Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
Phase: PHASE1
Conditions: Rheumatologic Disease
Sponsor: VA Office of Research and Development

Protocol Summary (ERICA) 
 
IRB_00038705 
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IRB Approval 12/15/2020 
 
 
Systemic sclerosis (SSc) vasculopathy: Improved clinical 
monitoring and treatment 
 
Protocol Summary 
 
 
 
IRB Approval 
Date of 
Current 
Version: 
12/15/2020 
University of 
Utah IRB #: 
IRB_00038705 
Sponsor: US DEPARTMENT OF VETERANS AFFAIRS 
  
Principal 
Investigator: 
Tracy Frech 
Internal Staff 
and  Sub-
Investigators: 
Site Name 
Staff Names 
Veterans Affairs SLC Health Care 
System (VAMC) 
Tracy Frech 
 
Jordan Tucker 
 
Jessica Gonzalez 
 
Jennifer Godina 
 
Anthony Donato 
 
Samuel Bloom 
 
Kathryn Peterson 
 
Martha Finco 
 
Nadia Grant 
 
Julieanne Hall 
University of Utah 
Tracy Frech 
 
Melodie Weller 
 
Jordan Tucker 
 
Kalani Raphael 
 
Jessica Gonzalez 
 
Jennifer Godina 
 
James Fang 
 
Mary Scholand 
 
Joseph Allen 
 
PATRICE MIMCHE NSANGOU 
 
Eric Tuday 

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Andrew Gawron 
 
Sally Ibrahim 
 
Anthony Donato 
 
Samuel Bloom 
 
Kathryn Peterson 
 
Maureen Murtaugh 
 
Martha Finco 
 
Nadia Grant 
 
Julieanne Hall 
 
John Ryan 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 

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Background and Introduction 
 
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by multi-organ 
vascular alterations (vasculopathy) with subsequent varying degrees of fibrosis. It is a 
devastating autoimmune disease with limited therapeutics available. While both genetic and 
environmental factors are recognized as important in pathogenesis, much work needs to be 
done to characterize these effects in the setting of a heterogeneous clinical phenotype. 
 
 
 
Purpose and Objectives 
 
This study is being done to try to find out the causes of systemic sclerosis which is an 
autoimmune condition associated with changes to blood vessels (vasculopathy) and abnormal 
scarring (fibrosis) of skin, lungs, heart, gastrointestinal tract, and kidneys. We want to 
determine if there is a gene responsible for this disease, and we are interested in finding 
biomarkers (a biochemical characteristic that can be used to measure the progress of disease or 
the effects of treatment) that will help doctors predict who is at risk for developing lung, 
kidney, and gastrointestinal vasculopathy and fibrosis manifestations of this disease, and how 
best to treat them. 
 
 
 
Study Population 
 
Age of Participants: 14-17 yo and 18+ 
 
Sample Size: 
At Utah: 
850  
All Centers: 
850 
 
Inclusion Criteria: 
A diagnosis of systemic sclerosis. 
We will include age cohort 14-17 to our already approved 18+ cohort 
  
Family members of patients with a diagnosis of systemic sclerosis to be used as a control 
group. 
Additionally, disgarded clinical forearm skin biospy specimens (de-identified) will used for 
comparison. 
Number of participants: 
University of Utah: 

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Affected: 500 
Controls: 300 
VA: 50 total 
 
 
Exclusion Criteria: 
None 
 
 
Design  
 
Prospective Biomedical Intervention or Experiment 
 
 
Serum, biopsy tissue and DNA collection and storage. 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
Dr. Frech will identify affected participants during the patients routine care visits from her 
scleroderma clinic, the general rheumatology clinics, or as an inpatient at the University of 
Utah and George E. Wahlen VA.  Dr. Frech and sub-investigators will also identify healthy-
control patients during routine care visits from the general rheumatology clinics at the 
University of Utah and George E. Wahlen VA.  We plan to enroll healthy controls from 
families of consented and enrolled affected subjects.  We will ask affected subjects if they 
want to approach friends or family members about participating as control subjects.  If 
affected subjects decide they want to approach friends or family members, they will be 
instructed to give interested individuals an ICF and to have each interested person individually 
contact study staff to discuss the study and their participation.  Those interested in 
participating will have their own separate study visit. 
Dr. Gourh will use the analysis from the UPDB to help detect genetic relationships in SSc and then analyze DNA from certain 
pedigrees. Dr. Pravitt Gourh may be involved in evaluating and examining the SSc patients at the University of Utah Hospital 
and Clinics. He may interview the family members and, if needed, examine them at the University of Utah Hospitals and 
Clinics. Dr. Gourh will also be involved in reviewing identifiable data from patients and their family members that may have 
already been collected and stored in the study.  
Dr. Gourh is an NIH fellow that is using his funding to better understand the genetic risk of SSc. With his help, this project 
will be funded. 
Dr. Gourh will not conduct any research at the VA Medical Center and will not have access to any information obtained at the 
VA.  
All study procedures and assessments will be performed at both the University of Utah and the 
George E Wahlen VA with the exception of the whole genome or exome sequencing. Dr. 
Pravitt Gourh from the NIH will not examine or see patients from the VA or collect any 
specimens from VA participants. 

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Informed Consent: 
Description of location(s) where consent will be obtained:  
University of Utah Medical Center Rheumatology Clinic 2 and at the George E. Wahlen VA 
Medical Center Internal Medicine Clinic 
 
Description of the consent process(es), including the timing of consent:  
No formal waiting period, unless requested by participant. Patients will be consented by Dr. 
Frech or her designated research staff. Consent form will be thoroughly reviewed with the 
patient and the patient will be given the opportunity to ask any questions. No study procedures 
will be performed prior to obtaining consent. The ICF will be signed by both parties and the 
patient will be given a copy for their records.  
 
Requested Waivers/Alterations of Consent: 
Waiver of Informed 
Consent 
We request a waiver of consent for those participants who have 
already been consented to this study. Patients in this study 
have already consented to genetic research with the aim of 
improving the understanding the role of genetics in 
scleroderma. Linking patients to IRB# 31854 will allow 
additional scleroderma  pedigrees to be created that assess 
potential links between scleroderma and other diseases. This 
will be a valuable tool and is consistant with the stated aims of 
the study. If/when participants are re-contacted for any further 
studies requiring face to face contact for this study, reconsent of 
participants will happen at that time. 
Waiver of Informed 
Consent 
We request a waiver of consent for patients who have already 
been consented to IRB#38705.  Patients in this study have 
already consented to genetic research with the aim of improving 
understanding of the role of genetics in scleroderma. Linking 
patients to pedigrees created by IRB#31215 will be a powerful 
tool in achieving this aim and is consistent with the stated aims 
of the study. If/when participants are re-contacted for any 
further studies requiring face-to-face contact for IRB #38705 or 
#31215, re-consent of participants will happen at that time 
Waiver of Informed 
Consent 
The purpose of this waiver is to collect disregarded forearm 
specimens for comparison to forearm specimens of scleroderma 
patients. 
 
Procedures: 
SSc participants and the controls (family members) will be identified from clinic (Clinic 2, 
SSc clinic, VASLCHSC).  If they are 18+, they will have serum drawn and biopsy performed 
in clinic. If they are part of the 14-17 yo cohort, they will only have a blood draw. 
STUDY PROCEDURES 
Baseline and Follow-Up Visits 

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No study-related procedures will be performed until patients have signed this consent form 
and agree to take part in this study.  
Baseline Visit 
This Baseline Visit will be scheduled to coincide with one of  routine care visits.  During this 
Baseline Visit the following procedures will be performed: 
• Provide a complete medical history, family medical history and review past and current 
medications. This information will be obtained from medical records and questions 
answered by the patient. Examples of the types of records we may review include but 
are not limited to routine echocardiograms, pulmonary function tests, upper and lower 
endoscopy reports, pathology reports, questionnaires, blood work (such as 
chemistries), stool studies, radiographic images, diet or symptom diaries, and urine 
analyses. This information we obtain for this study will only be collected if it was 
performed as a procedure/assessment as part of a patient's standard of care visit; 
• Have a physical exam with height, weight, and vital signs measured (such as blood 
pressure, heart rate, etc).  These procedures are routine and normally performed during 
a routine care visit; 
• Provide routine blood and urine samples that will be tested for clinical assessment and 
disease activity.  These samples are normally collected for routine care; 
• We may collect research-related blood samples including a DNA blood sample.  The 
DNA sample will only be collected one time during the course of this study. If a DNA 
blood sample is not collected at the baseline visit, it may be obtained at the next 
available follow up visit. These samples may be collected for study-related purposes, 
and would not be collected for routine care.  These samples are in addition to the 
samples collected for disease activity.  No more than 5 tablespoons of blood (includes 
blood drawn for routine and study-related purposes) will be collected for this visit; 
• We may ask for a skin biopsy. Biopsy specimens may provide key information about 
the causes of scleroderma. Family members and friends that agree to take part in this 
study, as part of the control group, may also be asked to provide a skin biopsy to use as 
a comparison to affected skin. Patients would not have this skin biopsy procedure as 
part of your routine care and this would be performed for study purposes only.  Dr. 
Frech will collect two 3-4 millimeter biopsies using a punch biopsy instrument; 
• Complete several questionnaires that will ask the patient to assess the impact of 
scleroderma on their quality of life and their physical and mental health. This will take 
about 20 minutes to complete. Participants will be asked to complete these 
questionnaires for the study and would not normally be asked to complete 
questionnaires during a routine care visit; 
• Have other tests that may be ordered by your doctor for routine care.  
Follow-Up Visits 
Participants will be asked to return for first follow-up visit six months after the 
Baseline Visit, and then for a follow-up visit every six months thereafter for the 
duration of the study. Every effort will be made to have follow-up visits coincide with 
routine Rheumatology care visits. Visits are piggy-backed on standard of care, 

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participants will be seen when their visits correlate with their standard of care visits. If 
participant is not seen every six months we will capture study data when the participant 
returns to clinic.  
During the Follow-Up Visit the following procedures will be performed: 
• Review  health and medication (s) for changes since the last visit. We would normally 
collect this information during a routine care visit.This information we obtain for this 
study will only be collected if it was performed as a procedure/assessment as part of a 
patient's standard of care visit; 
• Have a physical exam with height, weight, and vital signs measured (such as blood 
pressure, heart rate, etc).  These procedures are routine and normally performed during 
a routine care visit; 
• Provide routine blood and urine samples that will be tested for clinical assessment and 
disease activity.  These samples are normally collected for routine care; 
• We may collect research-related blood samples. These samples will be collected for 
study-related purposes, and would not be collected for routine care.  These samples are 
in addition to the samples collected for disease activity.  No more than 2-4 tablespoons 
of blood (includes blood drawn for routine and study-related purposes) will be 
collected per visit; 
• We may ask for a skin biopsy. Biopsy specimens may provide key information about 
the causes of scleroderma and may be collected up to three more times during your 
study participation. Patients would not have this skin biopsy procedure as part of their 
routine care and this would be performed for study purposes only.  Dr. Frech will 
collect two 3-4 millimeter biopsies using a punch biopsy instrument. 
• Complete several questionnaires that will ask the patient to assess the impact of 
scleroderma on their quality of life and their physical and mental health. This will take 
about 20 minutes to complete. Participants will be asked to complete these 
questionnaires for the study and would not normally be asked to complete 
questionnaires during a routine care visit; 
• Have other tests that may be ordered by your doctor for routine care. 
Questionnaires 
Patients will be asked to complete questionnaires in-person at every study related visit as 
described above. If they would like to complete them electronically, they will have the option 
to provide the research staff with an email address. The electronic version of the 
questionnaires are identical to the paper version but will be made available through a link 
provided in an email and will allow patients access to a study portal called “REDCap” 
from their smart phone, mobile device or computer. Patients may switch between completing 
the questionnaires using the study portal or the paper version. 
If you they the study portal to complete the questionnaires electronically, the email they 
receive will provide instructions on how to utilize the portal. The email address they provide 
to the study team will be used solely for the purpose of sending a link and instructions. It will 

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not be shared or disclosed in any other matter. Additionally, standard data rates that apply will 
be their responsibility. 
Other examinations 
Other examinations that may be performed at both baseline and follow-up visits include 
peripheral nerve testing and a nailfold capillary exam. The nailfold capillary exam is a simple 
and non-invasive test that uses a special microscope to look at the capillaries along the 
nailbed. This test can help determine any vascular changes or abnormalities associated with 
Raynaud’s phenomenon and/or SSc. The peripheral nerve test is also a simple and non-
invasive exam that assesses specific nerves and senses by placing the tip of a tuning fork on to 
certain extremities such as your toes and legs to see if patients can sense vibrations. 
We may also measure blood flow in patients with SSc and their family members. Blood flow 
will be measured with an ultrasound machine. This is a non-invasive procedure. A blood 
pressure cuff will be wrapped around the forearm or around the lower leg. Gel will be applied 
on the area of the arm or leg that will be used for measuring blood flow. The blood pressure 
cuff will be inflated to 250 mmHg, the upper end of the normal inflation range, for five 
minutes to stop blood flow of the artery that will be examined for change in diameter upon 
cuff deflation using the ultrasound machine. This procedure is referred to as the measurement 
of flow-mediated vasodilation (FMD). Since obstructing the blood flow for five minutes may 
be painful for some individuals it should be noted that if patients wish to stop this test at any 
point during the measurement the research personnel will do so. This assessment may take 
about 30 minutes and will be performed at every study visit. 
Another blood flow measurement may be collected by taking an image of the vessels under the 
tongue (sublingual) using a specific type of camera called a Laser Speckle Imaging (LSI) 
device. Patients will be asked to hold their mouth open wide and place the tip of their tongue 
on the roof of their mouth for a couple of minutes while the doctor captures images of the 
blood vessels under the tongue. This procedure is non-invasive and will take approximately 5 
minutes. 
Peripheral nerve testing, nailfold capillary exam, flow mediated dilation and sublingual 
imaging. These examinations will only be performed on the adult (18+) participants. 
If patients undergo any assessments, procedures, or treatment as part of their routine care for 
digital ulcers and/or hand contractures, we ask that we be allowed to obtain records and 
information related to this care and use the data as part of this study to learn more about 
vasculopathy and fibrosis. 
If an adverse event occurs (ie, bruising, bleeding) then it will be addressed in clinic. 
After subjects at the University of Utah are identified through these sources, patient PHI 
(names, dates of birth, gender, and phenotypic information) will be passed to the Genetics and 
Molecular Characteristics of Interstitial Lung Disease study (IRB#31215) on which Dr. Frech 
is a co-investigator. Dr. Scholand is the primary investigator on IRB# 31215 and a co-
investigator on this study. Subjects from the VA will be excluded in this portion of the study. 

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The information obtained from the control group (unaffected family members) in this 
study will be used in conjunction with IRB study #: 31854- An Improved Definition of 
Hereditability of Systemic Sclerosis (SSc), SSc Overlap Conditions, and Raynaud's 
Phenomenon Through Use of the Utah Population Data Base (UPDB). MRNs from the 
control subjects will be submitted to the UUHSC EDW through Dr. Frech's 31854 project in 
order to obtain UPDB numbers. This information (from controls only) will then be used to 
perform a kinship analysis under 31854 for SSc data identified from the University of Utah 
Health Sciences Center. Dr. Frech oversees both projects as the PI. Please refer to the study #: 
31854 for further information. 
The study will utilize the Master Subject Index that links the demographic records from the 
UUHSC EDW to the UPDB under IRB_00045234, Master Subject Index between the Utah 
Population Database and the University of Utah Health Sciences Center (Ken Smith, PI). 
All data will remain behind the HSC computer firewall on password protected computers. 
Only associates affiliated with this research project and project #s 38705 & 31215 will have 
access to study information. Any information discussed or shared via email between the 
investigators will be encrypted. 
The study staff for the Genetics and Molecular Characteristics of Interstitial Lung Disease 
study (IRB#31215) will submit the medical record numbers to the UUHSC EDW so that a 
UPDB number can be obtained from the Pedigree and Population Resource, the group that 
manages the UPDB. 
The Pedigree and Population Resource will develop pedigrees as well as link participants to 
any existing pedigrees identified under IRB #31215. All UPDB pedigree data will be stored 
electronically by the Pedigree and Population Resource on their secure server, and may be 
shared with investigators for this trial as well as Dr. Pravitt Gourh, an external investigator for 
this study. 
Pedigree information obtained in the IRB_31854 study will be coded by UPDB number, and 
phi will be removed.  Pedigrees for analysis will retain the UPDB number, diagnoses, 
environmental exposures, other de-identified test data, age at diagnosis, demographic data 
essential for analysis (e.g., gender, race), and pedigree structure.  This data, along with 
molecular data generated on pedigree members, will be shared by Drs. Scholand and Frech. 
The GI biopsy specimens from healthy controls will be identified through Drs. Peterson and 
Gawron during routine endoscopy schedule.  If they have extra tissue from a biopsy in a 
healthy control or irritable bowel specimen that is obtained for medically indicated reasons 
(not study purposes) they may bring the de-identified tissue to Tracy Frech for analysis.  Thus, 
Dr. Peterson & Dr. Gawron will de-identify the patients and it will not be linked to PHI.  The 
only information the investigators will have is that the patient does not have SSc and is healthy 
or has irritable bowel. 
Study participant's family members may also be consented and included in the study as control 
subjects. 

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Whole Genome or Exome Sequencing: Research samples collected as part of this study may 
be analyzed for genetic purposes. In addition to standard genetic tests, we may want to 
perform whole genome or whole exome sequencing of the DNA from affected patients, and 
DNA from the controls if they are willing to provide DNA samples. A detailed description of 
genome and exome sequencing is provided in the ICF. The sequencing would be done by Dr. 
Pravitt Gourh at the NIH. These samples would be shipped to his lab at the NIH in Bethesda, 
Maryland where they would be stored for an undetermined amount of time. This is an optional 
sub-study offered to participants at the University of Utah only. VA participants are excluded 
from this optional sub-study. 
Dr. Frech would like to share some de-identified, limited data sets with Dr. Baron and his 
group at Jewish General Hospital in Quebec, Canada. Dr. Baron's research in SSc mimics the 
data collected by Dr. Frech for the IRB 38705 project. Data would come from the assessments 
& related outcomes collected as part of the 38705 study. The UPDB data that is obtained as 
part of the linked project, IRB 31854, will not be used for this collaboration. 
 
 
Procedures performed for research purposes only:  
Research blood samples in the 14-17 year old cohort. 
Research blood samples and skin biopsies in the 18+ cohort. 
Nail fold capillary exam 
Flow mediated dilation 
Sublingual imaging 
For participants at the VA, the above procedures/assessments will be performed for resear
purposes only and at no cost to the veteran. 
  
 
 
Statistical Methods, Data Analysis and Interpretation 
 
Statistics will be run using SAS version 9.2.  None of the variables will have an 
assumption of normality. SSc patient characteristics will be summarized using 
means and frequencies when appropriate.  General linear models will be used 
to compare age-adjusted characteristics.  T-test will be used to compare 
biopsy outcomes by the patients defined by bivariate clinical 
characteristics.  Spearman correlation will be used to assess clinical and biopsy 
variables. 
 
 
  
 

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