evaluate patient safety and 
risks/benefit (Criteria #3) 
resulting in decision to continue 
or discontinue
Recruitment slows to two per month until data review is complete
Review patient safety and 
risk/benefit (Criteria #3)
DSMB 
Reviews data
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 24  
Data Collection.  
Patient data for all study-related activities will be maintained on paper source documents stored in the 
Slocum Foundation office at the Slocum Center for Orthopedics & Sports Medicine. Each patient will 
have a dedicated patient binder for tracking all study-related activities. Data will be abstracted from the 
paper source documents and/or electronic health records (Slocum Center and PeaceHealth) and entered 
onto an electronic spread sheet (e-Case Report Form, CRF). Data abstracted onto the eCRF will include a 
patient identifier (no names) and all data points captured during the patient’s enrollment.  
The following source documents will be updated and reviewed with the patient at each study time 
point:  
 
Health history, new health events (updated by study coordinators) 
 
Medication log (updated by study coordinators) 
 
Study medication log (completed by patient) 
 
D20 intake log (completed by patient, Aim #1 only) 
The study logs can be reviewed in Appendix 2. 
 
Sources of Materials.  
Patient history, body composition, strength and functional data, blood samples, and muscle & fat tissue 
samples will be obtained specifically for research purposes.  Coded data will be stored on computers 
that are password protected and in locked offices. Data on paper will be stored in files in a locked file 
cabinet (printouts) and computers in a key-code-access-only lab in a badge-access building. All data and 
material collected will be coded. Codes linked to subjects’ names will be stored in the PI’s office (key 
lock) on a MacPro with password protection and backed up to a protected and locked time capsule 2T 
external storage device. All MR images will be transferred as DICOM files to Dr. Dreyer’s laboratory via 
encrypted electronic data transfer protocol currently established by the collective efforts of our IT 
department at the University of Oregon.  
All research personnel will have access to the coded data, and coded blood and coded tissue specimens. 
Only the PI, physicians, and study coordinators will have access to the identifiable private information. 
Only the study coordinator will have access to patient coding. 
Please see Data Elements Table (Appendix 1) for a list of all elements needed to complete the aims of 
this trial. 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 25  
Data Analysis.  
Keith Smolkowski, PhD, will be responsible for the statistical analysis of this project. He will be 
responsible for the statistical modeling and, along with Lisa Strycker, MA, will analyze all data points in 
our study (Oregon Research Institute). 
 
Aim #1: Aim 1 will compare differences between the two groups (EAA vs. Placebo) across 
experimental conditions in the change in post-TKA metabolism (synthesis & breakdown) from 
baseline to 1 and 2 wk post-TKA. 
 
 
Aim #2 (trials 1 & 2): Aim 2 will also compare measures of functional mobility with muscle cell 
structure (CSA) and mitochondrial function (respiration), including accelerometer and quality of 
life measures. 
 
Analysis of covariance. ANCOVA will be used to answer research questions for aim 1 & 2. ANCOVA 
maximizes statistical power by incorporating the pretest measure as a regression-based control, 
reducing individual variance. Power improves as the pre-post correlations increases. Our preliminary 
data indicate that pre-post correlations for many key endpoints are highly correlated (e.g., muscle 
volume r = .96 for operative leg and r = .97 for non-operative leg; strength r = .42 to .89; stair-climb 
down time r = .78).  
 
Power analyses. For our power calculations, we have assumed a Type I error rate (α) of .05, two-tailed. 
We based power calculations on effect sizes (d) that we derived from analysis of preliminary data 
preliminary data and prior studies (10, 30, 32, 33, 36, 41, 51, 113). We calculated d as the standardized 
mean difference between treatment conditions at follow-up: d = (xC – xT)/S, where x re presents the 
primary outcome mean in the Placebo and EAA conditions and S is the pooled standard deviation, after 
adjusting x for pretest scores and covariates (sex, tourniquet time, age, body mass index, 
fat/carbohydrate/protein intake).  
 
We propose to enroll 40 total subjects for Aim 1 who are retained through protocol completion 
(20/group, EAA and Placebo, randomized to either 1 week or 2 week post-operative biopsies), and 80 
total subjects (40/group, EAA and Placebo) for Aim 2 who are retained through protocol completion to 
account for possible attrition and to ensure sufficient power to test the hypotheses that EAA therapy up-
regulates basal levels of muscle protein synthesis, and reduces post-operative atrophy bilaterally, 
preserves quadriceps strength, and improves functional mobility relative to a Placebo condition. 
 
Effect sizes. Effect sizes were as follows: (a) Cell and FSR data: REDD1 d = 1.24, SLC36A2 d = 1.27, and 
FSR d = 1.51 (FSR calculated from mean change from baseline). The mean effect across outcomes was d 
= 1.37, reflecting large effects. (b) Physiological and functional data (percent change from Baseline to 6 
wk): operative quadriceps volume d = 1.52, and isometric strength d = .90; non-operative quadriceps 
volume d = 1.05, and isometric strength d = .66; timed up-and-go test d = 1.03, timed stair ascent d = 
1.08, timed stair descent d= 1.13, and six-minute walk test d= .70. Mean effect size was d = 1.01, 
reflecting large effects.  
 
Power calculations.  Power calculations were based on the sample size and minimally detectable ES 
(MDES) as follows:  
 
 
Aim #1: For a sample size of 20 completed subjects/group (10/group for metabolic studies, 
however, EAA vs. Placebo = 20 total EAA and 20 total Placebo).Aim1, proposed study can detect 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 26  
ESs of d > 1.10 with 85% power, assuming no pretest covariate, and the minimally detectable ES 
drops to 0.95 or 0.72 with pretest covariates of r = .50 or .75, respectively. The preliminary 
results show ESs averaged 1.37 for Cell and FSR outcomes, and all exceeded .95. The proposed 
study would thus have the power to detect anticipated condition effects for Cell and FSR 
outcomes in Aim 1 with 10 subjects per condition. We can also detect moderation effects for sex 
if the associated interaction accounts for at least 21% to 31% of the variance, assuming 
covariate of r = .75 or .50, respectively. 
 
 
Aim #2: For a sample size of 40 completed subjects/group (EAA and Placebo), the proposed 
study can detect ESs of d > .79 with 85% power, and the minimally detectable ES drops to .68 or 
.52 with pretest covariates of r = .50 or .75, respectively. Preliminary results show an average ES 
of d = 1.01 across all Aim 2 outcomes, so this study will have power to detect anticipated 
physiological and functional effects with 40 subjects per condition. We can detect condition-by-
sex moderation effects if the associated interaction accounts for at least 12% to 19% of the 
variance, assuming covariate of r = .75 or .50, respectively. The tests of sex-by-condition 
interactions in both aims are likely underpowered for some important effects, so we will also 
consider the size of the effect, even if not statistically significant, as an indicator of potentially 
important sex-related differences.   
 
Random coefficients analysis. Keith Smolkowski, PhD, will run random coefficients analysis (RCA) to 
model muscle, strength, and functional mobility across time as well as data points generated from 
accelerometer and functional analysis. RCA models trajectories from assessments nested within subjects 
(48); tests of condition are represented by the interaction between a time factor and treatment 
condition. The RCA avoids the many pitfalls associated with traditional repeated measures ANOVA (52, 
91, 101). RCA adjusts for within-individual dependence or autocorrelation in the data (48, 91, 108), and 
with four measurements, the RCA can model nonlinear growth. It does not require fixed spacing among 
assessments, accommodates missing values over time, and allows piecewise models (i.e., splines) (48). 
RCA provides a more powerful analysis than ANCOVA. Power estimates of growth models, however, 
require several assumptions that are not easily established. Thus we rely on the fact that the power for 
RCA has been shown to surpass that of ANCOVA (53, 86) especially when applied to four or more 
assessments (118). The RCA, then, will detect smaller differences between conditions than the mixed-
model ANCOVA. Finally, optimal Type I error rates do not depend heavily on normally distributed data 
(48, 52, 74, 85). These methods are also appropriate for relatively small samples, such as those planned 
for the present study (74).   
 
Missing data. Most longitudinal trials result in missing data. The proposed methods will reduce bias due 
to missing data (6, 73). Maximum likelihood methods that model time as random, such as RCA, use any 
available data across time, reducing bias and increasing power (43, 91). Our preliminary data show that 
we have been successful in collecting >92% of all data points. However, to minimize missing data, the 
study coordinator and staff will devote significant time and effort to data collection and retention of 
study subjects. 
 
Potential Limitations.  
We do not expect problems with the proposed experimental design or data collection. Our research 
team has performed every test and used each method included in this proposal. We have identified and 
addressed issues that may present potential problems and proposed solutions in the Potential Problems 
and Solutions section of Aim 1. We are well aware of the potential issues related to enrollment goals 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 27  
and attrition when conducting a clinical trial. Our subjects are older adults who are undergoing a major 
operation. However, our preliminary studies are evidence that we are very experienced with this patient 
population. The average number of TKA patients who complete our studies is 3-5/mo. We are therefore 
very confident that we will be able to complete studies on 40 TKA patients (Aim 1) and 80 TKA patients 
(Aim 2); 120 over the entire 5 year study. Issues that present potentially unique problems to our longer-
term study are addressed below.   
 
Statins. A potential limitation with long-term muscle cell function of our clinical study is concurrent use 
of statins, which have a strong potential to compromise muscle mitochondrial function (7, 68, 109, 117). 
Over 50% of our TKA subjects use statins. Mitochondrial dysfunction may introduce sample bias as well 
as negatively impact short and longer-term function. To account for this, we propose to measure 
mitochondrial respiration using the Oroboros O2k respirometer, and normalize results statistically and 
use the n0n-operative leg as internal control. Thus, measuring mitochondrial respiration will allow us to 
determine the effects of muscle preservation and accelerated recovery of functional mobility (EAA) 
while accounting for statin use between groups as well as between sex and over time statistically. 
 
Research Population & Recruitment Methods 
Study populations for Aim #1 and Aim #2 are identical. In addition, the recruitment process does not 
differ between the short-term, biochemistry study (Aim #1) and the longer term, physiologic study (Aim 
#2).  
 
Target Population.  
Both aims will target older adults, ages 50 – 80 years (Aim 1) and 40 – 80 years (Aim 2) for have elected 
to undergo primary total knee arthroplasty performed at PeaceHealth Sacred Heart Medical Center at 
RiverBend or Slocum Ambulatory Surgery Center by Dr. Jewett, Lantz, Mohler or Shah. Between 2005-
2010, they performed a total 2,066 TKAs. Of those, 1,406 of the patients were between 50-80 years of 
age (68%). A total of 120 subjects will be enrolled in the two study aims.  
 
 
Aim #1.  The biochemistry study aim will obtain complete data on 40 subjects, 
randomized to either EAA supplementation or placebo, and further randomized to 
receive 1 week or 2 week post-surgical biopsies. Randomization is stratified by gender. 
Up to 70 subjects will be enrolled to account for withdrawal and attrition. 
 
Aim #2. The physiology study will obtain complete data on 80 additional subjects, 
randomized to either EAA supplementation or placebo. Up to 160 subjects will be 
enrolled to account for withdrawal and attrition.  
 
The target population will not include pregnant women as the study population are patients who have 
scheduled a total knee arthroplasty. Patients will not be scheduled for surgery if they are pregnant as 
per standard of care.  The point in which study coordinators approach patient for recruitment, they have 
already been scheduled for TKA. Furthermore, women of potential childbearing age will be asked if they 
are or could possibly be pregnant. A hormone pregnancy test will be administered to those women who 
cannot verify pregnancy status prior to ingestion of amino acid supplement. Women who are surgically 
sterile (e.g., hysterectomy); or who are otherwise incapable of pregnancy (e.g. menopause) will not have 
to undergo pregnancy testing.  
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 28  
Inclusion & Exclusion Criteria.  
 
Study Aim #1 
 
Inclusion Criteria.  
 
Patient is 50 – 80 years old 
 
Patient is having a primary, unilateral TKA 
 
Patient has signed the current, IRB approved informed consent document  
 
Exclusion Criteria.  
 
Patient has previous TKA and/or total hip arthroplasty surgery on ipsilateral lower extremity. 
 
Patient has previous TKA on contralateral leg 
 
In the judgment of the physicians the patient is not anticipated to have contralateral TKA before 
end of treatment is completed (6 weeks Aim #1) 
 
Patient has dementia or related mental issues that may potentially put the subject at risk as 
determined by the surgeon. 
 
Patient has untreated endocrine disease (hypo/hyper thyroidism, Addison’s Disease or Cushing’s 
syndrome, etc.) 
 
Patient has uncontrolled diabetes; defined by lab result of hemoglobin A1c level > 8.0 mg/dL at 
the pre-anesthesia testing visit, which must occur before the patient begins the study 
medication or heavy water ingestion. 
 
Patient has significant heart, liver, kidney or respiratory disease.  
 
Patient has peripheral vascular disease.  
 
Patient has active cancer.  
 
Patient has taken anabolic steroids in the prior six months.  
 
Patient has known current alcohol or drug abuse.  
 
Patient has conditions that prohibit Magnetic Resonance Imaging (MRI).  
 
Patient discharge status is known to be to care facility. 
 
Patient is on oral blood thinner such as Warfarin, Coumadin, Eliquis, etc. 
 
Study Aim #2 
 
Inclusion Criteria – Biopsy Participant.  
 
Patient is 40 – 80 years old 
 
Patient is having a primary, unilateral TKA 
 
Patient has signed the current, IRB approved informed consent document 
 
Patient can schedule pre-operative biopsy at least 4 weeks prior to date of TKA   
 
Exclusion Criteria – Biopsy Participant.  
 
In the judgment of the physicians the patient is not anticipated to have other lower extremity 
total joint arthroplasty before end of treatment is completed (6 months). 
 
Patient has had previous lower extremity total joint arthroplasty surgery within 6 months of 
starting -8 week to -1 week (+1 day) study activities. 
 
Patient has dementia or related mental issues that may potentially put the subject at risk as 
determined by the surgeon. 
 
Patient has untreated endocrine disease (hypo/hyper thyroidism, Addison’s Disease or Cushing’s 
syndrome, etc.) 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 29  
 
Patient has uncontrolled diabetes; defined by lab result of hemoglobin A1c level > 8.0 mg/dL. at 
If the patient has consented to biopsies, confirmation of the first step (below) must occur before 
patient can have pre-operative biopsy. Two-step verification process for this will occur; (1) 
patient self-report, with the addition of any available medical records Slocum Orthopedics has 
regarding patient diabetic status, and (2) Upon completion of standard of care pre-operative 
blood draw, we will confirm results of HbA1c. If the patient has not consented to have biopsies, 
the same verification process will occur before the patient begins taking the supplement.   
 
Patient has significant heart, liver, kidney or respiratory disease.  
 
Patient has peripheral vascular disease.  
 
Patient has active cancer.  
 
Patient has taken anabolic steroids in the prior six months.  
 
Patient has known current alcohol or drug abuse.  
 
Patient discharge status is known to be to care facility. 
 
Patient is on oral blood thinner such as Warfarin, Coumadin, Eliquis, etc. 
 
Inclusion Criteria – Non-Biopsy Participant  
 
Patient is 40 – 80 years old 
 
Patient is having a primary, unilateral TKA 
 
Patient has signed the current, IRB approved informed consent document 
 
Exclusion Criteria – Non-Biopsy Participant  
 
In the judgment of the physicians the patient is not anticipated to have other lower extremity 
total joint arthroplasty before end of treatment is completed (6 months). 
 
Patient has had previous lower extremity total joint arthroplasty surgery within 6 months of 
starting -8 to -1 week (+ 1 day) study activities. 
 
Patient has dementia or related mental issues that may potentially put the subject at risk as 
determined by the surgeon. 
 
Patient has untreated endocrine disease (hypo/hyper thyroidism, Addison’s Disease or Cushing’s 
syndrome, etc.) 
 
Patient has uncontrolled diabetes; defined by lab result of hemoglobin A1c level > 8.0 mg/dL. at 
If the patient has consented to biopsies, confirmation of the first step (below) must occur before 
patient can have pre-operative biopsy. Two-step verification process for this will occur; (1) 
patient self-report, with the addition of any available medical records Slocum Orthopedics has 
regarding patient diabetic status, and (2) Upon completion of standard of care pre-operative 
blood draw, we will confirm results of HbA1c. If the patient has not consented to have biopsies, 
the same verification process will occur before the patient begins taking the supplement.   
 
Patient has significant heart, liver, kidney or respiratory disease.  
 
Patient has peripheral vascular disease.  
 
Patient has active cancer.  
 
Patient has taken anabolic steroids in the prior six months.  
 
Patient has known current alcohol or drug abuse.  
 
Patient discharge status is known to be to care facility. 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 30  
Research Sites.  
The study will be conducted at multiple research sites. Patients will be asked to travel to various clinical 
and research-specific locations to complete study-related activities.  
 
 
Table 3: Participant Research Sites, Essential Amino Supplementation vs. Placebo in TKA.  
Research Site 
Location 
Study-Related Activities 
Slocum Center for Orthopedics 
& Sports Medicine  
 
Slocum Research & Education 
Foundation 
 
Slocum Ambulatory Surgery 
Center 
55 Coburg Road 
Eugene, OR  
Routine standard of care for TKA 
patients; participant identification, 
screening, enrollment, consenting, 
& follow-up; completion of 
patient-reported outcome 
measures; main study-
coordination site;; functional 
mobility tests, strength tests 
(including central activation) (Aim 
#1 and #2); alternative MRI site in 
the event LCNI is unavailable or 
Slocum is preferred by the patient 
(Aim #1 only); pre/post-operative 
bilateral biopsies; outpatient 
surgery center (Aim #2 only). 
Dreyer Laboratory, University 
of Oregon  
 
Pacific Hall 
Analysis of blood specimens (Aim 
#1 only); function and strength 
testing; strength & central 
activation deficit; pre/post-
operative bilateral biopsies (Aim 
#1 and #2). 
Lewis Center for Neuroimaging, 
University of Oregon  
Lewis Integrative Sciences 
Building 
1440 Franklin Boulevard, 
Eugene, OR 97403 
MRI (Aim #1 only) 
PeaceHealth Laboratories 
Various (patient choice 
possible, RiverBend for pre-
admit labs as standard of 
care) 
Blood draws (Aim #1 only). 
PeaceHealth Sacred Heart 
Medical Center at RiverBend 
3333 RiverBend Drive 
Springfield, OR 97477 
 
Routine standard of care for TKA 
patients plus study-specific 
procedures: blood draws, food 
diary population, supplement 
ingestion, standardized physical 
therapy procedures (Aim #1 and 
#2).  
NW Compounders 
2734 SW Orchard Hill Lane 
Lake Oswego, OR 97035 
Aim 1 only -EAA supplement is 
being compounded at this 
pharmacy and shipped to the 
Dryer Lab. The pharmacy is 
required per standard of care by 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 31  
the Board of Pharmacy to have on 
file known allergies of the patient. 
This will be provided from the 
patients’ medical history on file 
with Slocum Center for 
Orthopedics & Sports Medicine 
(Aim #1). 
 
Participant Recruitment.  
Patients eligible for enrollment with pre-operative biopsies will be recruited a least four to eight weeks, 
and no more than six months prior to surgery from the clinics of Dr. Jewett, Lantz, Mohler or Shah, all 
fellowship trained, board certified orthopedic adult knee reconstruction surgeons. Patients eligible for 
functional testing only (non-biopsy) may be enrolled with enough time to complete functional testing 
baseline assessments prior to start of supplement (complete functional testing by -1 week + 1 day).  
 
Primary Recruitment Approaches. In-person consenting will assure all subjects receive a consistent 
informed consent process and have all questions answered prior to enrollment.  
 
1. Physician Co-Investigators will identify potential subjects for enrollment during a routine clinic 
appointment that results in a decision by the subject to proceed with total knee arthroplasty. The 
initial informed consent, screening and enrollment may occur up to six months prior to surgery.  
The physician will request via the Medical Assistants or Surgery Schedulers (“physician 
extensions”) the study coordinator be contacted to provide study information and complete the 
informed consent process. Physician extensions will not be engaged in any research-related 
activities, but will identify subjects as potentially eligible or not based on past medical history, 
which is disclosed to the physician extension per standard of care. Only the research coordinators 
or physician Co-Investigators perform informed consenting or formally screen candidates for 
inclusion/exclusion criteria. (Please see Informed Consent Process below for information about 
the activities involved in subject consenting). 
 
2. Pre-screen/identify potential subjects for recruitment based on inclusion/exclusion criteria from 
existing surgical appointment list. Potential subjects would be contacted by phone and asked to 
make an appointment with the study coordinator to have a thorough discussion of study-related 
procedures and to obtain written informed consent. Additionally, potential subjects could be 
mailed a recruitment letter with ability to contact research coordinators to identify themselves as 
interested in participating. Strong preference will be given to an in-person consenting process; 
however, should the patient live out of town, a phone consenting process with mailed in 
executed consent form is allowable. Should a participant elect to mail in the informed consent 
document, the research coordinator will re-verify all questions have been answered and the 
patient understands all study-related procedures at the pre-operative study appointment (1 to 6 
weeks prior to surgery). No study related procedures will be initiated prior to confirming patient 
eligibility, understanding and willingness to participate. Patients will have to have an in-person 
discussion (see Informed Consent Process below) before enrolling into the study.  
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 32  
Secondary Recruitment Approaches.  
1. Medical Assistants of participating physician co-Investigators will have access to a study 
information flier (Appendix 4) which may be distributed to interested subjects, or subjects that 
in the judgment of the physician Co-Investigator, are potential candidates for enrollment.  
 
2. Information about the study will be included in Slocum Foundation or Slocum clinic newsletters, 
which will be available in clinic waiting areas. The following text will be used on printed 
materials accessible to patients for Aim #1: 
 
Interested in helping Slocum and University of Oregon researchers discover better ways to 
recover after knee surgery? Consider participating in our Amino Acid Supplementation & Total 
Knee Replacement Research Study funded by the National Institute on Aging, which is one of 
the National Institutes of Health.  
 
The goal of the research is to determine if providing amino acid supplementation (building blocks 
for protein) can stimulate recovery and reduce muscle loss after surgery. Our preliminary studies 
suggest taking essential amino acid supplements prior to surgery and for two weeks after 
surgery helps prevent muscle atrophy. 
 
To find out more information, please see our website at www.slocumfoundation.org, or ask your 
physician.  At this time, Dr. Jewett, Dr. Lantz, Dr. Mohler, and Dr. Shah are the surgeons 
participating in the Essential Amino Acids study. You can also come to a study information 
session at Slocum on the 2nd Wednesday of each month at 12:00p. Please RSVP by calling 
541-868-3232 if you plan to attend an information session. A light lunch will be provided.  
 
3. Information about the study will be included on the Slocum Foundation website. The following 
text will be used on the website: 
 
Interested in helping Slocum, Oregon Research Institute and University of Oregon researchers 
discover better ways to recover after knee surgery? Consider participating in our Amino Acid 
Supplementation & Total Knee Replacement Research Study funded by the National Institute 
on Aging, which is one of the National Institutes of Health.  
 
The goal of the research is to determine if providing amino acid supplementation (building blocks 
for protein) can stimulate recovery and reduce muscle loss after surgery.  
 
Who Can Participate?  
Patients having total knee replacement surgery performed by Dr. Jewett, Dr. Lantz, Dr. Mohler, 
or Dr. Shah may be able to participate. Your physician and the study coordinator from the 
Slocum Foundation will determine whether or not you qualify for the study.  
 
 
What’s Involved?  
Each participate will be randomly assigned to either receive the essential amino acid supplement 
or a placebo, which is a small drink without any essential amino acid supplement. Like a coin flip, 
you have about a 50-50 chance of receiving the real essential amino acid supplement. You would 
need to take the supplement two times per day, after breakfast and lunch, one week before 
surgery and six weeks after surgery.  
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 33  
 
MRI so we can measure how much muscle you have in your legs before surgery.  
In addition to taking the supplement, we need to test how strong you are before surgery and 
how well you can do certain activities. For example, we would ask you to walk as far as you are 
able for six minutes. You would also be asked to wear a pedometer that measures you level of 
activity each day and record your food intake in a daily food diary.  
 
While you are in the hospital and under anesthesia, your surgeon will be taking a biopsy of your 
muscles. After your surgery, staff from RiverBend hospital will collect blood samples each 
morning before you have breakfast.  
 
You will be asked to have biopsies during and after surgery and repeat many of the study 
procedures you had before surgery (example: MRI, tests that measure your ability to 
move around). 
 
A study coordinator from the Slocum Foundation will make sure you understand all the steps and 
procedures, as well as the risks and potential benefits, involved in the study before you agree to 
participate.  
 
Has anyone participated in a study like this before?  
Yes, Drs. Jewett, Lantz and Shah participated in the pilot data project. The pilot data was 
published in the Fall of 2013. You can read the study results in the Journal of Clinical 
Investigation: http://www.jci.org/articles/view/70160.  
 
What can you tell me about the potential benefits of the study?  
Our preliminary studies suggest taking essential amino acid supplements prior to surgery and for 
two weeks after surgery prevents muscle atrophy. Preventing muscle atrophy is important 
because improving muscle strength and functional after knee replacement may decrease 
recovery time; however, this is part of what we are investigating. There is a chance you would 
receive the placebo (no real supplement), in which case you may not benefit from study 
participation directly, but you would play an important part in helping us determine whether or 
not EAA supplementation is beneficial.  
 
Who can I contact to find out more information? You may contact your physician or the Slocum 
Foundation at 541.868.3232 or email info@slocumfoundation.org.  
 
4. Monthly information sessions. One time per month the Slocum Foundation will host an 
information session for potential subjects.    
 
5. Information flier posted in patient exam rooms (Appendix 4).   
 
 
For Aim #2, the following material will be available on the Foundation website:  
 
Interested in helping Slocum, Oregon Research Institute and University of Oregon researchers 
discover better ways to recover after knee surgery? Consider participating in our Amino Acid 
Supplementation & Total Knee Replacement Research Study funded by the National Institute on 
Aging, which is one of the National Institutes of Health.  
 
Research Compliance 
Services 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 34  
 
The goal of the research is to determine if providing amino acid supplementation (building blocks 
for protein) can stimulate recovery and reduce muscle loss after surgery.  
 
Who Can Participate?  
Patients having total knee replacement surgery performed by Dr. Jewett, Dr. Lantz, Dr. Mohler, 
or Dr. Shah may be able to participate. Your physician and the study coordinator from the 
Slocum Foundation will determine whether or not you qualify for the study.  
 
 
What’s Involved?  
Each participate will be randomly assigned to either receive the essential amino acid supplement 
or a placebo, which is a small drink without any essential amino acid supplement. Like a coin flip, 
you have about a 50-50 chance of receiving the real essential amino acid supplement. You would 
need to take the supplement two times per day, after breakfast and lunch, one week before 
surgery and six weeks after surgery.  
 
In addition to taking the supplement, we need to test your functional mobility before surgery and 
after to see how well you can do certain activities. For example, we would ask you to walk as far 
as you are able for six minutes. You would also be asked to wear a pedometer that measures you 
level of activity before and after your surgery.  
 
 
You will be asked to have one muscle biopsy on both legs before your surgery (four to eight 
weeks), and again six weeks and 6 months after surgery. You may choose to participate in the 
study without having the biopsies. In addition, if your surgery date is less than 4 weeks away, 
you may be eligible to participate in the study and complete functional testing and non-biopsy 
activities only.  
 
A study coordinator from the Slocum Foundation will make sure you understand all the steps and 
procedures, as well as the risks and potential benefits, involved in the study before you agree to 
participate.  
 
Has anyone participated in a study like this before?  
Yes, Drs. Jewett, Lantz and Shah participated in the pilot data project. The pilot data was 
published in the Fall of 2013. You can read the study results in the Journal of Clinical 
Investigation: http://www.jci.org/articles/view/70160. In addition, the first part of this new 
study was completed in 2016. In the new study, 40 patients took the supplement and 
participated in similar study activities for six weeks after surgery.  
 
What can you tell me about the potential benefits of the study?  
Our preliminary studies suggest taking essential amino acid supplements prior to surgery and for 
two weeks after surgery prevents muscle atrophy. Preventing muscle atrophy is important 
because improving muscle strength and functional after knee replacement may decrease 
recovery time; however, this is part of what we are investigating. There is a chance you would 
receive the placebo (no real supplement), in which case you may not benefit from study 
participation directly, but you would play an important part in helping us determine whether or 
not EAA supplementation is beneficial.  
 
 
Research Compliance 
Services 
 
RECEIVED 
January 04, 2019
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01/26/2019-11/06/2019


5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 35  
Who can I contact to find out more information? You may contact your physician or the Slocum 
Foundation at 541.868.3232 or email info@slocumfoundation.org.  
 
 
Informed Consent Process.  
Research participants will be presented with a thorough description of all study-related procedures in-
person. Participants will be required to read, review, and discuss the study with study coordinators prior 
to executing the informed consent document. Study coordinator review of the ICF will include reviewing 
all of the bullets on the last page of the consent form with the patients and ensuring participants 
understand the document fully before authorizing consent.  
 
Participants will have an opportunity to ask their surgeon or the study coordinators any questions prior 
to obtaining informed consent. No study-related procedures will be initiated prior to obtaining written 
consent. To accommodate out of town patients, this protocol allows for consenting conversations to 
happen by phone, and patients who agree to participate may mail in their executed ICF. However, 
patients who elect this option will be required to review study procedures and verbally re-consent on 
the day of their screening, before any study related procedures are initiated.  
 
Surgeons will have responsibility for approving participants for study entry, specifically for ensuring 
study inclusion and exclusion criteria have been met. If a study subject has questions related to study 
procedures at the Dreyer Lab, Lewis Neuroimaging Center, the study coordinator will answer participant 
questions. In the event the study coordinator does not know the response or for which more expertise is 
necessary to be fully addressed, the study PI will be contacted, and all questions answered in advance 
obtaining participant consent.  
 
In addition to the Informed Consent Form, participants will also be asked to sign a HIPAA Authorization 
form which allows information to be transferred from HIPAA-compliant entities (e.g. hospital and clinic) 
to the research team.  
 
Enrollment & Randomization.  
The study coordinators will communicate participant enrollment to the study PI through a secure, 
encrypted electronic study management interface hosted by the Slocum Foundation, under the 
information technology physical and technological safeguards of the Slocum Center for Orthopedics & 
Sports Medicine. The PI will retain a list of Patient Identification Numbers (PID), which will randomly 
assign subjects to EAA or placebo, ensuring blinding of participants, research staff and study 
statisticians. The PI will disseminate supplement to the research coordinators to ensure blinding.  
 
Following enrollment, before supplement ingestion begins, patients will be provided with a Study 
Patient Binder. The Study Patient Binder will provide patients with instructions regarding supplement 
and/or heavy water administration, accelerometer use, and food diary entries. The Study Patient Binder 
will also provide patients with directions to testing locations (e.g. labs, MRIs).  
 
Participant Compensation.  
Participants are asked to spend extra time and travel to various research sites to complete study-related 
activities. Participants who complete the study will receive:  
 
 
Aim #1: $300.00 payable upon completion of week 6 study activities (study completion), but 
prorated at the following schedule:  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 36  
o $50 for completion of one or more -6wk study events  
o $50 for completion of one or more -1wk study events 
o $50 for completion of one or more day of surgery study events 
o $50 for completion of one or more 1 week post-op study events 
o $50 for completion of one or more 2 week post-op study events 
o $50 for completion of one or more 6 week post-op study events 
 
 
 
Aim #2: Maximum of $300.00 payable upon completion of six-month post-TKA study activities 
(study completion), but prorated at the following schedule:  
Compensation plan with biopsies: 
o $100.00 for completion of preoperative biopsy 
o $100.00 for completion of six week postop biopsy 
o $100.00 for completion of six month postop biopsy (study completion) 
o No compensation for two week and three month study activities 
 
 
Compensation plan without biopsies: 
o $20.00 for completion of preoperative testing 
o $20.00 for completion of two week postop testing 
o $20.00 for completion of six week postop testing 
o $20.00 for completion of three month postop testing 
o $20.00 for completion of six month postop testing (study completion) 
 
Should a participant not reach one of the defined compensation endpoints above, the amount of 
remuneration will revert back to the last completed interval (no pro-rating between study intervals). For 
example, a participant in Aim #1 who completes one or more study activities on day of surgery would 
receive $150.00. For Aim #2, if a patient completes six week postop biopsy would receive $200.00 
Provisions for Participant and Data Confidentiality.  
Study Team Training.  
All key personnel have completed and passed the certification exam of the NIH-mandated course on 
protection of human subjects. The screening tests will allow us to exclude a priori subjects with 
potentially higher risk of developing complications. All methods and treatments within this proposal are 
IRB approved and have been tested for feasibility, patient tolerance, and adverse reactions. Identifiable 
issues have previously been eliminated. Protections against risks for all subjects in the proposed study 
will be as follows: 
 
Technological and Physical Safeguards.  
To minimize this risk, only the investigators, study personnel, research sites, and the Medical Records 
department of the Sacred Heart Medical Center at River Bend and Slocum Center will have access to all 
data containing personal information.  As a participating research site, Northwest Compounders will 
have access to patient names and allergies, which are required to dispense the study medication by law 
(Aim 1). As a HIPAA covered entity, Northwest Compounders is obligated by law to follow the 
technological and physical safeguards consistent with healthcare standards for privacy and 
confidentiality (Aim 1). No coded or de-identified data and/or samples will be provided to anyone 
outside of the research team. 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 37  
Slocum Center clinical staff, who routinely access PHI as part of routine business operations will provide 
the research team with de-identified files, containing a unique research-specific identifier for 
tests/procedures performed at Slocum . Only study staff directly involved in the administration of 
patient care or study-specific procedures or testing will have access to identifiable health information.  
 
Confidentiality risks are minimized through our approach and data security practices. All de-identified, 
coded data will be stored on a secure, encrypted server, housed within the Slocum Center for 
Orthopedics & Sports Medicine. Slocum Center administers the highest level of technological safeguards 
the industry offers. The study-specific server is entirely dedicated to the Slocum Research & Education 
Foundation, sharing no networks with the Slocum Center. The software used to manage study patients 
allows for multiple levels of data sharing and permissions. For example, study coordinators and team 
members involved in direct coordination of patient care will have access to identifiable patient 
information, while collaborating statisticians will have access to only de-identified data files. In addition, 
any provider information contained in the eCRFs will be limited to a physician ID number only.  
 
Patient binders will be stored behind a limited access, key-entry door, further protected by the 
biometric finger sensors required to access Slocum after-hours.  Because the primary study coordination 
team (Owen and Kirkpatrick) are housed within a HIPAA compliant, highly secure data protection 
environment, research data are protected by the safe physical, technical and policy protections as 
patient medical records.  
 
Finally, a single laptop will be used to capture accelerometer data in the field (e.g. hospital, Dreyer lab). 
The laptop has multiple fail-safes, which secure the data even if the laptop should be stolen. Using a 
total hard-drive encryption software program, the laptop will not power on without first entering the 
encryption key. Accelerometer data are further protected by using only the unique patient identification 
number when downloading data offsite.  
 
Upon study completion, licensing of the PAM tool requires transmission of de-identified, limited data 
sets to Insignia Healthcare. Data will be transferred through a secure, encrypted FTP upload. Transferred 
files will contain only summary level information (e.g. consistent with a limited data set and containing 
no full sets of patient reported outcome questionnaires). Only the rolled up result data will be 
transferred to Insignia to fulfill licensing requirements.  
 
As is standard with a clinical trial, information about participation in the research study, including the 
individual having consented to study participation will be included in the Slocum medical record. When 
the study coordinators are tracking participation, they may note any important health events and 
correspondence with the patient in the electronic medical record at Slocum. The patient’s surgeon 
needs this information documented to manage care and monitor their patient’s health and well-being. 
Potential Research Risks or Discomforts to Patients  
Risks.  
This is a moderate risk study. Potential risks for all subjects participating in this clinical research project 
are as described below.  
 
Confidentiality.  
Disclosure of personally sensitive data is a risk of clinical investigations involving human subjects. All 
subjects will sign a HIPAA form acknowledging the PHI included in data collection. Staff at Northwest 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 38  
Compounders will know research participants by name and document allergy information, as required 
by law (Aim 1). Northwest Compounders is study medication per standard of care and retains limited 
patient information as a result (Aim 1). 
 
A copy of the laboratory results collected for study-related procedures will be provided to the patient’s 
primary care provider. Transmission of results will occur under standard HIPAA protocols for clinic to 
clinic sharing of information (e.g. fax). The patient’s primary care provider may elect to follow-up on 
results to assure high quality care and care management. Patients will authorize lab result sharing 
through the study-specific HIPAA Authorization for Research.  
Under the agreement with MEND Nutrition, Inc., aggregate, de-identified study data will be shared back 
with MEND, limited to functional testing results and patient reported outcome measures 
(questionnaires) only. No patients will be directly identifiable through aggregate data, and any cells with 
resulting counts less than 5 in a table will be omitted to protect patient confidentiality.  
 
Physical injury.  
Physical injury (including falls) is a risk when being asked to perform exercise/strength assessment 
and/or physical independence/performance measures. This risk is increased for persons TKA surgery 
because of issues related to the surgery and the potential need for assistive devices. 
 
 
Blood draws (Aim 1 only). The total amount of blood drawn for the purposes of the study will be 
depend on the study. The potential risks include infection at the site of the blood draw.  Careful sterile 
technique will minimize the chances of infection at the blood draw site.  There is a risk for redness, 
itching, bruising and soreness at the blood draw site.  Your blood will be drawn from a site on your arm.  
Additional blood may be drawn during surgery as determined by the hospital staff and/or doctors 
outside the purpose of this research study. 
Aim 1 (N=40, 20/group) and Aim 2 (N=80, 40/group) will have the same total amount of blood 
drawn, at study intervals.  
 
Muscle biopsy. Biopsies will be collected from all TKA patients (Aim 2 patients will have the choice to 
participate with or without muscle biopsies).  
 
Aim 1 (N=40, 20/group) will have 1 muscle and 1 fat biopsy per leg during TKA (in the OR) 
(N=40) and at 1 week post-TKA (N=20); or 2 weeks post-TKA (N=20). 
 
 
Aim 2 (N=80, 40/group) will have 1 muscle biopsy per leg at Baseline, 6wk & 6mopost-TKA.  
 
The biopsies will be obtained from the vastus lateralis using a 5mm Bergstrom biopsy needle with 
applied suction under sterile conditions. A single incision of 0.5 cm will be made in the skin down to the 
level of the fascia, and approximately 150 mg of muscle tissue will be removed during each biopsy.  
 
The potential risks are pain, bleeding, infection, and loss of superficial sensation (light touch, hot/cold) 
to an area around the biopsy site. There will be a scar approximately 0.6 cm long. The risk of bleeding 
from the biopsy site is 0.2%; the risk of hematoma is 1.4%; the risk of infection is so small that the 
precise number is unknown; and the risk of a loss of superficial sensation is 0.5% (55). After the biopsy, 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 39  
there is a 50% chance that the subject will experience pain at the biopsy site for 24- 48 hrs. However, 
over the counter pain medications have been successful in mitigating pain from the biopsy site.  
 
Aim 1: It is important to note the biopsies are in a fasting state (no food since dinner the night before). 
For the first biopsies in the hospital on the day of surgery, fasting is required per routine care before 
surgery. For the second biopsies, occurring at one OR two weeks after surgery, fasting may lead to some 
discomfort. Patients may have to delay taking their pain medication, or risk upset stomach if they take 
their pain medication without food.  
 
Aim 2: It is important to note the biopsies are in a fasting state (no food since dinner the night before). 
Fasting may lead to some discomfort. Patients may have to delay taking their pain medication (if taking 
any), or risk upset stomach if they take their pain medication without food.  
 
 
Risk from heavy water (Aim #1 only).  Brief periods (< 30 minutes) of dizziness have been reported in 
a small number of people (< 5%) after drinking tracer water.  This is due to the tracer water being 
“heavier” than normal water.  “Heavier” water can temporarily disrupt the inner ear’s ability to control 
balance, producing a sensation of dizziness. 
 
Magnetic stimulation (Aim #1 only). Magnetic stimulation of the peripheral nerve is a safe and non-
invasive way of supplying information to the muscle. Because this pulse is magnetic, and not electric, the 
procedure is painless. No long-term side effects have been reported; however, on rare occasions, 
individuals find the stimulation uncomfortable.  
 
Magnetic Resonance Imaging (MRI, Aim #1 only). The U.S. Food and Drug Administration (FDA) has 
set guidelines for magnet strength and exposure to radio waves, and we will carefully observe those 
guidelines. For the exposure in our ongoing study, no negative effects have been seen. Some people 
may feel uncomfortable or anxious during the MRI. On rare occasions, some people might feel dizzy, get 
an upset stomach, have a metallic taste, or feel tingling sensations or muscle twitches. These sensations 
usually go away quickly. MRI poses some risks for certain people. If an individual has a pacemaker or 
some metal objects inside the body, the strong magnets in the MR scanner may do harm. Another risk is 
a metallic object flying through the air toward the magnet and hitting the subject.   
 
Risk from falls.  There is a possibility that a participant may fall and hurt yourself during this study.  
Knee pain may impact a participant’s ability to control muscles.  It takes time to heal from this type of 
surgery and we are asking you to perform physical tasks that may be challenging to you.  You will be 
supervised at all times when completing the tests that help us determine your ability to move and your 
strength. 
 
Pregnancy risk. The risks of the amino acid supplement to the human embryo or fetus have not been 
studied. Women who are pregnant are not eligible to participate in this study.  Women of potential 
childbearing age will be asked if they are or could possibly be pregnant. It is possible a hormone 
pregnancy test will be administered to verify pregnancy status. 
 
Adequacy of Protection Against Risks. 
 
Participant Confidentiality. Described in the Confidentiality section above.  
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 40  
MEND Nutrition, Inc. MEND has the potential as a for-profit supplement company to benefit directly 
from the outcome of this research. We have purchased the supplement from MEND because MEND’s 
proprietary approach to masking the bittering taste associated with EAAs overcomes a significant barrier 
to enrollment. MEND is not paying for the study, involved in study design, or execution. MEND has no 
control over the publication/dissemination of study results. There is no difference between researching 
EAA supplementation provided by MEND versus another commercial supplement provider such as GNC.  
 
The physicians on this study are not receiving compensation from MEND. Should the nature of this 
relationship between MEND and any member of the research team (including physicians) change, 
formal submission per IRB requirements will be executed.  
 
Physical injury. To minimize this risk each subject will be supervised by a member of the research team 
at all times during testing. All aspects of this proposal are currently used and implemented by the study 
team. 
 
 
Blood draws (Aim 1). Each blood tube collected is between 2.7mL and 7.0mL, depending on the blood 
test requirements. The amount of blood collected at each blood draw is between 28mL and 35mL (high 
estimate).  As reference, when a person donates blood, 500-550mL of blood are donated. Even with 
seven tubes of blood, the amount collected at each draw is approximately 7% of the amount required at 
a typical blood donation.  
 
Muscle biopsy. Pain during tissue sampling will be eliminated by anesthesia. Moreover, pain-control 
measures initiated postoperatively by the research team will be sufficient to control for potential pain at 
the biopsy sites during inpatient hospitalization (TKA). However, over-the-counter medications such as 
ibuprofen are sufficient to control such discomfort for all subjects as needed and after the single 
bilateral biopsies performed at the PI’s lab. The risk of bleeding will be reduced with manual direct 
pressure for 10 minutes or until bleeding has stopped. The risk of infection is minimized by the use of a 
sterile field. We have performed numerous muscle biopsies in the OR (10, 100) as well as post-
operatively at 6 wk post-TKA without incident. Due to the necessity of a fasting state for the one OR two 
week post-operative biopsies (Aim #1) the study team will accommodate as early as 6:00am for 
scheduling the biopsies to help minimize any potential discomfort.  
 
Heavy water (Aim #1). Our study coordinators will continually remind subjects via telephone or in 
person of the potential for balance issues with deuterium oxide (heavy water).   
 
Magnetic stimulation (Aim #1).  Participants will be asked to complete a standard Transcranial 
Magnetic Stimulation Safety Screening Questionnaire. In the event that a subject answers “yes” to one 
of the questions on the questionnaire, magnetic stimulation will not be used with these participants. If a 
subject experiences discomfort at any point, this portion of the protocol will be stopped immediately.  
 
There is significant overlap with regards to TMS and MRI safety screening questionnaires (e.g., Do you 
have a pacemaker?), so, in most cases, people who answer “yes” to a question in the TMS safety 
screening would be excluded from the study, as they would not qualify for an MRI. 
  
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 41  
Magnetic Resonance Imaging. All participants will be asked to complete a standard MRI safety 
screening questionnaire. If it is deemed unsafe for an individual to have an MRI, they will be excluded 
from the study (see exclusion criteria).  
 
All of the above testing and procedures will be performed either at the hospital where the TKAs are 
performed (Sacred Heart Medical Center, River Bend), in the PI’s lab (which is immediately adjacent to 
the Sacred Heart Medical Center, University District’s Emergency Department), or in the Lewis Center 
for Neuroimaging (LCNI, location of MRI) (which is 0.5 miles from the Sacred Heart Medical Center, 
University District’s Emergency Department), or Slocum Center for Orthopedics & Sports Medicine 
located in Eugene.  
 
Risk from falls.  Participants will be supervised at all times when completing the tests that help us 
determine your ability to move and your strength. 
 
Pregnancy risk. Women who are pregnant are not eligible to participate in this study.  Women of 
potential childbearing age will be asked if they are or could possibly be pregnant. It is possible a 
hormone pregnancy test will be administered to verify pregnancy status. 
 
 
 
Data Safety Monitoring Plan 
 
The ultimate responsibility for data and safety monitoring rests with the Principal Investigator. It is 
equally clear that the institution must promote an environment that facilitates detailed ongoing review 
and safe conduct of high-priority research studies. Effective data and safety monitoring is not the result 
of a single committee or individual, but is a shared responsibility within our protocol management 
scheme. The risk level associated with this study is estimated to be moderate and reasonable.  
 
Plan for Monitoring and Safety Review.  
 
 
Hans Dreyer, PhD, PT, the Principal Investigator, will be responsible for monitoring the safety 
environment of the participants during the entire study. The orthopedic surgeon Co-
Investigators Brian Jewett, MD, Brick Lantz, MD, Craig Mohler, MD, and Steven Shah, MD, will be 
medically responsible for the subjects’ care relative to the surgery and post-operative medical 
coverage.   
 
 
Older subjects will be patients of the Sacred Heart Medical Center, continuously monitored by 
nursing and hospital staff during inpatient stay after TKA, and followed by the surgeons and 
research team.  
 
 
Thorough monitoring of the recruitment, enrollment, retention, informed consent process, 
adverse events, study procedures, and evaluation of primary and secondary endpoints will be 
closely observed by the PI, Hans C. Dreyer, PT, PhD., and Co-Investigator Brian A. Jewett, MD.  
 
 
DSMB: We have designed a data and safety monitoring committee and plan. The members of 
the DSMB will be: 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 42  
o Carmen Castaneda-Sceppa, MD., PhD 
Professor and Director, Graduate Programs in Exercise Science 
Department of Health Sciences 
 
o Subashan Perera, PhD 
Associate Professor of Medicine 
Co-Director & Senior Statistician, Data Management and Analysis Core of the Pittsburgh 
Claude D. Pepper Older Americans Independence Center 
 
o Kevin Yarasheski, PhD 
Professor of Medicine, Cell Biology & Physiology, and Physical Therapy  
Assistant Director, Biomedical Mass Spectrometry Research Laboratory 
 
Committee members will participate in the completion of the DSMB Charter, Guidelines, 
assuring all DSMB items identified by NIH via the DSMB Checklist are satisfied.  
 
 
Adverse Event Reporting. Adverse Event Grading Scale as defined by the AE reporting form and study 
stop criterion (See Study Forms, Appendix 2). Dr. Dreyer, the Principal Investigator, will be responsible 
for monitoring and reporting the occurrence of adverse events throughout the study. Subjects will be 
monitored continuously throughout each testing session, and will be followed by phone or email to 
verify compliance with study protocol and to monitor for any un-anticipated events. 
Anticipated Adverse Events discussed in the Informed Consent Form for this study will include: potential 
pain, bruising, and/or infection from the blood draws and muscle biopsies and during functional and 
strength testing. Should an adverse event occur, the Co-Is will be immediately notified and a note will be 
entered in to the subject’s study record using the grading scale listed below.  
 
The research team will follow the IRB Adverse Event Policy on mandatory reporting of Serious Adverse 
Events (SAEs), and will also report them immediately both orally and in writing to the IRB Program 
Director or RSA within 24 hours of occurrence or recognition. The PI, Hans Dreyer, PT, PhD, will be 
responsible for all AE and SAE reporting. 
 
Annual report. Dr. Dreyer will review the protocol on a continuing basis for subject safety and include 
results of the review in the annual progress reports submitted to the IRB and the appropriate NIH 
agency as necessary. The annual report will be provided to the Office for the Protection of Human 
Subjects and will include a list of adverse events. 
 
Content of annual report. The annual report will address: (1) number of adverse events and 
description of the event; (2) reason for dropouts from the study; (3) number of participants in the study; 
(4) whether the study should be continued based on the current data collected and the need to achieve 
the aims stated.  
Potential Research Benefits to Participants 
 
The proposed research is based on strong preliminary evidence that EAA reduce post-operative muscle 
atrophy by 3-fold in the operative and non-operative lower extremities. Further in our pilot studies, 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 43  
these positive results extended to gains in strength in the non-operative quadriceps—important for 
long-term ability to normalize function, and to accelerated recovery of functional mobility (stair 
descent). These data are all derived from older adults. Preserving quadriceps strength is clinically 
important because poor strength is directly linked to reduced physical function and gait. Quadriceps 
weakness inhibits balance (84), reduces functional mobility (20, 82), and increases the risk of falls (83) in 
older adults. Our preliminary data suggest that patients on EAA treatment lost less muscle from their 
extremities compared to subjects on placebo. An additional potential benefit will be our potential to 
provide physical therapy to patients without insurance or in instances where the subjects insurance 
does not pay for the total number of visits we require for this study. These may be considered a 
potential benefit. 
 
We repeated this study with 39 patients in 2014-2016 and again found the group taking EAA lost less 
muscle than the placebo group. 
 
Investigator Experience 
 
University of Oregon 
Hans C. Dreyer, PT, PhD. (3.0 calendar months, 25% effort). Role: Principal Investigator. Dr. Dreyer is 
an expert in translational research on molecular muscle biology and measurements of human muscle 
metabolism in aging. He has received significant training as a post-doctoral fellow, K12 Research Scholar, 
and Mentored Research Scientist Development Awardee (K01), and is now at the end of his 5-year K01 
award, which seeks to determine the potential for amino acid supplementation to augment return of 
muscle metabolism and physical function in older adults during rehabilitation from total knee 
replacement surgery. He will assume overall responsibility for the management of the study, has assign 
responsibilities for the other members of the team, will ensure that informed consent is properly 
obtained from prospective patients, be the liaison to the Institutional Review Boards (IRB), oversight 
plan (DSMP), report adverse events and in discussions with the physicians determine if AE are study 
related or not, and ensure the accuracy of the data. As well, Dr. Dreyer will be responsible for subject 
recruitment, experimental procedures, tracer study supervision, tissue/data collection, data/tissue 
processing, data analysis, manuscript preparation, draft finalization, and annual reports to the NIH and 
ClinicalTrials.gov. Dr. Dreyer will consult via teleconference with Dr. Kuehl on a regular bi-weekly basis 
for the first six months of the study. Thereafter, they will teleconference once a month until study 
completion. Dr. Dreyer and Dr. Kuehl will be responsible for preparing annual and final report as well as 
post-enrollment activities. Dr. Dreyer will have direct contact with subjects and will have contact with 
identifiable and non-identifiable subject data. 
 
Anita Christie, PhD. Aim 1 (1.2 calendar months, 10% effort). Role: Co-Investigator. Dr. Christie is an 
expert in research on neuromuscular changes with advanced age in humans. She has received extensive 
training as a doctoral student and post-doctoral fellow in measuring both electrically- and magnetically-
evoked muscle potentials to assess nervous system (central) and muscle (peripheral) function. She also 
has extensive experience in the processing and interpretation of surface electromyographic signals. Dr. 
Christie and her lab assistants will be responsible for obtaining, processing, and interpreting measures of 
central activation deficits (CAD) of all subjects at Baseline and at 6 wks (Aim 1) and 6 mo and 1 yr (Aim 
2). Dr. Christie will meet with Dr. Dreyer on a regular basis to discuss data analysis and to provide 
technical expertise related to the effects of surgery on activation deficits. Dr. Christie’s research 
experience and publication record make her a valuable member of this research project. Dr. Christie’s 
office is on the 3rd floor of the Center for Medical Education and Research, the same building where Dr. 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 44  
Dreyer’s office is located. Dr. Christie will assist with data collection, data/tissue processing, data 
analysis, and manuscript preparation, and will present findings at national conferences. Dr. Christie will 
meet with the entire research team once a month to discuss issues related to the project. Dr. Christie 
will have direct contact with subjects and will have contact with non-identifiable subject data. 
 
Carry E. McCurdy, PhD. (<1 calendar months, 3% effort). Role: Co-Investigator. Dr. McCurdy is an 
expert in integrative physiology. She has received significant training as a post-doctoral fellow and 
Instructor. Dr. McCurdy is experienced in conducting mechanistic animal and cell culture experiments 
that are closely aligned with the proposed project. Dr. McCurdy will meet regularly with Dr. Dreyer to 
discuss data analysis, and to provide technical expertise related to the design, implementation and 
oversight of the cell culture studies and will, along with Dr. Dreyer, supervise the training of graduate 
students and technicians in methods of in vitro experimentation using cell culture. Dr. McCurdy will be 
responsible for oversight of the cell culture studies and will, along with Dr. Dreyer, supervise the training 
of graduate students and technicians in methods of in vitro experimentation using cell culture. Dr. 
McCurdy has a strong record of research and publications, and will be a valuable member of the 
investigative team.  Dr. McCurdy will not have direct contact with subjects or subject data. 
 
University Research Assistants 
 
Jonathan Muyskens, PhD. (12 calendar months, 100% effort). Role: Research Assistant. Perform human 
functional testing, strength determination, help with biopsies, MRI analysis, MRI scan buddy, and 
biochemistry (blood and tissue analysis).  
 
 
Slocum Education and Research Foundation 
Brian A. Jewett, MD (<1 calendar months, 3% effort). Role: Co-Investigator. Dr. Jewett is an orthopedic 
surgeon at the Slocum Center for Orthopedics & Sports Medicine. Dr. Jewett specializes in adult joint 
reconstruction. A Diplomate of the American Board of Orthopedic Surgery since 2003, Dr. Jewett has 
collaborated with Dr. Dreyer on projects investigating the beneficial effects of using essential amino acid 
supplementation to boost recovery following TKA surgery since 2009. Dr. Jewett will facilitate screening 
and recruitment of potential subjects into the study. Dr. Jewett and Dr. Dreyer, along with the other Co-
Investigator physicians, the study coordinator, and Erin Owen, MPH, the Director of the Slocum 
Education and Research Foundation, will meet regularly to discuss recruitment, enrollment, and 
retention profiles as well as any issues related to adverse events. Dr. Jewett’s office is housed in the 
Slocum Center for Orthopedics & Sports Medicine, which is located 0.5 miles from Dr. Dreyer’s 
laboratory and offices in the Center for Medical Education and Research. Dr. Jewett and Dr. Dreyer meet 
regularly each month for research meetings. Dr. Jewett will have direct contact with subjects and 
subject data, which is a component of his position as orthopedic surgeon. 
 
Brick A. Lantz, MD. (<1 calendar months, 3% effort). Role: Co-Investigator. Dr. Lantz is an orthopedic 
surgeon at the Slocum Center for Orthopedics & Sports Medicine. Dr. Lantz also serves as President of 
Slocum Research & Education Foundation, a 501(c) 3 organization dedicated to clinical research, 
outcomes research, and physician education projects. Dr. Lantz specializes in TKA, osteotomy, and 
treatment of lower extremity trauma. Dr. Lantz will facilitate screening and recruitment of potential 
subjects into the study. Dr. Lantz and Dr. Dreyer have collaborated on projects involving TKA patients 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 45  
since 2009. Dr. Lantz and Dr. Dreyer, along with the other Co-Investigator physicians, the study 
coordinator, and Erin Owen, MPH, the Director of the Slocum Education and Research Foundation, will 
meet regularly to discuss recruitment, enrollment, and retention profiles as well as any issues related to 
adverse events. Dr. Lantz’s office is housed in the Slocum Center for Orthopedics & Sports Medicine, 
which is located 0.5 miles from Dr. Dreyer’s laboratory and offices in the Center for Medical Education 
and Research. Dr. Lantz and Dr. Dreyer meet regularly each month for research meetings. Dr. Lantz will 
have direct contact with subjects and will have contact with non-identifiable subject data, which is a 
component of his position as orthopedic surgeon. 
 
 
 
Craig G. Mohler, MD. (<1 calendar months, 3% effort). Role: Co-Investigator. Dr. Mohler is an 
orthopedic surgeon at the Slocum Center for Orthopedics & Sports Medicine. Dr. Mohler specializes in 
TKA, osteotomy, and treatment of lower extremity trauma. Dr. Mohler will facilitate screening and 
recruitment of potential subjects into the study. Dr. Mohler and Dr. Dreyer, along with the other Co-
Investigator physicians, the study coordinator, and Erin Owen, MPH, the Director of the Slocum 
Education and Research Foundation, will meet regularly to discuss recruitment, enrollment, and 
retention profiles as well as any issues related to adverse events. Dr. Mohler’s office is housed in the 
Slocum Center for Orthopedics & Sports Medicine, which is located 0.5 miles from Dr. Dreyer’s 
laboratory and offices in the Center for Medical Education and Research. Dr. Mohler will have direct 
contact with subjects and will have contact with non-identifiable subject data, which is a component of 
his position as orthopedic surgeon. 
 
Steven N. Shah, MD. (<1 calendar months, 3% effort). Role: Co-Investigator. Dr. Shah is an orthopedic 
surgeon at the Slocum Center for Orthopedics & Sports Medicine. Dr. Shah specializes in primary and 
revision hip and knee replacement surgeries. His research interests include the treatment of hip and 
knee arthroplasty. Dr. Shah will facilitate screening and recruitment of potential subjects into the study. 
Dr. Shah and Dr. Dreyer have collaborated on projects involving TKA patients since 2010. Dr. Shah and 
Dr. Dreyer, along with the other Co-Investigator physicians, the study coordinator, and Erin Owen, MPH, 
the Director of the Slocum Education and Research Foundation, will meet regularly to discuss 
recruitment, enrollment, and retention profiles as well as any issues related to adverse events. Dr. 
Shah’s office is housed in the Slocum Center for Orthopedics & Sports Medicine, which is 0.5 miles from 
Dr. Dreyer’s laboratory and offices in the Center for Medical Education and Research. Dr. Shah and Dr. 
Dreyer meet regularly each month for research meetings.  
Dr. Shah will have direct contact with subjects and will have contact with non-identifiable subject data, 
which is a component of his position as orthopedic surgeon. 
 
Julie Embree, PT. Aim1 (1.0 calendar months, 8% effort). Role: Consultant. Ms. Embree is the Director 
of the Slocum Therapy Center. Her role in the proposed research, along with the PI, will be to establish 
standardized outpatient physical therapy at her site as well as at all local and distant sites per patient 
preference and insurance coverage. She will have bi-weekly meetings with Dr. Dreyer and Erin Owen, 
MPH, Director of the Slocum Education and Research Foundation, and our study coordinator, as well as 
phone/email contact as needed—in the proposed study. Ms. Embree’s office is on first floor of the 
Slocum Center for Orthopedics & Sports Medicine. Ms. Embree will communicate regularly with Dr. 
Dreyer regarding patient therapy. Ms. Embree will meet twice weekly with the study coordinator to 
discuss newly enrolled participant therapy center and facilitate recording/standardization of therapy at 
each location.  
Ms. Embree will have direct contact with subjects and will have contact with non-identifiable subject 
data, which is a component of her position at Slocum Physical Therapy. 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 46  
 
Study Coordinators 
 Erin Owen, Tessa Kirkpatrick & Michelle Bremer(12 calendar months, 100% effort). Role: Study 
Coordinator. The study coordinators will be responsible for coordinating all patient centered activity 
beginning with ensuring Slocum staff pre-identify TKA patients based on inclusion/exclusion criteria 
prior to clinic visits. The study coordinators and the surgeon will have a list of all potentially eligible 
subjects having appointments with Drs. Jewett, Lantz, Mohler, and Shah prior to arriving for clinic visits. 
Once entry criteria are verified by the surgeon, the study coordinator will explain the study, provide an 
informed consent and follow up with patients by phone. The study coordinator, along with Dr. Dreyer 
and Drs. Jewett, Lantz. Mohler, and Shah, will be responsible for ensuring enrollment be maintained at 
3+ subjects/month. The study coordinator will ensure data collection and management coordination 
with Dr. Dreyer and Dr. Smolkowski necessary for periodic and annual reports.  
 
Study coordinators of the Slocum Education and Research Foundation have office space located on the 
first floor of the Slocum Center for Orthopedics and Sports Medicine. Coordination through the Slocum 
Education and Research Foundation will allow for seamless integration with existing Slocum 
infrastructure with all the necessary credentialing and security clearances. The study coordinators have 
experience with clinical research. As such, the study coordinators will be responsible for the 
coordination of the study participants and retention via frequent phone and in person visits. The study 
coordinator and Dr. Dreyer will discuss subject enrollment goals on a day to day basis and meet 
biweekly. The study coordinators will be on-site and work with Slocum staff to maximize pre-screening, 
recruitment, enrollment, and retention of the 120 subjects over the 5 years of the proposed study. Each 
month, the Study Coordinator and Dr. Dreyer will meet with the full research team to provide study 
updates, to discuss all aspects of the project, and to ensure that the research is meeting its goals and 
objectives. Significant effort will be dedicated to subject enrollment and phone/email/in person follow-
up to ensure that we meet our targeted enrollment each month. Coordinators will have direct contact 
with subjects and will have contact with non-identifiable subject data, which is a component of her 
position at Slocum. 
 
Oregon Research Institute 
Biostatisticians 
Keith Smolkowski, PhD. [(1.2 calendar months, 10% effort)]. Role: [Co-Investigator.] Dr. Smolkowski is a 
Statistician with Oregon Research Institute, Eugene, OR. He will oversee statistical analysis and modeling 
in the proposed study. Dr. Smolkowski’s office is located less than 1 mile from Dr. Dreyer’s office. Dr. 
Smolkowski is currently collaborating with Dr. Dreyer and has frequently run statistical analysis for 
researchers from the Department of Human Physiology and the Department of Education at the 
University of Oregon. Dr. Smolkowski and his statistical team will meet with the research team once a 
month or more, as needed. Advanced statistical modeling will be employed to ensure we have the 
necessary power to correlate change in physical function with cellular data obtained from biopsies, 
blood samples, and imaging. Because we propose a longitudinal clinical trial which has the potential for 
missing data points, Dr. Smolkowski’s statistical analyses will use modeling methods to account for 
potential missing data points, further assuring that we will accomplish our aims within the 5-year study 
period. Consultation with Dr. Smolkowski is necessary for meeting both Aims of this proposal. Dr. 
Smolkowski will not have direct contact with subjects but will have contact with non-identifiable subject 
data. 
 
 
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UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 47  
Lisa Strycker, MA. (Consultant; no salary support requested). Role: Consultant. Ms. Strycker is a Senior 
Research Associate with Oregon Research Institute, Eugene. In the proposed investigation, she will be 
responsible for all data management and will assist Dr. Smolkowski with statistical analysis. She has 
office space adjacent to Dr. Smolkowski. She is currently collaborating with Dr. Dreyer, has analyzed all 
of the preliminary data for this grant proposal, and has more than 20 years of substantive and 
methodological experience in conducting health-related clinical trials involving adults, older women, 
chronic illness, physical activity, longitudinal designs, data imputation, and other research areas. She 
coauthored “An Introduction to Latent Variable Growth Curve Modeling” as part of Lawrence Erlbaum 
Associates’ Quantitative Methodology Series, which focuses on specialized analytic techniques for 
longitudinal data and mixed methods. For the proposed study, Ms. Strycker will update, clean, and 
manage the large volume of data collected in real time from the Study Coordinator; will be blinded to 
patient randomization; will routinely meet and provide data reports to the investigative team; and will 
help Dr. Smolkowski and the project investigators plan and conduct data analyses to answer the 
research questions and meet the Specific Aims.  Ms. Strycker will not have direct contact with subjects 
but will have contact with non-identifiable subject data.  
 
Oregon Health and Sciences University 
Kerry Kuehl, MD, DrPH. (<1 calendar months, 5% effort). Role: Co-Investigator. Kerry S. Kuehl, MD, 
DrPH, is Professor of Medicine and Co-Director of the Human Performance Laboratory in the Division of 
Health Promotion & Sports Medicine at OHSU. He is a primary care physician and clinical researcher 
specializing in health promotion and disease prevention strategies focusing on economic outcomes. Dr. 
Kuehl is the P.I. of the SHIELD Study assessing the effects of a worksite wellness program on police 
officers safety and health outcomes. He is a PHLAME Study co-investigator, and performed a 
retrospective analysis of workers’ compensation claims and reportable injuries among PHLAME and non-
PHLAME fire fighters finding a significant reduction in injury rates and costs among PHLAME 
departments. Dr. Kuehl received a prestigious K23 Career Development Training grant by the National 
Institutes of Health in 2003 and was the Principal Investigator of the CHOICE (Changing Healthy 
Outcomes In Clinical Environment) Study. Dr. Kuehl is an expert in clinical nutrition and sport 
supplements. As a Co-Investigator Dr. Kuehl will collaborate and provide expert advise on the oversight 
and administration of the clinical trial. Dr. Kuehl will email and teleconference with Dr. Dreyer on a bi-
weekly basis to discuss management issues and strategies to mitigate events that may arise during the 
course of the study. Once a month Dr. Kuehl will participate in a conference call with all key personnel 
on this project, organized by Dr. Dreyer. Dr. Kuehl will meet in person with Dr. Dreyer and key personnel 
twice yearly to discuss the progress of the trial and subject matriculation and recruitment 
goals/milestones. Dr. Kuehl will teleconference with the entire research team once a month for the 
duration of the study. Dr. Kuehl and Dr. Dreyer will be responsible for preparing annual and final report.  
Dr. Kuehl will not have direct contact with subjects or subject data. 
 
 
 
 
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UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
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UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
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Page | 54  
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Page | 56  
Appendix 1: Data Specifications Table  
Data elements required to meet study specific aims come from multiple sources: patient self-report, 
electronic health records or administrative data, study-specific questionnaires and surveys, functional 
tests and assessments, and results of study-specific procedures. The tables below describe each data 
element and intended use.  The study coordinators at the Slocum Foundation will abstract data from 
clinic and hospital electronic health records, and when required, capture data by patient-self report. 
Data Elements Table. Data specifications for hospitals and practice administrative data, hospital or 
practice electronic medical records, and/or client self-report.   
Data 
Element 
ID 
 
Data Element 
 
Type 
 
Description and Intended Use 
Specific 
Aim # 
1 
Client ID number 
Numeric 
Unique person identifier.  
1,2 
2 
Date of Birth 
Date 
Calculated age at study-specific time points; 
data analysis, stratification, independent 
covariate.  
 
1,2 
3 
Race 
String 
Data analysis, stratification, independent 
covariate. 
1,2 
4 
Ethnicity 
String 
Data analysis, stratification, independent 
covariate. 
1,2 
5 
Height 
Numeric 
Data analysis, stratification, independent 
covariate. 
1,2 
6 
Weight 
Numeric 
Data analysis, stratification, independent 
covariate. 
1,2 
7 
BMI 
Calculated 
Data analysis, stratification, independent 
covariate. 
1,2 
8 
Tourniquet up 
Time 
Data analysis, stratification, independent 
covariate. 
1,2 
9 
Tourniquet 
down 
Time 
Data analysis, stratification, independent 
covariate. 
1,2 
10 
Operating Room 
Time Start (In 
room) 
Time 
Data analysis, stratification, independent 
covariate. 
1,2 
11 
Procedure Start 
Time 
Data analysis, stratification, independent 
covariate. 
1,2 
12 
Procedure Stop 
Time 
Data analysis, stratification, independent 
covariate. 
1,2 
13 
Operating Room 
Stop Time (Out 
of room) 
Time 
Data analysis, stratification, independent 
covariate. 
1,2 
14 
Date of Admit 
Date 
Calculation of Length of Stay; Data analysis, 
stratification, independent covariate. 
1,2 
15 
Date of 
Discharge 
Date 
Calculation of Length of Stay; Data analysis, 
stratification, independent covariate. 
1,2 
 
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Data Elements Table.  Data specifications for hospitals and practice administrative data, hospital or 
practice electronic medical records, and/or client self-report (continued).    
Data 
Element 
ID 
 
Data Element 
 
Type 
 
Description and Intended Use 
Specific 
Aim # 
16 
Medication Name 
1 – x  
String 
Data analysis, stratification, 
independent covariate. 
1,2 
17 
Medication Dose  
(1 – x) 
Numeric 
Data analysis, stratification, 
independent covariate. 
1,2 
18 
Medication Route 
(1 – x) 
String 
Data analysis, stratification, 
independent covariate. 
1,2 
19 
Medication 
Frequency (1 – x)  
String 
Data analysis, stratification, 
independent covariate. 
1,2 
20 
Medication Start 
Date (1 – x) 
Date 
Data analysis, stratification, 
independent covariate. 
1,2 
21 
Medication Stop 
Date (1 – x) 
Date 
Data analysis, stratification, 
independent covariate. 
1,2 
22 
Health Condition 
(1 – x)  
String 
Data analysis, stratification, 
independent covariate. 
1,2 
23 
Health Condition 
Start Date  
(1 – x) 
Date 
Data analysis, stratification, 
independent covariate. 
1,2 
24 
Health Condition 
Stop Date  
(1 – x)  
Date 
Data analysis, stratification, 
independent covariate. 
1,2 
25 
Additional 
procedures (1 – 
x)  
String 
Any additional medical procedures or 
tests performed while patient is on the 
study protocol; Data analysis, 
stratification, independent covariate. 
1,2 
26 
Tobacco Use 
Categorical  
Data analysis, stratification, 
independent covariate. 
1,2 
27 
Tobacco Use 
Frequency 
Numeric 
Cigarettes/day; Data analysis, 
stratification, independent covariate. 
1,2 
28 
Alcohol Use  
Categorical  
Data analysis, stratification, 
independent covariate. 
1,2 
29 
Alcohol Use 
Amount  
Numeric 
Drinks/Day of beer, wine or liquor; Data 
analysis, stratification, independent 
covariate. 
1,2 
30 
Exercise 
Frequency  
Categorical  
Data analysis, stratification, 
independent covariate. 
1,2 
31 
Charlney 
Classification of 
Disease 
Categorical 
Degree of disability or disease in 
operative and non-operative knee; Data 
analysis, stratification, independent 
covariate. 
1,2 
 
 
 
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Page | 58  
Data Elements Table. Data specifications for hospitals and practice administrative data, hospital or 
practice electronic medical records, and/or client self-report.   
Data 
Element 
ID 
 
Data Element 
 
Type 
 
Description and Intended Use 
Specific 
Aim # 
32 
Physical Therapy 
Utilization  
Count 
Data analysis, stratification, 
independent covariate. 
1,2 
33 
Readmission 
Dichotomous 
(Yes/No) 
Data analysis, stratification, 
independent covariate. 
1,2 
34 
Reoperation 
Dichotomous 
(Yes/No) 
Data analysis, stratification, 
independent covariate. 
1,2 
35 
Clinic Visit 
Utilization 
Count 
Data analysis, stratification, 
independent covariate. 
1,2 
36 
Performing 
Surgeon ID 
Numeric 
Known confounder in TKA outcome 
studies; Data analysis, stratification, 
independent covariate. 
1,2 
37 
Discharge 
Disposition 
Categorical 
Patient discharged to home, 
rehabilitation or skilled nursing; 
potential confounder; data analysis, 
stratification, independent covariate. 
1,2 
38 
Hemoglobin 
(pre-admit 
through day of 
discharge) 
Numeric 
Data analysis, stratification, 
independent covariate. 
1,2 
39 
Blood 
Transfusions  
Dichotomous 
(Yes/No) 
Data analysis, stratification, 
independent covariate. 
1,2 
40 
Count of 
Transfusions 
(units) 
Count 
Data analysis, stratification, 
independent covariate. 
1,2 
41 
Study-specific 
Laboratory 
Assessment*  
Numeric 
Patient safety; data analysis, 
stratification, independent covariate. 
1 
42 
Blood Analysis 
Standard of Care 
and Study-
specific 
Laboratory 
Assessment*  
Numeric 
FDA requested monitoring of EAA use, 
patient safety; data analysis, 
stratification, independent covariate. 
1 
43 
Menopausal 
status 
Categorical 
DSMB recommendation; potential 
confounder of primary endpoints. 
1,2 
*Please refer to the protocol for study-specific lab assessments.  
 
 
 
 
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Page | 59  
Data Elements Table. Data specifications for data collected through patient questionnaires or 
surveys.    
Data 
Element 
Survey or 
Questionnaire 
Name 
Research 
Specific 
or 
Standard 
of Care 
 
Description and Intended Use 
Specific 
Aim # 
1 
VR-12 
Standard 
of Care* 
Health-related quality of life; Data analysis, 
stratification, independent covariate. 
1,2 
2 
Patient 
Activation 
Measure (PAM) 
Research 
Patient knowledge and confidence managing 
health conditions; Data analysis, stratification, 
independent covariate. 
1,2 
3 
Oxford Knee 
Score 
Standard 
of Care* 
Knee-specific functional assessment; Data 
analysis, stratification, independent covariate. 
1,2 
4 
Knee Injury and 
Osteoarthritis 
Outcome Score 
(KOOS) 
Research  Knee-specific functional assessment; Data 
analysis, stratification, independent covariate. 
1,2 
5 
Pain Scale or 
Visual Analogue 
Pain Scale 
Standard 
of Care* 
Pain assessments; Data analysis, stratification, 
independent covariate. 
1,2 
6 
Patient Health 
Questionnaire-
9 Item (PHQ-9) 
Research 
Screening for depression and documenting 
severity of depression (known confounder in 
TKA outcome studies); Data analysis, 
stratification, independent covariate. 
1,2 
7 
Serious Life 
Events 
Research  Identification of serious life events that may 
impact key study endpoints; Data analysis, 
stratification, independent covariate. 
1,2 
8 
The Pain 
Catastrophizing 
Scale (PCS) 
Research 
Types of thoughts and feelings experienced 
with pain; data analysis, stratification, 
independent covariate. 
2 
*Data transmitted securely to study team by Slocum Orthopedics. Standard of care instruments are 
collected by electronic data capture on iPads.   
 
 
 
 
 
 
 
 
 
 
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UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 60  
Data Elements Table. Data specifications for data collected through functional tests and study-
specific assessments.     
Data 
Element 
Test, 
Assessment, or 
Procedure 
Collection 
Method 
Description and Intended Use 
Specific 
Aim # 
1 
Food Log/Diaries  Patient self-
report 
Caloric intake, stratified by protein, fat, 
carbohydrate and total calories; Data 
analysis, stratification, independent 
covariate. 
1 
2 
Accelerometer  
Download of 
accelerometer 
data 
Patient mobility; Data analysis, 
stratification, independent covariate. 
1 
3 
Get Up and Go 
Test 
Study staff 
assessment 
Stand from sitting and walk; standardized 
functional test; study endpoint.  
1,2 
4 
6-minute Walk 
Study staff 
assessment 
Standardized functional test; study 
endpoint.  
1,2 
5 
Stair Climb Up 
Study staff 
assessment 
Standardized functional test; study 
endpoint. 
1,2 
6 
Stair Climb Down Study staff 
assessment 
Standardized functional test; study 
endpoint. 
1,2 
7 
Grip Strength – 
Hand 
Study staff 
assessment 
Standardized functional test; study 
endpoint.  
1,2 
8 
4 meter walk 
Study staff 
assessment 
Standardized functional test; study 
endpoint.  
1,2 
9 
Standing Balance 
Test 
Study staff 
assessment 
Standardized functional test; study 
endpoint. 
1,2 
10 
Chair Stand Test 
(Sit to stand five 
times) 
Study staff 
assessment 
Standardized functional test; study 
endpoint. 
1,2 
11 
MRI; Leg 
Composition 
Measurements  
Study staff 
assessment 
Bilateral assessment of leg  composition; 
study endpoint.  
1 
 
  
 
 
 
13 
Isometric 
Extensor 
Study staff 
assessment 
Bilateral assessment of quadriceps strength; 
study endpoint.  
1 
14 
Isometric Flexor 
Study staff 
assessment 
Bilateral assessment of hamstring strength; 
study endpoint.  
1 
15 
Essential Amino 
Acid or Placebo 
Supplementation 
Log 
Patient self-
report 
Compliance with study protocol; study 
intervention.  
1,2 
16 
Muscle & Biopsy 
Study staff  
Bilateral biopsy; study endpoint(s).  
1,2 
17 
Edema & Fluid 
Accumulation 
Study staff  
Bilateral biopsies; controlling for potential 
confounding of study endpoints. 
1,2 
#Please refer to the protocol for study-specific lab measurements.  
 
 
 
 
 
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Page | 61  
Appendix 2: Study Logs 
Medical Condition Log 
To be updated by study staff with patient 
 
Condition Name or Description 
Date of 
Onset 
Date 
Resolved 
 
Check if Ongoing 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
IRB Reviewer Note: For Aim #2, the study timeline check boxes will updated.   
 
 
 
 
 
 
 
       Page _______ of _________ 
 
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UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
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Page | 62  
Medication Log 
To be updated by study staff with patient 
IRB Reviewer Note: For Aim #2, the study timeline check boxes will updated. 
Page _________ of __________ 
 
Medication Name or 
Description 
Route  
Frequency 
Dose  
 
Check if Ongoing 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
 
☐ oral      ☐ nasal   
☐ IM        ☐ IV    
☐ Sub-q    
☐ prn     ☐ qd 
☐ bid      ☐ tid  
☐ __________ 
 
☐ - 6 week      ☐ week 1 
☐ - 4 week      ☐ week 2 
☐ - 1 week      ☐ week 6 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 63  
 
Study Medication – Essential Amino Acid or Placebo Log 
Week  ______ 
 
Patient Comments:  
 
 
 
 
Instructions: Each day at approximately 10 AM (but at least two hours after you have eaten breakfast) 
you will to mix one bottle of pre-weighed supplement into something of your choosing (juice or yogurt, 
for example) and ingest/drink.  You will do this again approximately 2 hours after lunch (~2 PM).  If you 
miss a time point you can make up that time point later in the day however we request that you do so at 
least 3 to 4 hours apart (supplements in a day) and that you record the time on your log.  
 
On those occasions when you receive physical therapy treatment you will ingest the supplement within 
one hour after treatment.  If you have treatment by physical therapy in the morning that will be your 
morning supplement for the day and your next supplement will be at approximately 2 PM. If you have 
physical therapy in the afternoon, your afternoon (second supplement of the day) will be ingested 
within one hour after therapy.  This is very important as our research has shown that supplement 
ingestion is much better for you if taken within one hour of exercise. 
 
If you have questions about your study medication, please call your research coordinators 
541.868.3232.  
 
 
 
 
Date 
 
Day of the Week 
 
Morning Dose Time 
Physical Therapy 
Time or No PT 
Today (check) 
 
Afternoon Dose Time 
 
01/01/2014 
 
Monday 
 
10:00a 
☐ No PT Today 
2:30p 
 
3:30p 
 
 
 
 
☐ No PT Today 
 
 
 
 
 
☐ No PT Today 
 
 
 
 
 
☐ No PT Today 
 
 
 
 
 
☐ No PT Today 
 
 
 
 
 
☐ No PT Today 
 
 
 
 
 
☐ No PT Today 
 
 
 
 
 
☐ No PT Today 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 64  
Pre-Operative Heavy Water Log 
Week  ______ 
 
Patient Comments:  
 
 
 
 
 
 
 
Instructions: In order to measure muscle metabolism you will also be asked to ingest tracer water 
(heavy water).The tracer water contains something called an isotope.  An isotope is a normal substance 
that contains an unusual number of neutrons (very, very small particles found in all things).  The isotope 
is usually present in normal water but the tracer water you will drink will contain more than usual.    We 
want you to drink the tracer water so that we can measure reactions in the body.  You will not 
notice/taste the isotope, nor will it change anything in your body.  Each day at approximately 10 AM, 2 
PM, and 7 PM, you will ingest 50 ml (1.7 ounces) of tracer water.  You will also be allowed to drink 
normal water.  Overall, 95% of people experience no side-effects from drinking heavy water. We want to 
use this heavy water to measure how your cells respond to supplement before surgery. 
 
 
If you have questions about taking heavy water, please call your research coordinators, Erin or Tessa 
at 541.868.3232.  
 
Date 
 
Morning  
Time 
 
Mid-Afternoon 
Time 
 
Evening Time 
 
Patient Comments 
 
01/01/2014 
 
10:00a 
 
2:00p 
 
7:00p 
 
No side effects.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 65  
Post-Operative Heavy Water Log 
Week  ______ 
 
Patient Comments:  
 
 
 
 
 
 
 
 
 
Instructions:  Just like before you had surgery you will again ingest tracer water (heavy water).   Each 
day at approximately 10 AM and 2 PM, you will ingest 50 ml (1.7 ounces) of tracer water.  You will 
continue to ingest the heavy water for one or two weeks after surgery, depending on randomization. 
You will also be allowed to drink normal water. We want to use this heavy water to measure how your 
cells respond to supplement after surgery. 
 
 
You are randomized to drink heavy water for ___________week(s) after surgery.  
 
 
If you have questions about taking heavy water, please call your research coordinators, Erin or Tessa 
at 541.868.3232.  
 
 
 
Date 
 
Morning  
Time 
 
 
 
Evening Time 
 
Patient Comments 
 
01/01/2014 
 
10:00a 
 
 
 
7:00p 
 
No side effects.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
January 2019 
 
Page | 66  
Accelerometer Log 
To be updated by study staff  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page  _______ of _________
 
Date 
 
Location 
 
Device Number 
Distributed  
(or N/A) 
 
Device Number 
Returned  
(or N/A) 
 
Coordinator 
Comments/Notes 
 
Coordinator 
Initials 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 67  
 
 
Patient Phone or Contact Log 
To be updated by study staff 
 
 
Page _______ of _______ 
 
 
 
Date 
 
Location 
 
Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 68  
 
Patient Physical Therapy Appointment Tracking Log 
Heavy Water Study 
To be updated by patient 
 
 
Page _______ of _______ 
 
 
 
 
 
 
Appt 
Number 
 
Date 
 
Location 
 
Notes 
1 
 
 
 
 
Post-Operative Day #5 
2 
 
 
 
Post-Operative Day #7 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 69  
 
 
Instructions for Keeping 3 Days of Food Records 
 
1. Keep a careful and accurate record of all FOOD and beverages (including coffee, water, gum, etc.) 
consumed during 3 days.   
2. Try to write down food as you eat it. Do not rely on your memory.  
3. Estimate the amounts in terms of household measures (like 1 cup, or 8 oz. milk, 3 oz. fish, 1 
teaspoon butter). 1 pat of butter is about 1 teaspoon. (See sample picture on next page.) 
4. 8 ounces = 1 cup ONLY when the item is FLUID. Do not use ounces unless the food is liquid (8 oz. 
milk) or you know what it weighs (3 oz. chicken). 8 oz. Cheerios does NOT equal 1 cup. 8 oz. 
Cheerios is half the box. 
5. Use the label and package when possible to write down specific amounts eaten. For example, if you 
eat a whole bag of chips, you can find the oz. wt. on the package. Make sure you look at the 
servings per package, and calculate accordingly. Often times, a bag of chips might have 2.5 oz. 
servings, so if you eat the whole package you would take that into account.  
6. 1 ounce cheese = 1 slice cheese = 1/4 cup shredded cheese.   
7. 3 oz. of meat is about the size of a deck of cards. 
8. Note the food’s preparation method (baked, fried, etc.). 
9. Be specific about the type of milk (whole, 2%, 1%, nonfat). 
10. Don’t forget the spreads on bread, water, salad dressings, gravies, cream and sugar in coffee, etc. 
11. For mixed dishes, like casseroles, estimate and record the amounts of the major ingredients.   
12. For fast food restaurants, record the name of the restaurant. 
 
 Please call Erin Owen or Tessa Kirkpatrick at 541.868.3232 if you have any questions about your food diary.  
 
A visual for estimating your portions.  
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 70  
 
Food Diary Day 1 
Day of the week: 
____________________________ 
Date:  
  
____________________________ 
Your initials:  
____________________________ 
 
1. BREAKFAST (time: ___________) 
4. SNACK (time: ___________) 
Amount 
Food 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. DINNER (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
2. SNACK (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. LUNCH (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. SNACK (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 71  
 
Food Diary Day 2 
Day of the week: 
____________________________ 
Date:  
  
____________________________ 
Your initials:  
____________________________ 
 
1. BREAKFAST (time: ___________) 
4. SNACK (time: ___________) 
Amount 
Food 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. DINNER (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
2. SNACK (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. LUNCH (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. SNACK (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 72  
 
Food Diary Day 3 
 
Day of the week: 
____________________________ 
Date:  
  
____________________________ 
Your initials:  
____________________________ 
 
1. BREAKFAST (time: ___________) 
4. SNACK (time: ___________) 
Amount 
Food 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. DINNER (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
2. SNACK (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. LUNCH (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. SNACK (time: ___________) 
 
 
Amount 
Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Report 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 73  
 
To be updated by study staff 
 
Subject Adverse Event Number:   
 ___________ 
 
Description of AE or Diagnosis:   
 
 
___________________________________________________________________________________ 
 
Study Relationship:   
☐  Not related  
☐  Possibly related 
☐  Probably related 
   ☐   Definitely related 
 
Severity Grading:            ☐  Mild 
☐  Moderate       ☐   Severe       ☐   Life Threatening 
 
Involves operative site/knee?   
☐   Yes  
☐    No 
 
 
 
 
Outcome: 
Date of outcome or 
outcome change: 
Physician 
Investigator initials 
& date 
Coordinator initials 
& date when study 
AE log is updated 
Ongoing 
 
 
 
Resolved, residual effects 
present and being treated 
 
 
 
Death 
 
 
 
Resolved, No sequel 
 
 
 
Unknown 
 
 
 
 
 
Action Taken Regarding Study Intervention: 
 
 
Other Action Taken:    ☐   None  
☐  None 
 
 
 
 
 
________________________________ 
☐  Discontinued Permanently 
☐  Discontinued Temporarily   
 
 
________________________________ 
☐  Reduced Dose 
☐  Delayed Dose 
 
 
 
 
________________________________ 
 
Did AE result in hospital  
admission (outpatient or inpatient)?    ☐   Yes  ☐    No  Æ If yes, readmission date: _______________ 
 
Was the event serious?  ☐   Yes   ☐    No    Æ  If yes, under what criteria (check below)?  
☐  Death 
☐  Life-Threatening 
☐  Hospitalization (initial or prolonged) 
☐  Disability or permanent damage 
☐  Required intervention to prevent permanent impairment 
Î Requires immediate reporting to IRB and DSMB if serious.   Report date: ________________ 
 
Physician Investigator Signature: __________________________________ Date: _________________ 
 
 
IRB Reviewer Note: For Aim #2, the study timeline check boxes will updated. 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 74  
 
Protocol Deviation or Violation Report 
To be updated by study staff 
 
Protocol Deviation Report Number:  
_____________________ 
 
Description of Event:   
 
____________________________________________________________________________________ 
 
 
Study Interval:  
☐  - 6 weeks 
☐  - 4 weeks 
☐  - 1 week 
☐  Day of Surgery through Discharge 
☐  1 week  
☐  2 week 
☐  6 week 
 
Type of Deviation:  
☐  Missed study activity 
☐  Out of window 
☐  Patient refused 
☐  Investigator judgment or decision 
 
Result of Deviation:  
☐  Subject withdrew from study participation 
☐  Investigator withdraws subject from study participation 
☐  Subject continues enrollment and participation per protocol  
☐  Other: ______________________________________________________________________ 
 
 
Did this event increase the risk or decrease the benefit, affect subject’s rights, safety or welfare, or integrity of 
the data? 
☐  Yes     ☐  No  Æ  
If yes, report protocol violation to the IRB and DSMB.   
 
 
 
 
 
 
 
Date reported: _______________ By: _____________ 
 
 
 
 
PI Signature: ________________________________________________________ Date: ____________ 
 
Physician Investigator Signature: _______________________________________  Date: ____________ 
 
IRB Reviewer Note: For Aim #2, the study timeline check boxes will updated. 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 75  
 
 
Appendix 3: Patient-Reported Questionnaires 
Social Readjustments Rating Scale – Life Events Questionnaire (Administered on paper) 
 
Give to patient to fill out themselves or read through with patient. To measure stress according to the Holmes 
and Rahe Stress Scale, the number of "Life Change Units" that apply to events in the past year of an individual's 
life are added and the final score will give a rough estimate of how stress affects health. 
 
Life Event 
Life Change Units 
Death of a spouse 
100 
Divorce 
73 
Marital separation 
65 
Imprisonment 
63 
Death of a close family member 
63 
Personal injury or illness 
53 
Dismissal from work 
47 
Marital reconciliation 
45 
Retirement 
45 
Change in health of family member 
44 
Pregnancy 
40 
Gain a new family member 
39 
Business readjustment 
39 
Change in financial state 
38 
Death of a close friend 
37 
Change to different line of work  
36 
Change in frequency of arguments 
35 
Major mortgage 
32 
Foreclosure of mortgage or loan 
30 
Change in responsibilities at work 
29 
Child leaving home 
29 
Trouble with in-laws 
29 
Outstanding personal achievement 
28 
Spouse starts or stops work 
26 
Beginning or end of school 
26 
Change in living conditions 
25 
Revision of personal habit 
24 
Trouble with boss 
23 
Change in working hours or conditions 
20 
Change in residence 
20 
Change in schools 
20 
Change in recreation 
20 
Change in church activities 
19 
Change in social activities 
18 
Minor mortgage or loan 
17 
Change in sleep habits 
16 
Change in number of family reunions 
15 
Change in eating habits 
15 
Vacation  
13 
Christmas 
12 
Minor violation of law 
11 
Score above 300 = At risk of illness 
Score of 150 – 299 = Risk of illness is moderate (reduced by 30% from above risk) 
Score < 150: Only have slight chance of illness 
Holmes TH, Rahe RH (1967). "The Social Readjustment Rating Scale". J Psychosom Res 11 (2): 213–8. doi:10.1016/0022-3999(67)90010-4 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 76  
 
 KOOS KNEE SURVEY (Administered on paper) 
 
Today’s date: _____/______/______ Date of birth: _____/______/______  
 
Name: ____________________________________________________  
 
INSTRUCTIONS: This survey asks for your view about your knee. This information will help us 
keep track of how you feel about your knee and how well you are able to perform your usual activities.  
Answer every question by ticking the appropriate box, only one box for each question. If you are 
unsure about how to answer a question, please give the best answer you can.  
 
Symptoms  
These questions should be answered thinking of your knee symptoms during the last week. 
 
S1. Do you have swelling in you knee? 
 
 Never  
☐
Rarely  
☐
Sometimes  
☐
Often  
 ☐
Always  
 ☐ 

S2. Do you feel grinding, hear clicking or any other type of noise when your knee moves? 
Never  
☐
Rarely  
☐
Sometimes  
☐
Often  
 ☐
Always  
 ☐ 

S3. Does your knee catch or hang up when moving? 
Never  
☐
Rarely  
☐
Sometimes  
☐
Often  
 ☐
Always  
 ☐ 

S4. Can you straighten your knee fully? 
Never  
☐
Rarely  
☐
Sometimes  
☐
Often  
 ☐
Always  
 ☐ 

S5. Can you bend your knee fully? 
Never  
☐
Rarely  
☐
Sometimes  
☐
Often  
 ☐
Always  
 ☐ 

Stiffness  
The following questions concern the amount of joint stiffness you have experienced during the last week in 
your knee. Stiffness is a sensation of restriction or slowness in the ease with which you move your knee 
joint. 
 
S6. How severe is your knee joint stiffness after first waking in the morning? 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
S7. How severe is your knee joint stiffness after sitting, lying or resting later in the day? 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
Pain 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 77  
 
P1. How often do you experience pain? 
Never  
   ☐
Monthly  
☐
Weekly  
☐
Daily  
    ☐
Always  
   ☐
 
What amount of knee pain have you experienced in the last week during the following activities? 
 
P2. Twisting/pivoting on your knee 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
P3. Straighten knee fully 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
P4. Bending knee fully 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
P5. Walking on flat surface 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
P6. Going up or down stairs 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
P7. At night while in bed 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
P8. Sitting or lying 
 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
P9. Standing upright 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 78  
 
Function, daily living  
The following questions concern your physical function. By this we mean your ability to move around and 
to look after yourself. For each of the following activities please indicate the degree of difficulty you have 
experienced in the last week due to your knee. 
 
A1. Descending stairs 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A2. Ascending stairs 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
For each of the following activities please indicate the degree of difficulty you have experienced in the last 
week due to your knee. 
 
A3. Rising from sitting 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A4. Standing 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A5. Bending to floor/pick up an object 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A6. Walking on flat surface 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A7. Getting in/out of car 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A8. Going shopping 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A9. Putting on socks/stockings 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
 
A10. Rising from bed 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A11. Taking off socks/stocking 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A12. Lying in bed (turning over, maintaining knee position) 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A13. Getting in/out of bath 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
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Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 79  
 
A14. Sitting 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A15. Getting on/off toilet 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
For each of the following activities please indicate the degree of difficulty you have experienced in the last 
week due to your knee. 
 
A16. Heavy domestic duties (moving heavy boxes, scrubbing floors, etc.) 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
A17. Light domestic (cooking, dusting, etc.) 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
 
Function, sports and recreational activities  
The following questions concern your physical function when being active on a higher level. The questions 
should be answered thinking of what degree of difficulty you have experienced during the last week due to 
your knee. 
 
SP1. Squatting 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
SP2. Running 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
SP3. Jumping 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
SP4. Twisting/pivoting on your injured knee 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
 
SP5. Kneeling 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 80  
 
Quality of Life 
 
Q1. How often are you aware of your knee problem? 
Never  
 ☐
Monthly  
☐
Weekly  
   ☐
Daily  
    ☐
Constantly  
     ☐
Q2. Have you modified your life style to avoid potentially damaging activities to your knee? 
Not at all  
 ☐
    Mildly  
☐
Moderately  
☐
      Severely  
☐

        Totally  
      ☐

 
Q3. How much are you troubled with lack of confidence in your knee? 
Not at all  
 ☐
Mildly  
 ☐
Moderately  
 ☐
Severely  
 ☐
Extremely  
 ☐
Q4. In general, how much difficulty do you have with your knee? 
None  
 ☐
Mild  
☐ 
Moderate  
 ☐
Severe  
 ☐
Extreme  
 ☐
 
 
Thank you very much for completing all the questions in this questionnaire. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 81  
 
PHQ-9 Questionnaire (Administered on paper) 
 
Patient Name  
Date  
 
 
1. Over the last 2 weeks, how often have you been bothered by any of the 
following problems?  Read each item carefully, and circle your response. 
 
 
Not 
at all 
Several 
days 
More than 
half the days 
Nearly 
every day 
 
0 
1 
2 
3 
a. Little interest or pleasure in doing things 
 
 
 
 
b. Feeling down, depressed, or hopeless 
 
 
 
 
c. Trouble falling asleep, staying asleep, or 
sleeping too much 
 
 
 
 
d. Feeling tired or having little energy 
 
 
 
 
e. Poor appetite or overeating 
 
 
 
 
f. Feeling bad about yourself, feeling that you are 
a failure, or feeling that you have let yourself 
or your family down 
 
 
 
 
g. Trouble concentrating on things such as 
reading the newspaper or watching television 
 
 
 
 
h. Moving or speaking so slowly that other 
people could have noticed. Or being so fidgety 
or restless that you have been moving around a 
lot more than usual 
 
 
 
 
i. Thinking that you would be better off dead or 
that you want to hurt yourself in some way 
 
 
 
 
Totals 
 
 
 
 
 
 
2. If you checked off any problem on this questionnaire so far, how difficult 
have these problems made it for you to do your work, take care of things at 
home, or get along with other people?  
 
 
 
Not Difficult At All 
Somewhat Difficult 
Very Difficult 
Extremely Difficult 
0 
1 
2 
3 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 82  
 
Oxford Knee Score (Administered Electronically via iPad or on paper) 
Please answer the following 12 questions. Choose only one answer per question. The value for each answer is indicated to 
the right of the answer. Total up all of your answers to obtain a total score out of 48 points. Please only consider how you 
have been getting on during the past four weeks. 
 
 
 
 
Total Score:                  /48 
 
 
 
1. 
How would you describe the pain you have usually from 
your knee? 
Score 
8. 
Have you been able to do your own household shopping 
on your own? 
Score 
None – 4 
 
Yes, easily – 4 
 
Very mild – 3 
With little difficulty – 3 
Mild – 2 
 With moderate difficulty – 2 
Mild moderate – 1 
 With extreme difficulty – 1 
Severe – 0 
No, impossible – 0 
 
 
 
 
2. 
 Have you had any trouble with washing and drying 
yourself all over because of your knee? 
 
9. 
For how long have you been able to walk before the pain 
from your knee became severe (with or without a stick)? 
 
No trouble at all – 4  
 
No pain, even after more than 30 minutes – 4 
 
Very little trouble – 3 
16-30 minutes – 3 
Moderate trouble – 2 
5-15 minutes – 2 
 Extreme difficulty – 1 
Around the house only – 1 
 Impossible to do – 0 
Unable to walk at all – 0 
 
 
 
 
3. 
Have you had any trouble getting in and out of a car or 
using public transport because of your knee? 
 
10. Have you been able to walk down a flight of stairs 
 
No trouble at all – 4  
 
 Yes, easily – 4 
 
Very little trouble – 3 
With little difficulty – 3  
Moderate trouble – 2 
 With moderate difficulty – 2 
 Extreme difficulty – 1 
 With extreme difficulty – 1 
 Impossible to do – 0 
 No, impossible – 0 
 
 
 
 
4. 
If you were to kneel down could you stand up afterwards? 
 
11. After a meal (sat at a table) how painful has it been for you 
to stand up from a chair because of your knee? 
 
 Yes, easily – 4 
 
Not at all painful – 4 
 
With little difficulty – 3  
 Slightly painful – 3 
 With moderate difficulty – 2 
 Moderately painful – 2 
 With extreme difficulty – 1 
Very painful – 1 
 No, impossible – 0 
Unbearable – 0 
 
 
 
 
5. 
Have you been limping when walking because of your 
knee? 
 
12. How much pain from your knee interfered with your usual 
work (including housework)? 
 
Rarely/never – 4  
 
 Not at all – 4 
 
Sometimes or just at first – 3  
 A little bit – 3 
 Often, not just at first – 2   
 Moderately – 2 
 Most of the time – 1 
 Greatly – 1 
All of the time – 0 
Totally – 0 
 
 
 
 
6. 
Have you felt that your knee might suddenly give way or 
let you down? 
 
13. Have you been troubled by pain from your knee in bed at 
night? 
 
Rarely/never – 4  
 
No nights – 4 
 
Sometimes or just at first – 3  
 Only 1 or 2 nights – 3 
 Often, not just at first – 2   
Some nights – 2  
 Most of the time – 1 
 Most nights – 1 
All of the time – 0 
 Every night – 0 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 83  
 
VR-12 (Administered Electronically via iPad or on paper) 
Instructions: This questionnaire asks for your views about your health.  This information will help keep track of how you feel 
and how well you are able to do your usual activities. 
 
Answer every question by marking the answer as indicated.  If you are unsure how to answer a question, please give the best 
answer you can. 
 
(Circle one number on each line) 
1.  In general, would you say your health is: 
 
 
EXCELLENT 
 
 
VERY GOOD 
 
 
GOOD 
 
 
FAIR 
 
 
POOR 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
2.  The following questions are about activities you might do during a typical day. 
Does your health now limit you in these activities?  If so, how much? 
 
YES, 
LIMITED 
A LOT 
 
YES, 
LIMITED  
A LITTLE 
 
NO, 
NOT 
LIMITED 
AT ALL 
 
a.  Moderate activities, such as moving a table, pushing a vacuum cleaner, 
bowling, or playing golf? 
 
 
1 
 
2 
 
3 
 
b.  Climbing several flights of stairs? 
 
 
 
1 
 
2 
 
3 
 
3.  During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a 
result of your physical health? 
 
 
 
NO, 
NONE 
OF THE 
TIME 
 
YES, 
A LITTLE  
OF THE 
TIME 
 
YES, 
SOME  
OF THE 
TIME 
 
YES, 
MOST 
OF THE 
TIME 
 
YES,  
ALL  
OF THE 
TIME 
 
a.  Accomplished less than you would like. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
b.  Were limited in the kind of work or other 
activities. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
4.  During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
 
 
NO, 
NONE 
OF THE 
TIME 
 
YES, 
A LITTLE  
OF THE 
TIME 
 
YES, 
SOME  
OF THE 
TIME 
 
YES, 
MOST 
OF THE 
TIME 
 
YES,  
ALL  
OF THE 
TIME 
 
a.  Accomplished less than you would like. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
b.  Didn't do work or other activities as carefully as 
usual. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
THE VETERANS RAND 12 ITEM  
HEALTH SURVEY (VR-12)
 
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5-year Clinical Trial: Essential Amino Acid Supplementation & TKA 
PI: Hans C. Dreyer, PhD, PT 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187 
November 2018 
5.  During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home 
and house work)?  
 
 
NOT AT ALL  
 
 
A LITTLE BIT 
 
 
MODERATELY 
 
 
QUITE A BIT 
 
 
EXTREMELY 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
These questions are about how you feel and how things have been with you during the past 4 weeks.  For each 
question, please give the one answer that comes closest to the way you have been feeling. 
 
6.  How much of the time during the past 4 weeks: 
 
 
 
ALL OF 
THE 
TIME 
 
MOST OF 
THE TIME 
 
A GOOD BIT 
OF 
 THE TIME 
 
SOME OF 
THE TIME 
 
A LITTLE 
OF 
THE TIME 
 
NONE OF 
THE TIME 
 
a.  Have you felt calm and 
peaceful? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
b.  Did you have a lot of 
energy?  
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
c.  Have you felt downhearted 
and blue?  
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
 
 
7.  During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with 
your social activities (like visiting with friends, relatives, etc.)? 
 
 ALL OF THE TIME 
 
 MOST OF THE TIME 
 
 SOME OF THE TIME 
 
A LITTLE OF THE 
TIME 
 
 NONE OF THE TIME 
 
      
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
Now, we'd like to ask you some questions about how your health may have changed. 
 
8.  Compared to one year ago, how would you rate your physical health in general now? 
 
MUCH BETTER  
 
SLIGHTLY BETTER 
 
ABOUT THE SAME  
 
SLIGHTLY WORSE  
 
MUCH WORSE  
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
9.  Compared to one year ago, how would you rate your emotional problems (such as feeling anxious, depressed or 
irritable) now? 
 
MUCH BETTER  
 
SLIGHTLY BETTER  
 
ABOUT THE SAME  
 
SLIGHTLY WORSE  
 
MUCH WORSE  
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 85  
 
Patient Activation Measure (Administered Electronically via iPad or on paper) 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 86  
 
Visual Analogue Pain Scale (Administered Electronically via iPad or on paper) 
 
 
 
 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 87  
 
The Pain Catastrophizing Pain Scale (PCS – administered on paper) 
 
 
 
 
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5-yr Clinical Trial: EAA Supplementation & TKA   
            
 
        
Principal Investigator:  Dreyer, Hans C.  
 
UO IRB Protocol #12272013.024   PeaceHealth Protocol #551187-1 
May 2017 
 
Page | 88  
 
Appendix 4: Patient Information Flier (Aim 2) 
 
 
 
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TKA – 6 month follow-up  
               
        Dreyer R01: Aim 2 
UO IRB Protocol #12272013.024; PeaceHealth Protocol #551187; Last Modified: 1-2019 
1 
PARTICIPANT CONSENT FORM 
 
Title:  
Mechanistic approach to preventing atrophy and restoring 
function in older adults: The long-term follow-up study 
 
Principal investigators:  
Hans C. Dreyer, PT, PhD, Brian A. Jewett, MD, Brick A.  
Lantz, MD, Craig G. Mohler, MD, and Steven N. Shah, MD.  
 
Approved by the following institutional review boards: 
 
 
 
 
Sacred Heart Medical Center at RiverBend.   
University of Oregon. 
 
Questions?   
 
Please call your study coordinator at 541.868.0658 or  
 
 
 
 
 
541.868.3217 
 
Why am I being invited to participate in this clinical study?  
 
You are being asked to participate in this clinical research study because you are between 40-80 
years of age and scheduled to undergo a total knee replacement (TKR; also known as total knee 
arthroplasty or TKA) surgery at Sacred Heart Medical Center, RiverBend or Slocum ASC under 
the care of orthopedic surgeons Brian Jewett, MD, Brick Lantz, MD, Craig Mohler, MD, or Steven 
Shah, MD.  
 
This study is being sponsored by a grant from the National Institutes of Health (NIH).  A total of 80 
TKA patients will be recruited for this particular study. This study is one of two clinical studies that 
seeks to further demonstrate if recovery from surgery for older adults can be improved. The first 
study was completed in 2016 and included 39 patients who completed all the study activities.  
 
This is an important form. Please read it carefully. It tells you what you need to know about this 
study.  If you agree to take part in this research study, please sign the form.  Your signature 
means that you have read this document and have been told about the study and what the risks 
are.  Your signature on this form also means that you want to take part in this study and that you 
are willing to undergo all of the testing outlined below. Participation in this study is voluntary. 
Please note that this consent form is for the research study only and that consent for surgery will 
be obtained at a later time by the surgical team.  
 
What is the purpose of the study?  
 
This study will determine the effect of ingesting essential amino acids (EAA) twice-daily for 1 week 
before through 6 weeks after your total knee replacement surgery.  Each participant will be 
randomly assigned to either receive the EAA or a placebo (a non-essential amino acid called 
alanine) supplement.  Like a coin flip, you have about a 50-50 chance of receiving the real essential 
amino acid supplement.  Two groups (EAA or placebo) will then be compared for things such as 
muscle protein synthesis, muscle architecture and functional mobility. We want to see if 
supplementing your diet with EAA will reduce muscle loss and boost recovery. 
 
What will happen?   
 
Below is an outline of what we require for your participation in this study and when study activities 
happen.  It is very important that you complete each of the testing sessions, measures, and 
questionnaires to the best of your ability.  To assist you with this a study coordinator will be in 
regular contact with you during the course of this study.  Phone calls by the research staff and 
regular staff of the Slocum Center for Sports Medicine & Orthopedics will occur often.  Below is an 
overview of the entire study. This provides a general outline of what is involved. 
 
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TKA – 6 month follow-up  
               
        Dreyer R01: Aim 2 
UO IRB Protocol #12272013.024; PeaceHealth Protocol #551187; Last Modified: 1-2019 
2 
 
 
 
 
Study Activities 
 
Study activities as described above and their time points will be scheduled/coordinated with you 
and your study coordinator. You will be required to make extra trips for study only activities. Your 
study coordinators will try and minimize these trips by combining as many study activities as 
possible (within study window) into one visit. They will work with you to determine what works 
best for your travel needs.  
 
 
 
 
 
 
 
EAA or Placebo
week -1
TKA
week 6
3 months
functional mobility,
daily accelerometer 
recordings 
completed prior to 
3 mo. visit (start 
week prior), 
questionnaires
6 months
daily accelerometer 
recordings complete 
by 6 mo visit (start 
week prior); bilateral 
biopsyB, 
functional mobility,
questionnaires
Overview of Aim #2 study timeline, activities, measures and procedures.
Schedule of Events
Time
-6 mo
max
-8 wks to 
-1 wks 
(+ 1 day)
-1
wk
(± 0 day)
TKA
(Day 0)
2
wk
(± 1 week)
6
wk
(± 1 week)
3
mo
(± 2 weeks)
6
mo
(± 2 weeks)
Enrollment
X
X
Screening
X
X
Questionnaires
X
X
X
X
Functional Mobility Test
X
X
X
X
X
Accelerometer 
XA
X
XA
XA
Supplement*
start
Stop
Bilateral Muscle BiopsyB
XB
X
X
Functional testing & biopsy: Performed at the Dreyer Lab, University of Oregon or the Slocum Center.
A Subjects will have the accelerometer ON daily during waking hours (off while sleeping and showers) for a 7 consecutive day period ending at this time point.
BOptional muscle biopsy as per patient choice; Biopsies must be completed a minimum of 4 weeks prior to TKA; patients who are enrolled between 
-4 weeks and -1 week (+ 1 day) will not be eligible to participate in the biopsy arm. 
*Twice daily ingestion of supplement (subject and investigators are blinded to treatment group); Ingestion will occur within1 hour after daily physical therapy.
supplement start 
-6 mo max
informed 
consent, 
enrollment 
and 
screening
-8 weeks to -1 week (+ 1 day) 
functional 
testing, 
questionnaires, 
stop ingestion of 
supplement. 
Bilateral muscle 
biopsyB; daily 
accelerometer 
Screening or re-verify 
screening if previously 
enrolled, administer 
questionnaires, start 7 day 
accelerometer collection, 
perform, functional 
mobility, biopsyB. 
Week 2
Functional 
testing only
 
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TKA – 6 month follow-up  
               
        Dreyer R01: Aim 2 
UO IRB Protocol #12272013.024; PeaceHealth Protocol #551187; Last Modified: 1-2019 
3 
 
Pre-TKA supplement ingestion (before surgery).   
 
Starting 7 days before your surgery, you will begin supplementation.  Each day at approximately 
10 AM (but at least two hours after you have eaten breakfast) you will mix two level scoops of 
supplement into water or beverage of choice (e.g. smoothie) and and drink.  You will do this again 
approximately 2 hours after lunch (~2 PM).  If you miss a time point you can make up that time 
point later in the day however we request that you do so at least 3 to 4 hours apart (supplements 
in a day) and that you record this in the log book we provide you.  Any questions you have please 
call your study coordinator at the Slocum Foundation. They can be reached at 541-868-0658 or 
541-868-3217. 
 
 
Post-TKA supplement ingestion (after surgery).   
 
Just like before you had surgery you will again ingest supplement twice each day for 6 weeks.  
This will occur while you are in the hospital (not on day of surgery) and after you are discharged. 
Each day at approximately 10 AM (but at least two hours after you have eaten breakfast) you will 
be given your supplement tor drink. This will occur again in the afternoon at approximately 2 PM.  
If you miss a time point you can make up that time point later in the day however we request that 
you do so at least 3 to 4 hours apart (supplements in a day) and that you record this in the logbook 
we provide you.  Any questions you have please call your study coordinator at 541-868-0658 or 
541-868-3217. 
 
After surgery you will have physical therapy which is routine and prescribed by your doctor.  On 
those occasions when you receive physical therapy treatment you will ingest the supplement 
within one hour after treatment.  If you have treatment by physical therapy in the morning that will 
be your morning supplement for the day and your next supplement will be at approximately 2 PM. 
If you have physical therapy in the afternoon then your afternoon (second supplement of the day) 
will be ingested within one hour of therapy.  This is very important as our research has shown that 
supplement ingestion is much better for you if taken within one hour of exercise. 
 
 
Logbooks.   
 
Over the course of the study we will help you keep track of certain components that are important 
for us to record.  For example the logbook will help you to keep track of when you take your 
supplement.  
 
The study team will also keep logbooks as part of the study.  We will ask you about your 
demographics (example: age, race/ethnicity), health status, mental health status, medications 
and any health-related changes or tests that happen to you during the study.  We have to track 
these details to determine how essential amino acid supplementation impacts your recovery after 
surgery.  The study coordinators will help you keep your logbook, and ours, up to date. 
 
 
 
 
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Accelerometer.   
 
In order to measure how active you are, we ask that you wear an accelerometer at your waist.  
Wearing the accelerometer will begin close to when you start the study. The accelerometer will 
be worn as a piece of clothing and put on in the morning and kept on until you go to bed each 
day.  The accelerometer will be worn at four time points during the study for seven consecutive 
days:  
 
(1) Once between 8 to four weeks before your surgery  
(2) Once at six weeks post surgery 
(3) Once at three months post surgery 
(4) Once at six months post surgery 
 
This device will help us to gauge the effect of overall physical activity on recovery and how this 
may explain some of the positive results.  
 
 
Questionnaires.   
 
You will be asked to complete questionnaires over the course of this study that will help us to 
understand your health, health-related quality of life, and ability to move around factor into your 
progress.  These questionnaires will be completed before TKA surgery and at 6 weeks, 3 months, 
and 6 months after surgery.  The questionnaires will help us compare participants in the study 
over time and help us better understand the role essential amino acid may have on your recovery 
after surgery. 
 
 
Function (ability to move around and strength).  
 
Here are the tests we will ask you to do during this study that will help us measure your ability to 
get around and how strong you are before and after surgery:  
 
standardized grip strength,  
 
standing balance,  
 
chair stand test,  
 
timed up-and-go (TUG),  
 
timed stair ascent (up) and timed stair descent (down),  
 
four-meter walk and  
 
You will complete each of the above between 8 weeks and 4 weeks before your surgery, and at 
2 weeks, 6 weeks, 3 months, and 6 months after TKA surgery.   
 
Grip strength will allow us to assess changes in each hand over time. Standing balance will 
measure changes over time. The chair stand test measures the time it takes for the participant to 
stand and sit five times. TUG will measure the time (seconds) needed to stand from a chair, walk 
3 meters, turn around, walk back and be seated again.  Timed stair ascent (10 steps) and descent 
will be recorded. We have experience with these functional measures. The 4 meter walk will tell 
us how long it takes  you to walk a short distance (4 meters).  Functional tests will be performed 
at the University of Oregon or the Slocum Center. 
 
Completing the functional mobility assessment is the main component of this study that we are 
looking to change in a positive sense with supplementation.  Older adults who have this surgery 
may be able to do much more if the supplementation helps regain mobility. 
 
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About the biopsies (optional). 
 
This study involves optional biopsies. These biopsies will only be performed if you elect to have 
them done and if the biopsy can be scheduled for at least 4 weeks before your total knee 
replacement surgery. If a biopsy cannot be scheduled at least 4 weeks prior to your surgery, you 
may still be able to participate in this study, but you would not have the choice whether to 
participate in the biopsies or not. If it is too close to your surgery date, you are eligible to participate 
in all the study activities, and take the supplement, but would not have any biopsies before or 
after surgery.The following information is if you elect to have the biopsies performed.  
 
A small incision about the size of this dash “___" approximately at mid-thigh, through which a 
needle about the size of this letter "O" will be advanced into the muscle.  A piece of tissue will 
then be removed.  This will be done on each leg.  
 
Your biopsies will be performed by the Principal Investigator, Dr. Dreyer, who is running this trial. 
Dr. Dreyer has performed over 500 biopsies. The biopsies will be performed by Dr. Dreyer in his 
lab at the Center for Medical Education and Research, or at the Slocum Center, in the morning 
before you’ve had food (fasted state). This procedure involves the taking of a small piece of 
muscle tissue from your leg. The skin is cleaned and made sterile, and the skin and tissue below 
are injected with local anesthetic, lidocaine (numbing medicine), to eliminate pain.  Afterwards, 
the skin will be closed with a single stitch and/or steri-strips and a dressing.  The stitch, if used, 
will be removed by research study staff in about 7 days (plus or minus one day to accommodate 
your schedule). 
 
 
If you choose, you will have biopsies at three time points, one biopsy in each leg (total of six):  
(1) 4 to 8 weeks before surgery 
(2) 6 weeks after surgery 
(3) 6 months after surgery 
 
The Dreyer Lab will be measuring your muscle weight, comparing the wet biopsies to dried muscle 
samples. The samples will tell the study team how much edema (fluid accumulation) you have in 
your leg before and after surgery. 
 
From your muscle biopsies we will isolate primary muscle cells called satellite cells.  Under the 
right conditions in cell culture, these primary cells, isolated from you muscle tissue samples, can 
increase in number and form primitive muscle cells.  Recently, this type of work has shown that 
these cells can inform us about how your muscles may respond to various conditions.  We will 
perform primary cell isolation in order to conduct experiments on your muscle cells that we could 
not perform on you (For example, we can block metabolic processes from happening and 
evaluate the impact on muscle tissue) and increase the amount of muscle tissue we have to work 
with. You will be fasting (no breakfast) before your muscle biopsies.  
 
This research will help us to learn much more about how your muscle cells respond to treatment 
over the course of the clinical trial. 
 
The Primary Cell Isolation Experiment is Not Long-term Storage of Your Cells. The primary 
cell isolation technique is not a way to develop perpetual (long-term) cell lines.  Once we isolate 
primary cells we will keep them frozen at -80°C until we are ready to perform cell culture 
experiments on them.  However, once they are in cell culture, they have a finite life span and will 
expire within 2 to 4 weeks.  After the experiments on your cells are completed they will be dead 
already or destroyed. 
 
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Muscle biopsy option – For patients who are able to have biopsies at least 4 weeks prior 
to surgery only 
 
You have the option to choose whether you would like to participate in this research study with or 
without having the muscle biopsies. You do not have the option to have biopsies if your date of 
surgery is less than four weeks away and/or you cannot schedule your biopsy to be completed at 
least four week prior to surgery.  
 
You may choose to participate in the study having muscle biopsies at three different time periods 
or you may choose to forego the muscle biopsies and continue participation in the rest of the 
study without them.  
 
If you decide to have muscle biopsies, you still have the right to change your mind at any point in 
the study, whether you have already had a biopsy or not and still continue participation. 
 
You choose: (check box and initial) 
 
☐ to have muscle biopsies   __________ 
 
☐ to not have muscle biopsies    __________ 
 
How long will I be in the study?  
 
You will officially be in the study from the date you sign this consent form, which could be up to 
six months before surgery until the last study activity is completed six months after surgery. Your 
study-related activities don’t begin until approximately 8 weeks before surgery and end 
approximately 6 months after your surgery.  Most people will be actively participating in the study 
for about eight months.  
 
 
IMPORTANT:  Participation in this study will not affect your hospital length of stay, which is 
determined by your orthopedic surgeon.  
 
What are the risks of participating in this research?   
 
This study may include risks that are unknown at this time.  Possible risks and discomforts you 
could experience during this study include: 
 
Risk from biopsies.  The potential risks of this procedure are some pain, bleeding, bruising, 
infection, and scar at the site of biopsy.  Careful sterile technique should reduce the likelihood of 
any of these complications.  The risk of bleeding from the biopsy site is 0.2%; the risk of bruising 
or blue-and-black mark is 1.4%; and the risk of infection is so small that the precise number is 
unknown.  Additionally, you may experience numbness around the area of the biopsy site 
(approximately 2x2 inches in area), which will likely go away with time (sensation returns) but in 
very rare instances sensation may never return.  The risk that you experience numbness is less 
than 0.5% and the risk that the numbness never goes away is much less.  Pre-TKA (4-8 weeks 
prior to surgery) and Post-TKA biopsies (6 weeks and 6 months) will be performed using local 
anesthetic (lidocaine), which will remove or eliminate sensation of the biopsy.  After a biopsy you 
have a 50% chance of experiencing soreness at the site of biopsy for 24 to 48 hours.  Over the 
counter medication will be enough to eliminate any potential pain from the biopsy site.  The scar 
will be approximately long like this dash “___”.  We have performed muscle biopsies on over 100 
older adults during and after TKA without side-effects.   
 
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It is important to note the biopsies occur while you are fasting (no food since dinner the night 
before). On the morning of your post-operative biopsies you may have to delay taking your pain 
medication, or risk upset stomach if you take your pain medication without food. The study team 
can accommodate post-operative biopsies as early as 6:00am to help minimize any potential 
discomfort.  
 
Risk from falls.  There is a possibility that you may fall and hurt yourself during this study.  This 
is mentioned because your knee pain affects your ability to control your muscles.  Also, it takes 
time to heal from this type of surgery and we are asking you to perform physical tasks that may 
be challenging to you.  You will be supervised at all times when completing the tests that help us 
determine your ability to move and your strength. 
 
Pregnancy.   The risks of the amino acid supplement to the human embryo or fetus have not 
been studied. Women who are pregnant are not eligible to participate in this study.  Women of 
potential childbearing age will be asked if they are or could possibly be pregnant. It is possible a 
hormone pregnancy test will be administered to verify pregnancy status. The study staff can 
answer any questions you may have about this process.  
 
Are there benefits to taking part in this study?  
 
You will likely receive no direct benefit from your participation in this study.  Essential amino acids 
have been shown to reduce muscle loss in persons having TKA such as yourself.  For example, 
in a study we recently completed we found that patients in the EAA group lost less muscle from 
their legs as compared to those in the placebo group.  This may be considered a potential benefit.  
However, that study included only 28 participants total, which clinically is considered a very small 
sample.  We repeated this study with 39 participants in 2014 – 2016 and again found the group 
taking EAA lost less muscle than the placebo group. Thus, the purpose of this study is to replicate 
those findings in a much larger group of participants, and determine how EAA supplementation 
may be working at the cellular level. Neither you nor the investigators working directly with you will 
be aware of which study group you are in (EAA or Placebo).  This is called a placebo controlled 
double blind study for this reason.  
 
Will you receive new information about the study? 
 
You will be told about any new findings/information that might change your decision to be in this 
study. You may be asked to sign a new consent form if this occurs to ensure you full understand 
the changes. 
 
What other choices do I have if I don’t participate in this research study?   
 
This research is being conducted to gather information.  You are free to choose not to take part 
in this study. Should you decide to withdrawal participation, your surgeon and care providers will 
care for you according to their routine standard care procedures. Payment for your routine care 
after withdrawal from the study will be the same as if you did not participate in the study, which 
you will have to work out between your surgeon, care facilities and your insurance company.  
 
Are there any costs associated with this research study?   
 
You will not pay for any tests or procedures that are performed for the purposes of this research 
study.  You will be compensated for participating in the study.  This money is to compensate you 
for your time and any inconvenience it presents to you.  If you do not complete the study, you will 
receive a reduced amount of money based on study timeline events completed: 
 
 
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TKA – 6 month follow-up  
               
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8 
 
Compensation plan if you choose to have muscle biopsies (maximum $300): 
 
$100.00 for completion of preoperative biopsy 
 
$100.00 for completion of six week postop biopsy 
 
$100.00 for completion of six month postop biopsy (study completion) 
Please note that you will not be compensated for the two week and three month 
study activity time points. Compensation only reflects the study time points in which 
you have biopsies. 
 
Compensation plan if you choose NOT to have muscle biopsies (maximum $100):  
 
$20.00 for completion of preoperative testing 
 
$20.00 for completion of two week postop testing 
 
$20.00 for completion of six week postop testing 
 
$20.00 for completion of three month postop testing 
 
$20.00 for completion of six month postop testing (study completion) 
 
If you decide to withdrawal participation from the study or your physician or research staff 
withdrawals your participation, you will be compensated for the maximum time-point above 
completed. For example, if you complete your six week post-op biopsy, you would be 
compensated $200.00. If you complete your six week post-op testing, you would be compensated 
$60.00. 
 
Please note, compensation from participation in Human Subjects Research studies is taxable 
income.  If your compensation totals $600 or more in a calendar year, the University of Oregon is 
required to report the income to the IRS.  The University requires its departments to tack 
participant compensation and may contact you to complete a Form W-9 for tax reporting 
purposes.  Because of the federal and University tracking requirements, your name will be 
associated with participation in research.  Department and University administrators will have 
access to this information, but will not have access to research data.  
 
 
Where does the study supplement come from?  
 
The study team has learned from the first two EAA studies we have done that essential amino 
acids have a very bitter taste. To overcome this barrier, we have partnered with a company called 
MEND Nutrition, Inc. (“MEND”) who adds all natural flavoring to the supplement so patients are 
able to take it without too much trouble. MEND worked directly with our team to create a custom 
supplement that meets our requirements regarding the composition of EAAs we are studying. 
MEND has provided the supplement to our study for only the cost of shipping. In exchange for 
making our supplement and the placebo for us to study, the Slocum Center will sell the other 
MEND products that are commercially available nutritional supplements. The profits from the sale 
of the other MEND nutritional products will go back to the nonprofit Slocum Foundation to support 
our research program. Neither the Slocum Center nor the physicians affiliated with this study profit 
from the sale of MEND nutritional products at Slocum.  
 
 
Who can answer my questions?  
 
You may talk to your orthopedic surgeon, Dr. Brian Jewett, MD, Dr. Brick Lantz, MD, Dr. Craig 
Mohler, MD, or Dr. Steven Shah, MD (all principal investigators), or to the co-principal investigator 
Dr. Hans Dreyer, PT, PhD. You will have regular contact with our study coordinators, who will call 
you on a regular basis over the course of the study.  Any questions you have please call your study 
coordinator at 541-868-3232. 
 
 
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What are my rights if I take part in this study?  
 
Taking part in this research study is your decision.  You do not have to take part in this study, but 
if you do, you can stop at any time. Your decision whether or not to participate will not affect your 
relationship with your physician, or the Sacred Heart Medical Center/PeaceHealth or your surgery 
in any way. 
 
You do not waive any liability rights for personal injury by signing this form.   
 
All forms of medical diagnosis and treatment, whether routine or experimental, involve some risk 
of injury.  In spite of precautions, you might develop medical complications from participating in 
this study.  If such complications arise, the researchers will assist you in obtaining appropriate 
medical treatment but PeaceHealth, Slocum and University of Oregon do not provide financial 
assistance for medical or other costs. 
 
If you are physically injured because of the project, you and your insurance company will have to 
pay your doctor bills.   If you have no insurance the cost of treatment will be yours.  
 
Your relationship with University of Oregon, PeaceHealth, and the Slocum Center for Orthopedics 
& Sports Medicine will not be impacted by your participation in this study.  
 
If you experience harm because of the project, you can ask the State of Oregon to pay you.  If 
you have been harmed, there are two University representatives you need to contact.  Here are 
their addresses and phone numbers: 
 
 
General Counsel 
 
 
 
Research Compliance Services 
 
Office of the President 
 
 
5237 University of Oregon 
 
1226 University of Oregon 
 
 
Eugene, OR  97403 
 
Eugene, OR 97403 
 
 
 
(541) 346-2510 
 
(541) 346-3082 
 
A law called the Oregon Tort Claims Act limits the amount you can receive from the State of 
Oregon if you are harmed. 
 
 
What about confidentiality?  
 
Any information that is obtained in connection with this study and that can be identified with you 
will remain confidential and will be disclosed only with your permission. Participant identities will 
be kept confidential by assigning you a “participant identification number”. The names associated 
with each participant identification number will be kept in a locked file cabinet in Dr. Dreyer’s office 
area.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
 
UO Research Compliance Services, PeaceHealth Institutional Review Board, and/or authorized 
representatives of the National Institute of Health (NIH) may need to review records of individual 
participants.  As a result, they may see your name, but they are bound by rules of confidentiality 
not to reveal your identity to others. The Food and Drug Administration (FDA) may inspect records 
associated with this study.  
 
 
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TKA – 6 month follow-up  
               
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10 
Should you choose to have muscle biopsies, all of your muscle tissue will be used for study 
analysis.  For example for muscle we will look at changes in mRNA, cell signaling and changes 
in cell structure.  The researchers may store the information gathered during this study indefinitely. 
 
Information about your participation in the research study, including your willingness to consent 
to study participation will be included in your Slocum medical record. When your study 
coordinators are tracking your participation, they may note any important health events and 
correspondence with you in your electronic medical record at Slocum. Your surgeon needs the 
information documented to manage your care and monitor your health and well-being.   
 
The supplement is being supplied by MEND Nutrition, Inc. (“MEND”). MEND is providing the 
supplement for minimal cost and is interested in the results of the study. MEND will be given de-
identified study information for functional testing and patient questionnaires related to your study 
outcomes only. None of the information provided to MEND will contain information that could 
identify you. The information will be similar to what is published as study results in academic or 
medical journals.  
 
 
If I agree to participate, who can decide to end my participation?  
 
You may decide to end your participation at any time. The investigators may stop you from taking 
part in this study at any time if it is in your best interest, if you do not follow the study rules, or if 
the study is stopped.  
 
Your well-being is our primary concern. Throughout the study, we will be monitoring you very 
closely. Your surgeon, or the study team, can end your study participation at any time if it is in 
your best interest to protect your health and well-being.  
 
Having TKA surgery is a requirement of participation in this study. If for any reason you will not 
continue with the planned surgery or if the surgery is delayed, you may be withdrawn from 
continued participation or your participation disrupted until the surgery is rescheduled. In 
addition, should an individual become pregnant while enrolled in the study, participation would 
be discontinued as it is not known whether the investigational drug (i.e., EAA supplement) is 
safe for use by pregnant women.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Consent to Participate in the Research Study 
 
I have had an opportunity to have my questions answered.  I have been given a copy of this form.  
I agree to take part in this study.  If you have questions regarding your rights as a research 
participant, contact University of Oregon Research Compliance Services, 5237 University of 
Oregon, Eugene, OR 97403, (541) 346-2510 or the PeaceHealth Institutional Review Board, 
(541) 686-6949.  
 
You will be asked to sign a separate form that allows the study team members to communicate 
about you and your health information during the study.  
 
Your signature indicates that you have:  
 
 
read and understand the information provided above, 
 
all of your questions have been answered,  
 
you willingly agree to participate,  
 
you may withdraw your consent at any time and discontinue participation without penalty,  
 
you understand that should you withdraw your consent at any time you will continue to 
receive routine standard of care as determined by your surgeon and care providers, 
 
payment for the care you receive is the same as if you did not participate in the study, 
 
you will receive a copy of this form, and 
 
you are not waiving any legal claims, rights or remedies 
 
 
 
 
 
                                
                                                                             
(Date and Time)                 
(Signature of Participant)                              
 
 
 
 
 
 
 
                                                                             
                       
 
Printed Name of Participant                            
 
 
 
                                 ___________________________________________ 
(Date and Time)                 
(Signature of Individual Obtaining Consent) 
 
 
 
 
 
 
           ___________________________________________ 
 
                       
 
Printed Name of Individual Obtaining Consent                          
 
 
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