Intramuscular Mechanisms of Androgen Deprivation-related Sarcopenia
Conditions: Metastatic Prostate Cancer, Androgen Deprivation Therapy
Sponsor: Seattle Institute for Biomedical and Clinical Research

 
 
 
 
 
 
 
 
 
PILOT STUDY TO ANALYZE INTRAMUSCULAR MECHANISMS OF ANDROGEN 
DEPRIVATION RELATED SARCOPENIA 
 
[MIRB #01653] 
 
Funding Agency: Department of Defense, SIBCR 
 
Principal Investigator: Jose M Garcia MD PhD 
 
01/11/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Human Subjects Protocol 
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Abstract 
 
Over 200,000 new cases of prostate cancer (PCA) are diagnosed in the U.S. 
annually. Over the last two decades there has been a trend towards diagnosing 
less advanced disease, but more recently with a decrease in PSA-based 
screening for PCA, there has been concern that the incidence of metastatic 
disease will again rise. For the last 60 years androgen deprivation therapy (ADT) 
has remained the standard treatment for advanced and metastatic PCA. At this 
time, however, nearly 400,000 men remain on ADT for advanced PCA. As their 
disease progresses, additional therapies rely on greater suppression of androgen 
or inhibition of androgen targets. The impacts of ADT on men are great including 
sarcopenia, frailty, insulin resistance, obesity, loss of quality of life, and increased 
cardiovascular disease. Furthermore, age related testosterone deficiency may 
exert similar effects on aging men without PCA.  
 
Despite the large number of men being treated with ADT, there is a surprising paucity of 
research in humans to explain the mechanism of sarcopenia and its effects. How these 
changes are manifested histologically also remains unknown but may involve overall 
loss of muscle fibers, change in distibtrution of muscle fiber types, and distribution of 
satellite cells. Several hypotheses have been developed to explain the mechanism of 
ADT-related sarcopenia but the most plausible seems to be based upon an imbalance 
between opposing anabolic and catabolic pathways and cross-talk between these 
pathways. Androgens, the growth hormone/insulin-like growth factor-1 (GH/IGF1) axis, 
and follistatin activate anabolic pathways. While myostatin (a negative regulator of 
muscle mass and a member of the transforming growth factor β superfamily) and 
ubiquitin ligases regulate catabolic pathways.  
 
This is a pilot study to test the hypothesis that men on ADT will experience loss of 
muscle mass, loss of strength, loss of bone density, increased adiposity, and increased 
insulin resistance and that these changes will correspond to histologic alterations in 
skeletal muscle and change in relative expression of anabolic and catabolic pathway 
markers.  
 
This is very relevant to our Veterans since PCA remains one of the most commonly 
diagnosed cancers in this population with profound side effects of ADT in this population 
that affect function, comorbidity, and quality of life (QOL).  
 
 
 
 
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List of Abbreviations 
 
6MWT: 6-minute walk test 
ADT: Androgen deprivation therapy 
AIDS: acquired immunodeficiency syndrome 
ALT: alanine aminotransferase 
AST: aspartate aminotransferase 
CHF: congestive heart failure 
COPD: chronic obstructive pulmonary disease 
DXA: dual-energy x-ray absorptiometry  
EORTC QLQ-30: European organization for the research and treatment of cancer 
quality of life questionnaire 
EPIC: expanded prostate cancer index composite 
FACT-P: functional assessment of cancer therapy-prostate 
GH: growth hormone 
GnRH: gonadotropin-releasing hormone 
HGS: hand grip strength 
IGF: insulin-like growth factor 
IGFBP: insulin-like growth factor binding protein  
MRS: magnetic resonance spectroscopy 
OS: optical spectroscopy 
PCA: Prostate cancer 
PHI: protected health information 
PSA: prostate specific antigen 
QOL: Quality of life 
SCP: stair climb power 
TCMI: translational center for metabolic imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Contents 
Protocol Title: .................................................................................................................. 5 
1.0 
Study Personnel .................................................................................................... 5 
2.0 
Introduction ............................................................................................................ 6 
3.0 
Objectives .............................................................................................................. 7 
4.0 
Resources and Personnel ..................................................................................... 7 
5.0 
Study Procedures .................................................. Error! Bookmark not defined. 
5.1 Study Design .......................................................................................................... 7 
5.2 Recruitment Methods ........................................................................................... 10 
5.3 Informed Consent Procedures ............................................................................. 10 
5.4 Inclusion/Exclusion Criteria .................................................................................. 11 
5.5 Study Evaluations ................................................................................................ 11 
5.6 Data Analysis ....................................................................................................... 13 
5.7 Withdrawal of Subjects ......................................................................................... 14 
6.0 
Reporting ............................................................................................................. 14 
7.0 
Privacy and Confidentiality .................................................................................. 16 
8.0 
Communication Plan ........................................................................................... 17 
9.0 
References .......................................................................................................... 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Title:  INTRAMUSCULAR MECHANISMS OF ANDROGEN DEPRIVATION 
RELATED SARCOPENIA 
 
1.0 
Study Personnel 
 
Principal Investigator: Jose M Garcia MD PhD 
Clinician Investigator,  
Geriatric Research, Education and Clinical Center 
VA Puget Sound Health Care System 
Building 1, Room 815J 
1660 South Columbian Way (S-182-GRECC) 
Seattle, WA  98108-1597 
Phone: (206) 764-2984 
Fax: (206) 764-2569 
jose.garcia@va.gov 
 
Co-Investigator: 
 
Atreya Dash, M.D. 
Associate Professor, Urology, University of Washington 
VA Puget Sound Health Care System 
Phone: (206) 764-2265 
atreya.dash@va.gov 
1660 S. Columbian Way 
Seattle, WA 98108-1597 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.0 
Introduction 
 
Over 200,000 new cases of prostate cancer (PCA) are diagnosed in the U.S. 
annually. Over the last two decades there has been a trend towards diagnosing 
less advanced disease, but more recently with a decrease in PSA-based 
screening for PCA, there has been concern that the incidence of metastatic 
disease will again rise. For the last 60 years androgen deprivation therapy (ADT) 
has remained the standard treatment for advanced and metastatic PCA. At this 
time, however, nearly 400,000 men remain on ADT for advanced PCA. As their 
disease progresses, additional therapies rely on greater suppression of androgen 
or inhibition of androgen targets. The impacts of ADT on men are great including 
sarcopenia, frailty, insulin resistance, obesity, loss of quality of life, and increased 
cardiovascular disease. Furthermore, age related testosterone deficiency may 
exert similar effects on aging men without PCA.  
 
Despite the large number of men being treated with ADT, there is a surprising paucity of 
research in humans to explain the mechanism of sarcopenia and its effects. How these 
changes are manifested histologically also remains unknown but may involve overall 
loss of muscle fibers, change in distribution of muscle fiber types, and distribution of 
satellite cells. Several hypotheses have been developed to explain the mechanism of 
ADT-related sarcopenia but the most plausible seems to be based upon an imbalance 
between opposing anabolic and catabolic pathways and cross-talk between these 
pathways. Androgens, the growth hormone/insulin-like growth factor-1 (GH/IGF1) axis 
and follistatin activate anabolic pathways. While myostatin (a negative regulator of 
muscle mass development and a member of the transforming growth factor β 
superfamily) and ubiquitin ligases regulate catabolic pathways.  
 
This is a pilot study to test the hypothesis that men on ADT will experience loss of 
muscle mass, loss of strength, loss of bone density, increased adiposity and increased 
insulin resistance and that these changes will correspond to histologic alterations in 
skeletal muscle and change in relative expression of anabolic and catabolic pathway 
markers.  
 
This is very relevant to our Veterans since PCA remains one of the most commonly 
diagnosed cancers in this population with profound side effects of ADT in this population 
that affect function, comorbidity, and quality of life.  
 
 
 
 
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3.0 
Objectives 
 
This is a pilot study to test the hypothesis that men on ADT will experience loss of 
muscle mass, loss of strength, loss of bone density, increased adiposity, and increased 
insulin resistance and that these changes will correspond to histologic alterations in 
skeletal muscle and change in relative expression of anabolic and catabolic pathway 
markers. We will also identify functional changes, as will cytokine, chemokine, GH 
levels, and other markers of inflammation and anabolic function in subject plasma. 
Additionally, we will correlate muscle changes with non-invasive testing with magnetic 
resonance spectroscopy (MRS) for muscle energetics and optical spectroscopy (OS) for 
mitochondrial function and cell energetics. Data obtained in the study will not be used 
for future research and will be used only for purposes outlined in this protocol. 
 
4.0 
Resources and Personnel 
 
 Work will be conducted 1) within the VA at Dr. Garcia’s dedicated research 
space, at the Clinical Research Unit, and in the Urology clinic, and 2) at the 
Translational Center for Metabolic Imaging (TCMI) located at the University of 
Washington School of Medicine. 
 Dr. Garcia is the PI of the study and will oversee all study procedures 
including recruitment, consenting, administering surveys, performing data 
analysis, and coordinating all regulatory activities. Dr. Dash will identify and 
recruit prostate cancer patients seen in the Urology clinic at the VA and will 
be performing the study procedures occurring there. Lab technicians at the 
TCMI will be conducting the MRS and OS. Only VA personnel listed here will 
have access to protected health information (PHI). 
 
5.0 
Study Procedures  
 
5.1 Study Design 
One group will be included in this pilot study: Patients with advanced or 
metastatic PCA initiating treatment with primary ADT with a gonadotropin-
releasing hormone (GnRH) agonist. This group will include 60 subjects. 
  
There will be 4 study visits: 1) Screening, 2) Baseline, 3) Three-month visit and 
4) Six-month visit. Screening will be performed within 3 weeks prior to baseline. 
Informed consent will be obtained prior to any screening visit procedures. 
Informed consent will be scanned and entered into our electronic medical records 
per current VA guidelines. The subject's PHI that will be needed for pre-
screening and recruitment for this study is as follows; full medical history, name, 
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date of birth, social security number, demographics, age, telephone number, and 
home address. The patients that will be identified via chart review are patients of 
the VAMC Cancer Center. 
 
Review of inclusion/exclusion criteria and completion of informed consent will 
occur at the Screening visit, followed by review of medical history and a blood 
draw for safety laboratory measures. 
 
The following procedures will take place at the Baseline visit: Dual-energy x-ray 
absorptiometry (DXA) scan to measure body composition. Muscle performance 
as measured by hand grip strength (HGS), stair climb power (SCP), actigraphy, 
and 6-minute walk test (6MWT). Indirect calorimetry to measure VO2 peak. 
Fatigue and HR-QOL assessments by EORTC QLQ-30, EPIC Hormonal, and 
FACT-Prostate. Magnetic resonance spectroscopy (MRS), optical spectroscopy 
(OS), and muscle biopsy to measure muscular mitochondrial function. Blood 
samples will be collected to assess degree of androgen deprivation (total and 
free testosterone).  
 
All study procedures performed at baseline will be repeated at the 3- and 6- month 
visits with the exception of the muscle biopsy that will be performed at baseline and at 
the 6-month visit. Disease severity and disease progression will be assessed at each 
visit by measuring PSA level, and assessing stage, histologic grade (Gleason score 
and pattern) metastatic volume, secondary therapy, and castrate sensitivity status. 
Other clinical parameters to be captured will include demographics, comorbidities, and 
medication use. These parameters will be used as covariates in the analyses 
performed. Adverse events will also be recorded at the 3- and 6- month visits. 
 
Study procedures listed here may occur on multiple days per the patient’s 
availability. Patients may be exempt from completing some study procedures due 
to physical inability from disease/treatment-related symptoms. Determination of 
these exemptions will be left to the discretion of the study personnel. 
 
Subjects' medical records will be monitored for up to 5 years to assess for the 
development of complications (tumor progression, chemo response, hospital 
admission) and for survival. 
 
Risks associated with study procedures: 
-Blood Drawing: The risks of blood drawing include pain, bleeding, and/or a 
bruise where the needle was inserted. Serious complications such as blood clots 
or infection are very rare when proper precautions are taken. 
-DXA Scan: While we do not know whether any dose of radiation is completely 
safe, this amount of radiation is well within the limits considered safe by federal 
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and state regulations. The total amount of radiation used will be extremely 
small—approximately 0.04 milli-rem per examination or 1 milli-rem (0.001 mSv) 
total and less than one-tenth the dose of a standard chest x-ray, and less than a 
day's exposure to natural radiation.  X-rays in the diagnostic range for these 
exams are expected to have no side effects. 
 
-VO2 peak: risks include abnormal heart beats, abnormal blood pressure 
responses, muscle cramps, muscle strain and/or joint injury, delayed muscle 
soreness (1 to 2 days afterwards), light headedness, fatigue, and in rare 
instances, heart attack. This test will be performed under the direct supervision of 
a trained physician in the hospital where rapid access to emergency personnel 
and equipment including a crash cart, ECG, vitals assessment is available. 
 
-Muscle Biopsy: The risks of muscle biopsy include pain, bruising, infection, 
bleeding (including rare bleeding requiring further intervention), and/or hematoma 
where the biopsy needle was inserted. 
 
-Loss of confidentiality: The risks are deemed minimal and all necessary 
precautions as required by the IRB and VA R&D committee will be taken. 
 
-Functional Performance: There is a small risk of incurring injury during 
assessment of muscle performance. This risk will be minimized by properly 
instructing the participants, and by performing these tests under direct 
supervision of experienced research personnel. 
  
-MRS & OS: Some people may feel claustrophobic when in the MRS or feel 
uncomfortable while remaining still and holding the same position during the session. 
This will disappear soon after getting up and walking around once MRS is done. There 
are no known risks to breathing more oxygen than normal for the short periods of time 
we use in these experiments for OS. Breathing rate may speed up a little while breathing 
more oxygen than usual.  This will return to normal when the patient begins breathing 
standard room air. There may be discomfort when the blood pressure cuff is inflated 
including numbness or tingling, and the area under the cuff may ache. This is often 
done by doctors during surgery and there are not known side effects of these 
discomforts. For people who are more likely to develop blood clots, we do not know if 
having the pressure cuff inflated for several minutes at a time will further increase the 
risk of forming a blood clot. Patients will be given a handout with information about deep 
vein thrombosis. The exercise may induce muscular fatigue which will disappear soon 
after exercise is stopped.  There may be some mild muscular soreness for a day or two 
after the exercise.  This is a normal response that disappears on its own. 
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Fasting risks:  You may feel hungry or dizzy or have some stomach discomfort from 
not eating on the days you have to fast before your visit.  If you are a frequent coffee 
drinker, you may experience discomfort or headache from not having any caffeine. If 
you normally use nicotine products, you may feel the effects of not having nicotine in 
your system.  
Data and blood specimen banking will be done at the VAPSHCS Cachexia 
Tissue Repository. This is a new bank under this PI.  
 
5.2 Recruitment Methods 
We expect subjects to be recruited from the VA Urology clinic through Dr. Dash 
and his team.  Patients will be identified via chart review (pre-screening). A full 
medical history is needed to determine if the subject meets enrollment criteria 
and to analyze variables that might influence outcomes measured. This will 
include medical problems, treatments, and medications. The subject's private 
health information that will be needed for this study is as follows:  full medical 
history, name, date of birth, social security number, demographics, age, 
telephone number, and home address. The PI's relationship to the subject will be 
investigational. 
 
5.3 Informed Consent Procedures 
1-Study staff identifies potential participants from Urology clinic via medical records,  
2-Study staff reviews records to ascertain initial inclusion/exclusion criteria,  
3-Study staff sends list of potential subjects to clinical staff,  
4-Clinical staff brings up potential research study to patient at clinical visit and asks if 
they’re interested in learning more,  
5-Study staff then speaks with patients to provide more information,  
6-If subject is interested they sign a consent form,  
7-Study procedures are initiated (i.e. Screening visit) 
 
Patients will be assured of the voluntary nature of the trial and a member of the 
research staff will be available to answer all questions regarding the study. We will 
emphasize that their decision to participate in the clinical trial will not affect their 
treatment.  
 
A waiver of consent is requested for identification/pre-screening. The use or disclosure 
of PHI involves no more than minimal risk to the individuals and the waiver will not 
adversely affect the privacy rights and the welfare of the individuals. The risk is minimal 
because: 1) only trained personnel will have access to this information, 2) information 
will be accessed only from our research office at the VA and kept in a locked cabinet 
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behind locked doors or in password-protected computers and 3) only information 
absolutely required for research will be obtained and recorded.  
 
The research could not practicably be conducted without this waiver and could not 
practicably be conducted without access to and use of the PHI because accessing 
potential subjects’ medical records and their last 4 digits of their SSN and name is 
required to approach them to explain the proposed research and consent them. 
 
All study personnel are trained regarding human subjects’ protections 
requirements and how to obtain and document informed consent as it is required 
by local and Federal VA guidelines. 
 
5.4 Inclusion/Exclusion Criteria 
Inclusion Criteria:  
-Patients with histologically, cytologically or image based documented advanced or 
metastatic PCa initiating ADT with expected continuous treatment for a minimum of 6 
months 
-Willing/able to provide informed consent. 
 
Exclusion Criteria:  
-Other causes of sarcopenia such as: Liver disease (AST or ALT ≥3x normal levels)  
-Renal failure (creatinine ≥2.5 mg/dL)  
-Untreated thyroid disease  
-Class III-IV congestive heart failure (CHF) 
-AIDS  
-Other cancer diagnosed within the past five years other than non-melanoma skin 
cancer 
-severe chronic obstructive pulmonary disease (COPD) requiring home O2 
-An active, uncontrolled infection or cardiovascular disease including a recent 
myocardial infarction (MI), Cerebrovascular accident (CVA), arrhythmias or unstable 
angina (< 6 months) 
-Uncontrolled diabetes (HbA1c ≥9%) 
-Neuromuscular disorder contributing to sarcopenia 
–Current use (within one month) of investigational agent or testosterone, high dose 
steroids (20 mg of prednisone/day ≥1 month), megestrol, or anticoagulants 
-Previous treatment with ADT other than oral anti-androgen at initiation of ADT.  
 
5.5 Study Evaluations 
Body composition will be measured by dual energy fan-beam DXA scan. DXA 
scan uses low-doseradiation to determine fat mass, bone mass, and fat-free 
mass (whole body and segmental). Fasting is required 
 
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Functional performance will be assessed as follows: HGS, SCP, 6MWT, VO2 
peak, and actigraphy. HGS and SCP have been shown to correlate with VO2 
peak and are good tests of aerobic and functional capacity in cachectic states. 
HGS will be measured by a handheld dynamometer (Jamar Hydraulic 
Dynamometer, J.A. Preston Corp., Clifton, NJ). SCP, which allows measuring the 
maximal anaerobic power of the involved muscles, will be performed as follows: 
subjects will climb up ordinary stairs at the highest possible speed, according to 
their capabilities. The stairs will consist of 13 steps of 15.3 cm each, thus 
covering a total vertical distance of 1.99 m. An experimenter will measure the 
time employed to cover the test with a digital stopwatch. Anaerobic power (in 
Watts) will be calculated by using the following formula: “(body mass x 9.81 x 
vertical distance)/time” where body mass, vertical distance (i.e., 1.99 m) and time 
are expressed in kg, m, and s, respectively, and 9.81 m/s2 represents the 
acceleration of gravity (2–3 practice trials will be allowed so that the subjects 
gains a good control of the performing technique). In a 6MWT, the staff will ask 
subjects to walk for 6 minutes in a hallway at the facility and the distance will be 
recorded. For the VO2 peak test, participants will be instructed to put on a 
mask/mouth piece with a breathing valve to collect expired gases. Participants 
will be instructed to use hand signals to notify researchers about the need to stop 
the test. Participants will then be asked to pedal an exercise cycle at 
progressively harder workloads. The test will continue until the subject becomes 
fatigued and decides to stop, or other symptoms prohibit further exercise. Fasting 
is required for the VO2 peak test. Participants may be asked to rate their 
perceived exertion during the test using the Borg Rating of Perceived Exertion 
Scale. Actigraphs will be mailed to patients ahead of their visit, information will be 
recorded for 7 days and collected at their visit day. The devices will be worn by 
the subjects on the wrist and trained research coordinators will demonstrate its 
use and provide subjects with instructions in person as well as in writing. Data 
from returned monitors will be downloaded with companion software and 
analyzed for activity counts, daily steps, and estimates of energy expenditure. 
 
Questionnaires: The FACT-P, EORTC QLQ-30, and EPIC-Hormonal 
questionnaires/scales will be administered to assess changes in symptoms that 
play a role in performance such as fatigue. 
 
Muscle biopsy: The purpose of the sample collection is the following: histologic 
analysis and measurement of inflammatory, anabolic, and catabolic markers, in 
addition to assessment of muscular mitochondrial function. Muscle biopsies will 
be taken from the vastus lateralis. After anesthetizing the skin and muscle fascia 
with 2% lidocaine, a 1-cm incision will be made, where ~300 mg of muscle tissue 
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will be removed by using a 5mm biopsy needle.  After the procedure is 
completed, pressure is applied for 5-10 minutes to establish hemostasis, the 
incision is closed with Dermabond, and the leg is wrapped in an ace bandage.  
Subjects are asked to remain supine with leg elevated for 20 minutes.  Subjects’ 
blood pressure will be rechecked before allowing to stand up. Subjects will be 
given post care instructions including a telephone number in case of problems 
related to the procedure. 
 
Blood draw (fasted morning sample): The purpose of the sample collection is 
the following: 60mL sample for safety labs, inflammatory/cytokine profile, 
anabolic markers, and anabolic and sex hormones. Blood and muscle samples 
will be stored in a -80o freezer in the PI laboratory for no more than 5 years. The 
samples will be kept to allow time for analysis of the data. De-identified samples 
will be shared only with co-investigators listed in the IRB. The sample will be 
discarded after 5 years. If a subject withdraws from the study, they will not have 
the option to get the remaining portion of their sample back. Samples will be 
retained if a subject revokes authorization; however, in such as case, those 
samples will be stripped of identifiers and no code linking subject’s identity to the 
sample will be kept.  
 
MRS & OS: Patients’ quadriceps muscle will be imaged using MRS while in a 
relaxed state and while contracting at various levels of effort. MRS and OS will 
also involve non-invasive imaging during an ischemic state while wearing a 
compression cuff and during reperfusion after the cuff is released.  
 
5.6 
Data Analysis 
We will include 60 subjects (n=60). This is a pilot and exploratory study. The data 
generated through this trial will be used to power a future, larger clinical study 
and grant submissions. The sample size has been estimated based on the 
availability of subjects. 
 
All variables will be summarized descriptively by treatment using non-parametric 
statistical methods including N, median, SEM and standard deviation. When 
appropriate, analyses will be done using Kruskal-Wallis for continuous variables with 
Bonferroni's adjustments for multiple comparisons and chi-squared for categorical 
variables. Appropriate transformations will be applied to the outcome changes to 
improve distribution toward normality. The relationship between physiologic and 
histologic parameters, anabolic and catabolic markers, and sarcopenia will be 
established. 
  
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Potential confounding factors are, body weight at diagnosis, age at diagnosis, and 
presence of COPD or other co-morbidity. We will adjust for potential confounding 
factors by including them in the analysis. To determine whether there is a significant 
correlation between the histology, biomarkers, physiometry, and body composition each 
parameter will be compared by linear regression. 
 
Full disclosure and complete description of all endpoints will be included in public 
presentations of data to avoid bias. Safety, including adverse events, will be 
summarized descriptively by group.   
 
5.7 Withdrawal of Subjects 
It is unlikely that subjects will be withdrawn without their consent. This may happen if 
regulatory authorities (VA) decide to terminate the study. Participation is completely 
voluntary and patients may withdraw from this study at any time without any negative 
consequences or penalty for study withdrawal. To withdraw, patients will be instructed 
to advise study staff directly by calling the number in the consent form. Subjects will not 
have the option to get the remaining portion of their sample(s) back. Samples will not be 
destroyed but the sample will be kept anonymously and used for analysis.  
 
 
6 Reporting 
 
Clinical research information will be collected in case report forms that will be 
kept under double lock at the research site in accordance with local and Federal 
guidelines. Information collected will include an assessment of adverse events 
(AE) at each visit after enrollment in the study.  
 
Dr. Cyrus Zabetian is a neurologist and researcher who will be the monitor for this study. Dr. 
Zabetian will only serve in a monitoring capacity and will not be engaged in research. Dr. 
Zabetian will meet the monitoring criteria as follows per DOD guidelines below: 
 
Research monitor functions will include:  
 
• reviewing monitoring plans and UPIRTSO reports 
 
• overseeing data collection and analysis  
 
In addition, the research monitor:  
 
• may discuss the research protocol with the investigators, interview human subjects, and 
consult with others outside of the study about the research;  
 
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• shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report; 
Version: 15 April 2013 Page 4 of 7  
 
• shall have the responsibility to promptly report their observations and findings to the IRB 
or other designated official and the HRPO.  
 
The study coordinators will send Dr. Zabetian a detailed study report annually for his review. 
All AE/SAE’s will be reported to IRB by study staff as required following IRB guidelines. 
 
 
Adverse Event Management 
Any untoward or unfavorable event occurring following enrollment in the study 
and until conclusion of the study procedures will be considered an AE. A 
worsening of a pre-existing condition will be considered an AE as well. A pre-
existing condition which occurs with a known temporal frequency and severity 
(e.g., dysmenorrhea) will not be considered an AE unless the pattern or severity 
has changed.  
 
Seriousness: A serious adverse event (SAE) is any AE that results in: death, 
permanent or significant disability, hospitalization or a prolongation of an existing 
hospitalization; a congenital anomaly/birth defect; or is otherwise medically 
alarming.  
Severity: All adverse events will be rated according to the National Cancer 
Institute (NCI) Common Toxicity Criteria (CTCAE v4.0).  
 
Relationship to Study Procedure: All AE will be assessed by the Investigator to 
establish the presumed causal relationship with the study procedure considering: 
a) Temporal relationship, b) Pattern consistent with known effect of the 
intervention, and c) Presence of other potential etiologies.  AE will be assigned 
one of the following causal relationships: a) Unrelated (The study procedure 
almost certainly did not cause the event); b) Probably not related (It is more likely 
that the event is due to another etiology than due to the study procedure), c) 
Possibly related (It is equally likely that the event is due to the study procedure 
as it is due to another etiology), d) Probably related (It is more likely that the 
event is due to the study procedure than due to another etiology) and e) 
Definitely related (the evidence is compelling that the study procedure caused 
the AE). 
 
Monitoring Adverse Events: Subjects will be monitored for the onset of AEs 
throughout the course of the study. Any ongoing AE will be assessed at 
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appropriate frequency to document the date and time of resolution of the event. 
All events will be followed to resolution. Certain AEs (e.g., a cerebrovascular 
accident) will not be expected to resolve completely; in these cases, the date and 
time will be recorded when the event reaches its new, stable equilibrium and any 
remaining residua of the event will be documented. All AEs will be followed until 
resolution or until stable in cases where permanent sequelae are expected. 
All SAE will be reported to IRB with appropriate forms per IRB regulations (within 
5 days of study staff becoming aware), all other AEs will be reported to IRB 
annually. 
 
 
7 Privacy and Confidentiality 
 
Data collected in this VA research study, including identifiers, will be maintained 
for no more than 5 years by the VA facility. All study documents containing PHI 
will be kept in a locked cabinet inside a locked room (in Dr. Garcia’s research 
office 1/815) or behind VA firewall on VA password-protected computers on Dr. 
Garcia’s secured research drive. No data containing PHI will be accessible 
outside the study site. The room is kept locked with the door shut. No subject 
data is left out of the cabinets. Confidential information will be stored on servers 
managed and maintained by the VA-IT program. 
 
Lab technicians will be provided the subject study number in person when study 
staff accompany the patient to the TCMI lab. All paper and electronic data 
generated at UW for study purposes will be securely held in HSB AA025 in the 
TCMI. 
 
An adequate plan exists to protect health information identifiers from improper use and 
disclosure to minimize the risk of loss of confidentiality as recommended by VA 
guidelines. No social security numbers will be requested from subjects or potential 
subjects via phone Adequate written assurances exist in order to ensure that the PHI 
will not be reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other research for 
which the use or disclosure of the PHI would be permitted under the Privacy Rule to 
minimize the risk of loss of confidentiality as recommended by VA guidelines. 
 
The PI, VA collaborators, and his research staff, and VA research compliance 
monitors will have access to identifiable information. People who ensure quality 
from the institutions where the research is being done, federal, and other 
regulatory agencies will have access to all of the research data. No one else will 
VA Puget Sound IRB Approved 
01/17/2019

[Version 4, 1/11/19]  
VA Puget Sound IRB Protocol Template – Version: 2/2015 
Page 17 of 17 
 
have access to identifiable research data. An Accounting of Disclosure will be 
created and maintained for any disclosure of individually identifiable information 
outside the VA. The manual spreadsheet will include the date of the disclosure, 
nature or description of the individually identifiable information disclosed, purpose 
of each disclosure and the name and address of person or agency to which the 
disclosure was made. 
 
8 Communication Plan 
This is a single center study. All SAEs will be reported within 5 business days of 
study staff becoming aware of the incident the IRB. 
 
9.0      Information Security and Privacy 
Loss of confidentiality: The risks are deemed minimal and all necessary 
precautions as required by the IRB and VA R&D committee will be taken. Loss of 
confidentiality risks will be minimized by ensuring all personnel is properly trained 
in information security and by keeping all information secured inside locked 
cabinets in locked rooms inside the VA and on secure computer servers 
maintained by VA IT. 
 
Data collected in this VA research study, including identifiers, will be maintained 
for no more than 5 years by the VA facility. All study documents containing PHI 
will be kept in a locked cabinet inside a locked room (in Dr. Garcia’s research 
office 1/815) or behind VA firewall on VA password-protected computers on Dr. 
Garcia’s secured research drive. No data containing PHI will be accessible 
outside the study site. The room is kept locked with the door shut. No subject 
data is left out of the cabinets. Confidential information will be stored on servers 
managed and maintained by the VA-IT program. 
 
Lab technicians will be provided the subject study number in person when study 
staff accompany the patient to the TCMI lab. All paper and electronic data 
generated at UW for study purposes will be securely held in HSB AA025 in the 
TCMI. 
 
No social security numbers will be requested from subjects or potential subjects 
via phone. 
 
 
10.0 References 
 
1. Shanely, J Vis Exp 2014 
VA Puget Sound IRB Approved 
01/17/2019