Clinical trial NCT02370784
Conditions: Scleroderma
Keywords: early diffuse scleroderma Raynaud
Sponsor: Robyn T. Domsic, MD, MPH
Start date: 2015-02-01; Completion date: 2019-12-15
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn about the effect atorvastatin on blood vessel function and Raynaud symptoms in patients with early diffuse systemic sclerosis.

Systemic sclerosis is a disease characterized by blood vessel injury, immune system activation and fibrosis. Blood vessel injury is thought to be important early in the disease. Blood vessel complications of systemic sclerosis include Raynaud phenomena, finger and toe ulcers, and pulmonary hypertension. While atorvastatin reduces cholesterol, it is recognized to have many effects beyond cholesterol reduction. These include improvement of blood vessel function and reduction of fibrosis. We hypothesize that treatment with atorvastatin over 16 weeks will improve blood vessel function and Raynaud symptom in patients with early diffuse systemic sclerosis. We hope that by targeting therapy early in the disease we may delay blood vessel changes and improve Raynaud symptoms.

Detailed description:
Systemic sclerosis (SSc) is a multisystem autoimmune illness characterized by vasculopathy, immune system activation and fibrosis of the skin and internal organs. SSc affects approximately 240 people per million in the US, but is a disease for which there is no FDA approved medication. Current hypothesis of pathogenesis suggest that a vascular injury with endothelial dysfunction may be an inciting event contributing to immunologic activation and fibrosis in the pathogenesis of the disease. More than 90% of individuals with SSc have vascular complications including Raynaud phenomenon, digital ulcers or gangrene and pulmonary hypertension; with microvascular abnormalities felt to contribute to Raynaud and digital ulcerations.

Statin medications are well-recognized to have pleiotropic effects which may modify all three aspects of SSc pathogenesis. Early diagnosis and treatment of microvascular endothelial dysfunction and Raynaud phenomeonan may have the greatest effect in early disease. Thus, we hypothesize that treatment with atorvastatin in a well-defined cohort of early diffuse systemic sclerosis will produce beneficial results.

Participants will be patients with early diffuse systemic sclerosis and Raynaud phenomenon who have no history of cardiovascular disease or diabetes. A total of 30 patients will be enrolled and followed for 16 weeks. Half the patients will be randomized to atorvastatin and half to placebo. Patients will be allowed to continue underlying immunosuppressive and Raynaud therapy at stable doses during the trial. Since this is a pilot study, future larger controlled trials will be necessary to clearly demonstrate drug effectiveness. Investigators are hoping that this study will give us signals to guide a future multicenter clinical trial.

Arms: arm 1: atorvastatin 40 mg once daily for sixteen weeks arm 2: receive a placebo of similar appearance once daily for sixteen weeks
Interventions: intervention 1: atorvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy. intervention 2: oral drug of similar appearance to atorvastatin

Protocol documents:
Prot_SAP_000.pdf: 
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THE 
EFECT 
OF 
ORAL 
ATORVASTATION 
ON 
MICROVASCULAR 
ENDOTHELIAL FUNCTION AND RAYNAUD PHENOMENA IN EARLY DIFFUSE 
SYSTEMIC SCLEROSIS (TAMER)  
 
 
Atorvastatin on endothelial function and Raynaud in diffuse scleroderma  
Test drug: 
Atorvastatin 
Study purpose: 
Safety and efficacy 
Clinical study phase: 
II 
Sponsor: 
University of Pittsburgh   
PI:                                      Robyn T. Domsic, MD MPH 
Assistant Professor of Medicine 
Division of Rheumatology and Clinical Immunology  
S726  Biomedical Science Tower 
3500 Terrace St.  
Pittsburgh, PA  15261 
rtd4@pitt.edu  
 
Phone: 412.648.7040 
Fax: 412.648.9643 
 
 
 
 
 


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Synopsis 
 
Title 
The Effect of Atorvastatin on Microvascular Endothelial Function and 
Raynaud in Early Diffuse Scleroderma. 
 
Short title 
TAMER 
Clinical study phase 
II 
Study objective(s) 
The primary objective of this study is to assess the effect of 
atorvastatin therapy on change in microvascular endothelial 
function  
Test drug(s) 
Atorvastatin  
Name of active ingredient 
Atorvastatin  
Dose(s) 
40 mg once daily  
Route of administration 
Oral 
Duration of treatment 
16 weeks  
Reference drug(s) 
Placebo 
Name of active ingredient 
Not applicable 
Dose(s) 
Matching placebo tablets to atorvastatin 40 mg once daily 
Route of administration 
Oral 
Duration of treatment 
16 weeks 
Background treatment 
Not applicable 
Indication 
Early diffuse systemic sclerosis with Raynaud phenomenon  
Diagnosis and main criteria for 
inclusion 
1. Men or women aged 18 years and older 
2. Early diffuse SSc defined as:  
             < 3 years from the first symptom attributable to scleroderma  
             Meeting the 2013 the ACR/EULAR classification criteria 
3. Raynaud phenomenon 
4. No use of lipid lowering medication within 60 days of trial entry.  
5. women of childbearing potential must have a negative serum 
pregnancy test at the screening visit. 
Study design 
Randomized (1:1), double-blind, placebo-controlled, parallel-group, single-
center study  


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Methodology 
This study is designed to investigate the efficacy and safety of atorvastatin 40 
mg once daily in patients with early diffuse SSc on microvascular endothelial 
function and clinical Raynaud symptom.   
Type of control 
Placebo  
Number of subjects 
30 randomized subjects 
Primary variable 
Change in microvascular endothelial function as measured by EndoPAT  
Plan for statistical analysis 
An intention to treat analysis will be performed including all who receive one 
dose of drug. Initial analysis will describe the baseline population, 
sociodemographic and clinical characteristics, and compare by treatment 
group.  Means of continuous measures will be conducted using a t-test or 
Wilcoxon test and discrete measures compared with a chi-square test.  The 
goal of all trial analyses is to provide effect size estimates for design of a later 
phase 3 clinical trial for statin therapy in early diffuse SSc. The means of 
EndoPAT for the two groups will be calculated and a 95% confidence interval 
of the difference of the means will be generated.  A t-test will be used to 
compare the mean levels between the two groups. 
 


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Table of contents 
1. 
Introduction ....................................................................................................................... 7 
1.1 
Background ...................................................................................................................... 7 
1.1.1 
Scleroderma (systemic sclerosis).................................................................................. 7 
1.1.2 
Atorvastatin .................................................................................................................. 8 
1.1.3 
Mechanism of Action ................................................................................................... 8 
1.2 
Rationale of the study ...................................................................................................... 8 
2. 
Study objectives ................................................................................................................. 9 
3. 
Investigators and other study personnel ......................................................................... 9 
4. 
Study design ..................................................................................................................... 10 
4.1 
Design overview ............................................................................................................ 10 
5. 
Study population ............................................................................................................. 11 
5.1 
Eligibility ....................................................................................................................... 11 
5.1.1 
Inclusion criteria ......................................................................................................... 11 
5.1.2 
Exclusion Criteria ....................................................................................................... 12 
5.1.3 
Justification of selection criteria ................................................................................. 13 
5.2 
Withdrawal of subjects from study ................................................................................ 13 
5.2.1 
Withdrawal ................................................................................................................. 13 
5.2.2 
Replacement ............................................................................................................... 14 
5.3 
Subject identification ..................................................................................................... 14 
6. 
Treatment ......................................................................................................................... 14 
6.1 
Treatments to be administered ....................................................................................... 14 
6.2 
Identity of study treatment ............................................................................................. 14 
6.3 
Treatment assignment .................................................................................................... 14 
6.4 
Dosage and administration ............................................................................................. 14 
6.4.1 
Selection of doses in the study ................................................................................... 14 
6.5 
Blinding ......................................................................................................................... 15 
6.6 
Drug logistics and accountability................................................................................... 15 
6.7 
Post-study therapy .......................................................................................................... 15 
6.8 
Prior and concomitant therapy ....................................................................................... 15 
7. 
Procedures and variables ............................................................................................... 17 
7.1 
Schedule of procedures .................................................................................................. 17 
7.1.1 
Tabulated overview .................................................................................................... 18 
7.1.2 
Timing of assessments ................................................................................................ 19 
7.1.2.1 
Visit 0 − Screening .................................................................................................. 19 
7.1.2.2 
Visit 1 − Baseline (Day 0, Week 0) ........................................................................ 19 
7.1.2.3 
Visit 2: 8 weeks ....................................................................................................... 20 
7.1.2.4 
Visit 3: 16 weeks (end of study) .............................................................................. 20 
7.1.2.5 
Premature discontinuation of study drug treatment ................................................ 21 
7.2 
Population characteristics .............................................................................................. 21 
7.2.1 
Demographic .............................................................................................................. 21 
7.2.2 
Medical history ........................................................................................................... 21 
7.3 
Efficacy .......................................................................................................................... 21 


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7.4 
Pharmacokinetics / pharmacodynamics ......................................................................... 22 
7.5 
Safety ............................................................................................................................. 22 
7.5.1 
Adverse events ............................................................................................................ 22 
7.5.1.1 
Definitions ............................................................................................................... 22 
7.5.1.2 
Classifications for adverse event assessment .......................................................... 23 
7.5.1.2.1 
Seriousness ........................................................................................................... 23 
7.5.1.2.2 
Intensity ................................................................................................................ 23 
7.5.1.2.3 
Causal relationship ............................................................................................... 24 
7.5.1.2.4 
Action taken with study treatment ....................................................................... 24 
7.5.1.2.5 
Outcome ............................................................................................................... 25 
7.5.1.3 
Assessments and documentation of adverse events ................................................ 25 
7.5.1.4 
Reporting of serious adverse events ........................................................................ 25 
7.5.1.5 
Adverse events ........................................................................................................ 25 
7.5.1.6 
Adverse events of special safety interest ................................................................. 25 
7.5.1.7   Expected adverse event ............................................................................................ 26 
7.5.1.8  Unexpected adverse reaction ..................................................................................... 26 
7.5.1.9 Pregnancies ................................................................................................................. 26 
7.5.2 
Pregnancy testing ........................................................................................................ 27 
7.5.3 
Vascular Assessments ................................................................................................ 27 
7.5.4 
EndoPAT .................................................................................................................... 27 
7.5.5 
Laser Speckle Contrast Imaging ................................................................................. 28 
7.5.6 
Brachial FMD ............................................................................................................. 28 
7.5.7 
Exploratory Biomarkers ............................................................................................. 28 
7.5.8 
Raynaud’s attacks assessment .................................................................................... 28 
7.5.9 
Digital ulcer assessment ............................................................................................. 29 
7.5.10 Patient-Reported Outcomes (PROs) / Health-Related Quality of Life (HRQoL) 
questionnaires ............................................................................................................. 29 
8. 
Statistical methods .......................................................................................................... 30 
8.1 
General considerations ................................................................................................... 30 
8.2 
Statistical and analytical plans ....................................................................................... 30 
8.2.1 
Demographic and other baseline characteristics ........................................................ 30 
8.2.2 
Efficacy ....................................................................................................................... 30 
8.2.3 
Safety .......................................................................................................................... 30 
8.3 
Planned interim analyses ............................................................................................... 31 
8.4 
Determination of sample size......................................................................................... 31 
9. 
Data handing and quality assurance ........................................................................... 311 
9.1 
Data recording .............................................................................................................. 311 
9.2 
Archiving ..................................................................................................................... 311 
9.3 
Publications .................................................................................................................. 311 
9.4 
Confidentiality ............................................................................................................. 321 
10. Ethical and legal aspects ............................................................................................... 322 
10.1 Ethical and legal conduct of the study ......................................................................... 322 
10.2 Subject information and consent .................................................................................. 322 
11. References ...................................................................................................................... 332 


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List of abbreviations 
 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase (also known as SGPT, qv) 
AST 
aspartate aminotransferase (also known as SGOT, qv)  
ARB 
Angiotensin  receptor blocker 
AUC 
area under the plasma concentration versus time curve 
BMI 
body mass index 
CI 
confidence interval 
CPK 
creatine phosphokinase 
CRP 
C-reactive protein 
DU 
digital ulcers 
EPC 
Endothelial progenitor cell 
EULAR 
European League Against Rheumatism 
FMD 
Flow-mediated dilation 
g 
gram 
GFR 
glomerular filtration rate 
HR 
heart rate 
HRQoL 
health-related quality of life 
ICAM 
 intracellular adhesion molecule 
IDS 
 Investigational Drug Service  
IRB 
institutional review board 
ITT 
intent to treat 
kg 
kilogram 
L 
liter 
LSCI 
Laser speckle contrast imaging 
MD 
medical doctor 
mg 
milligram 
mL 
milliliter 
mmHg 
millimeters of mercury 
mRSS 
modified Rodnan skin score 
NO 
nitric oxide 
PDE 
phosphodiesterase 
PDE5 
phosphodiesterase 5 
RHI 
 reactive hyperemia index 
RP 
s 
Raynaud’s phenomenon 
second 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SHAQ 
Scleroderma Health Assessment Questionnaire 
SSc 
systemic sclerosis 
SUSAR 
suspected unexpected serious adverse reaction 


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US 
United States 
VAS 
visual analog scale 
VCAM 
vascular cell adhesion molecule  
VEGF 
vascular endothelial growth factor 
 
1. 
Introduction 
1.1 
Background 
1.1.1 
Scleroderma (systemic sclerosis) 
Systemic sclerosis (SSc) is an uncommon disease, however has the highest case specific 
mortality of any of the rheumatic disease.   The features of this disease include chronic, 
fibrosing, autoimmune responses characterized by small vessel vasculopathy, autoantibody 
production, and fibroblast dysfunction leading to increased deposition of extracellular matrix.1 
Systemic sclerosis is further divided into two subtypes defined by the extent of skin 
involvement: limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis2.  
According to LeRoy and colleagues, classification to limited or diffuse disease is based on the 
extent of skin tightening3.  In limited disease skin tightening is confined to the fingers, hands, 
and forearms distal to the elbows, with or without tightening of skin of the feet and of the legs 
distal to the knees. Proximal extremities and the trunk are not involved. In dcSSc, the skin of 
the proximal extremities and trunk is also involved. Both diffuse and limited SSc are 
associated with internal organ involvement; however, patients with diffuse SSc are at greater 
risk for clinically significant major organ dysfunction.  
SSc is an orphan disease with an estimated US prevalence of 276 patients /106 4.  
Vascular burden in SSc:  Raynaud’s phenomenon (RP) is an almost universal manifestation 
of SSc, with 95% of all patients being affected.  The burden of SSc-associated vascular 
complications is high, with up to 65% of patients experiencing DU, 10% gangrene or 
amputation, 15% renal crisis, 15%pulmonary hypertension and 17% peripheral vascular 
disease5 6. The progression of microvascular and macrovascular abnormalities in SSc and their 
associated complications are not well described.  Thus, we are unable to predict which 
patients will develop severe vascular complications. Moreover, there are no FDA-approved 
therapies for SSc-associated Raynaud phenomenon and DU. Identifying a therapy that 
diminishes or prevents the progression of SSc vasculopathy and complications would 
significantly improve outcomes, and increase our understanding of the underlying mechanistic 
abnormalities7.  
 
The goal of the current pilot study is to evaluate the efficacy and safety of a 16-week 
treatment with atorvastatin vs. placebo in patients with early diffuse SSc and Raynaud 
phenomenon.   


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1.1.2 
Atorvastatin  
1.1.3 
Mechanism of Action 
Atorvastatin is a HMG coenzyme-inhibitor, which was FDA approved in 1996.  Atorvastatin 
is a hydrophobic statin with the ability to enter endothelial cells and has a long history of 
safety in multiple diseases, including prior use in SSc patients.  Atorvastatin has been shown 
in other rheumatic diseases (rheumatoid arthritis, lupus, Behҫet disease) to improve 
endothelial function and disease activity8-10 and is available in a generic form.   
1.2 
Rationale of the study 
Raynaud phenomenon affects 95% or more of patients with SSc.  Unfortunately, there are no 
drugs approved in US for the treatment of Raynaud phenomenon.  Raynaud is felt to represent 
the earliest signs of microvascular endothelial dysfunction in SSc.      
 
Statins have beneficial pleiotropic effects on the vasculature and may modify all three aspects 
of the SSc disease process. Statins are known to improve endothelial function by increasing 
nitric oxide (NO) production (vasculopathy), down-regulating vascular adhesion molecules 
that subsequently inhibit lymphocyte migration from the vasculature (immune system 
activation)1, and inhibiting overproduction of matrix components (fibrosis)3 11 12. Given these 
mechanisms, statins have the potential to improve vascular dysfunction and abnormalities in 
SSc.   
 
Five small studies have examined the effect of statins on Raynaud and DU with mixed results 
10 13-16 in predominantly later disease SSc, when the vasculopathy may not have been 
amenable to intervention, and have assessed macrovascular endpoints such as brachial flow-
mediated dilation (FMD) for a microvascular disease.   Of the five studies, two small placebo 
controlled randomized trials of atorvastatin.  The lower dose study (atorvastatin 20 mg daily 
for 8 weeks) was negative but used patients with late disease (up to 47 years).  The higher 
dose study (40 mg daily) was positive, but also using late disease patients and found an 
increase in brachial FMD as a positive outcome.  No studies have evaluated the effect of 
statins on microvascular endothelial function in SSc, although this is the primary vasculature 
affected in Raynaud phenomenon and early SSc.  In our preliminary work in early SSc 
patients, arteriole-level microvascular changes appear attenuated by statin use (40% with 
abnormal EndoPAT in statin users versus 100% in non-statin users, p= 0.03).  Based on this, 
we propose that early statin intervention will improve microvascular endothelial function and 
thus reduce Raynaud activity.  
 
Benefit-risk assessment 
There are currently no disease-specific pharmacotherapies approved for Raynaud 
phenomenon.  Considering the mechanism of action and pleiotropic effects of atrovastatin we 
believe the potential benefits of atrovastatin include: 
• Improvement of microvascular endothelial function  
• Decrease severity of Raynaud’s attacks. 


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• Improvement of microcirculatory flow as evaluated by laser speckle contrast imaging 
• Improvement of macrovascular endothelial function as evaluated by brachial flow-
mediated dilation.  
• Taking into account the seriousness of the disease as well as the medical need for an 
effective and safe therapy, on balance the expected benefit to subjects with this 
condition outweighs potential risks. 
2. 
Study objectives 
The primary objective of this study is to assess the effect of atorvastatin therapy on change in 
microvascular endothelial function as measured by EndoPAT technology.   
The secondary objectives of this study are to assess the efficacy and safety of treatment with 
atorvastatin 40 mg once daily as follows:    
Secondary objectives 
• Change in Raynaud symptoms 
• Change in microcirculatory flow assessed by laser speckle contrast imaging 
• Change in macrovascular function assessed by brachial FMD 
• SHAQ and PROMIS 
• To assess serum biomarkers  
• To assess EPCs. 
• To assess nitrite analysis   
3. 
Investigators and other study personnel 
Principal investigator: 
 
 
 
Robyn T. Domsic MD MPH 
 
 
 
University of Pittsburgh 
 
 
 
S726  Biomedical Science Tower 
 
 
 
3500 Terrace St.  
Pittsburgh, PA  15213 
rtd4@pitt.edu 
Research coordinators: 
Dana Ivanco CCRC and Maureen Laffoon BS 
University of Pittsburgh 
 
 
 
S726  Biomedical Science Tower 
 
 
 
3500 Terrace St.  
Pittsburgh, PA  15261 
des2@pitt.edu 
mlaffoon@pitt.edu 
Phone: 412-648-7040 
Fax: 412-9643 
 
Data Manager: 
Mary R. Lucas RN, MPH 
University of Pittsburgh 


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S726  Biomedical Science Tower 
 
 
 
3500 Terrace St.  
Pittsburgh, PA  15261 
Mrl6@pitt.edu 
Study Statisticians:  Balasubramani Goundappa,  PhD and 
 
 
 
Stephen Wisniewski, PhD 
 
 
 
127 Parran Hall 
 
 
 
Pittsburgh, PA  15261 
 
 
 
BalaGI@edc.pitt.edu 
wisniew@edc.pitt.edu 
 
 
External data evaluation bodies 
An independent safety monitor will provide safety oversight.   
4. 
Study design 
4.1 
Design overview 
In this single-center, (1:1), double-blind, placebo-controlled, parallel-group study, a total of 
30 subjects are planned to be randomized (approximately 15 subjects to the atorvastatin group 
and 15 to the placebo group). 
The study design consists of a single 16 week study treatment phase  
• Screening phase:  up to 4 weeks 
• Main Study Treatment phase: 16 weeks of double-blind treatment  
• Termination Visit and Safety follow-up visit: A termination visit and a safety 
follow-up visit will take place for all patients who discontinue study drug or withdraw 
from the study.  
 
Figure 4-1: Study Design 
 
4.1.1 Screening phase (up to 4 weeks) 
After signing the informed consent document, subjects will undergo a screening to include 
baseline labs (creatinine and LFTs) and review of the inclusion/exclusion criteria.  Screening 


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and baseline can occur on the same day if clinical labs (creatinine and LFTs) have been drawn 
as part of routine care within 28 days of the baseline.  
 
4.1.2 Study Treatment phase (Week 0 to Week 16) 
At the baseline (week 0) visit, subjects who have met all of the inclusion and none of the 
exclusion criteria will be randomized using a 1:1 randomization scheme that will be regulated 
centrally through the UPMC IDS.   Each patient enrolling in the study will be assigned an ID.  
At week 0 patients will undergo assessment of Raynaud activity/severity and noninvasive 
vascular imaging.  
Patients will have a visit at week 8 to assess safety, tolerability and adverse effects of the 
study drug.  Raynaud activity/severity and DU will be assessed.   
Patients will have a final end of study visit at week 16 to assess safety, tolerability and 
adverse effects of the study drug.  They will also undergo assessment of Raynaud 
activity/severity and noninvasive vascular imaging. 
Dose Interruptions 
If treatment is interrupted for any reason the following rules should be applied: 
• ≤ 14 consecutive days without treatment it is at the discretion of the investigator if the 
study medication can be restarted 
• >14 consecutive days without treatment: withdraw the subject from study medication. 
4.1.3 Termination Visit and Safety Follow-up Visit 
A termination visit and a safety follow-up visit (30 days after last dose of study medication) 
should be performed for only those patients who withdraw or discontinue study drug before 
the completion of the trial at 16 weeks.  
In all other patients a follow-up phone call at 30 days will be used to assess and follow-up on 
adverse events.   
A detailed schedule of evaluations is presented in Sections 7.1.1 and 7.1.2. 
 
5. 
Study population 
5.1 
Eligibility 
5.1.1 
Inclusion criteria 
Subjects must meet the following criteria to be eligible for enrollment in the study: 
1. Written informed consent 
2. Men or women age 18 -70 years 
3. Systemic sclerosis, as defined by ACR/EULAR 2013 criteria17 with disease duration 
of less than 3 years from the first symptom attributable to SSc.   


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4. Raynaud phenomenon. 
5. No use of lipid-lower medication within 60 days.  
6. Ability to comply with the clinical visits schedule and the study-related procedures 
 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from enrollment in the 
study: 
• Medical and surgical history 
• History of known cardiovascular disease or myocardial infarction 
• History of  stroke  
• Diabetes mellitus 
• Hepatic-related criteria 
• Hepatic insufficiency classified as Child-Pugh C  
• Elevated liver enzymes > two times normal at screening 
• Renal-related criteria 
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 (MDRD 
formula), creatinine > 2.0 mg/dL or history of scleroderma renal crisis at the 
screening visit 
• Known allergy or adverse reaction to atorvastatin or another statin drug 
• Laboratory examinations 
• Subjects with elevated CPK (greater than two times normal) at screening. 
• Prior and concomitant therapy 
• Concomitant use of calcium channel blockers or angiotensin receptor blockers are 
allowed, provided the participant has been on a stable dose for four weeks or 
longer at the time of randomization.   
• Concomitant therapy with prostacyclin analogs.  
• nitrates or NO donors (such as amyl nitrate) in any form, including topical; 
phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as sildenafil, tadalafil, 
vardenafil); and nonspecific PDE5 inhibitors (theophylline, dipyridamole) 
• concomitant use of strong inhibitors of CYP 3A4 to include: clarithromycin, 
protease inhibitors, itraconazole, cyclosporine, gemfibrozil or other fibrates, 
niacin, rifampin, digoxin.   
• Other 
• Pregnant women  or breast feeding women 


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• Women of childbearing potential not willing to use adequate contraception (as 
defined in the aforementioned inclusion criteria, Section 5.1.1) and not willing to 
agree to pregnancy testing at weeks 8 and 16.   
• Smoking or tobacco use within four weeks of screening.  
• Any other condition or therapy that would make the subject unsuitable for this 
study and will not allow participation for the full planned study period 
Note:  One re-assessment of laboratory parameters is allowed during the screening phase to 
re-assess the eligibility of subjects. 
5.1.3 
Justification of selection criteria 
The selection criteria were carefully selected to exclude subjects from the study who may 
potentially be exposed to specific risks after administering the study drug as well as subjects 
with conditions that may have an impact on the aims of this study. 
5.2 
Withdrawal of subjects from study 
5.2.1 
Withdrawal 
Subjects must be withdrawn from the study for the following reasons: 
• At their own request or at the request of their legally acceptable representative 
At any time during the study and without giving reasons, a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result. 
• If serum transaminases are greater than 3 times the upper limit of normal  
• If serum CPK elevations are greater than 5 times the upper limit of normal.  
• If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being 
• Occurrence of AEs or intercurrent diseases which the investigator judges unacceptable 
for continuation of participation in the study 
• Occurrence of adverse drug reactions, which in the investigator’s opinion have a 
negative impact on the subject’s individual risk-benefit ratio.  
• Non-compliance with the conditions for the trial or instructions by the investigator 
• Although not preferred, subjects may interrupt their intake of study medication for 
reasonable circumstances/reasons at any time (eg, hospitalization in a remote hospital 
without study medication access, safety reasons, and side effects). If an interruption 
lasts longer than 14 consecutive days, the subject must be withdrawn.  In case 
treatment requires interruption for> 3 days and ≤ 14 days, it is at the discretion of the 
investigator if the study medication can be restarted.  
• In case of pregnancy or breast feeding. 
• In case the subject does not tolerate the drug. 
 


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5.2.2 
Replacement 
There will be no replacement of randomized subjects who withdraw from the study. 
5.3 
Subject identification 
After a subject signs the informed consent form, a subject identification number will be 
created.  This will be a unique code composed of study name and subject number 
First 5 letters = TAMER (to identify this as this trial) 
Last 4 digits =  Unique subject number  
6. 
Treatment 
6.1 
Treatments to be administered 
Test Drug: 
Atorvastatin 
Dosage: 
40 mg 
Route of administration:  
oral 
Time and frequency of administration: 
once daily 
6.2 
Identity of study treatment 
Atorvastatin   
Atorvastatin will be supplied at 40 mg as film-coated, immediate-release tablets.   All study 
drug and placebo tablets will be provided through the UPMC Investigational Drug Service, 
who will also be handling patient randomization.  
A complete record of batch numbers and expiry dates of all study treatment, as well as the 
labels, will be maintained in the study file. 
Matching placebo 
Matching placebo tablets will appear identical to active atorvastatin tablets but will not 
contain active study drug. 
6.3 
Treatment assignment 
This is a randomized, double-blind, placebo-controlled, parallel-group, single-center study. 
Subjects who complete all screening procedures and meet all the eligibility criteria are to be 
randomized in a 1:1 ratio by the UPMC IDS.   
6.4 
Dosage and administration 
6.4.1 
Selection of doses in the study 
Atorvastatin has been safe and well tolerated in previous clinical studies in the general 
population, cardiovascular disease populations and systemic sclerosis patients at doses of 40 
mg once daily.   40 mg once daily atorvastatin has been shown to improve brachial FMD in 
patients with cardiovascular disease as well as SSc13.    


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6.5 
Blinding 
The study will be conducted in double-blind fashion.  Active atorvastatin and placebo tablet 
formulations will be identical in appearance (size, shape, color) and smell. The packaging and 
labeling will be designed to maintain blinded conditions for the investigator and the study 
team.  The study data will remain blinded until database lock. 
Emergency unblinding by the investigator 
In case of emergency, the investigator is permitted to unblind individual cases.  However, this 
will be restricted to cases of emergency where the unblinding result is of importance for the 
acute treatment strategy.  The occurrence of an SAE should not routinely precipitate the 
immediate unblinding of the label. Date, time, and reason for unblinding will be captured.  
Unblinding will be coordinated through the Investigational Drug Service   
6.6 
Drug logistics and accountability 
A drug dispensing log will be completed for each subject. Subjects will receive all study 
medication dispensed at the baseline visit.  At weeks 8 and 16, subjects will be instructed to 
bring all study drug packaging, including unused study drug and empty packaging, to the 
investigative site at each study visit.  Tablets will be counted for a compliance check and drug 
accountability.  At week 16, unused study drug will be returned to the IDS for destruction.   
If a dose of study drug is missed, the subject should take a dose immediately if on the same 
day.  Otherwise, they can resume normal once daily dosing the following day. The dose 
should not be doubled to make up for a missed dose within the same day.  
6.7 
Post-study therapy 
In case subjects discontinue study drug treatment during this study, further therapy is at the 
discretion of the investigator. 
6.8 
Prior and concomitant therapy 
A summary of the prohibited prior and concomitant therapy, outlined in the exclusion criteria 
(Section 5.1.2), is provided in Table 6-1. 
 


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Table 6-1 
Prohibited prior and concomitant therapy 
Therapy 
Timeframe  
Concomitant use of calcium channel blockers and ARBS are allowed 
 
 
 
Nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE inhibitors 
(theophylline, dipyridamole) are prohibited 
 
Prostacyclin analogs are not allowed.  
 
Stable doses for four 
weeks prior to 
randomization 
 
Concomitant therapy with 
study drug 
 
 
 
Concomitant therapy with 
study drug 
 
Use of strong inhibitors of CYP 3A4 to include: clarithromycin, 
itraconazole, cyclosporine, gemfibrozil or other fibrates, niacin, rifampin, 
digoxin and colchicine.                    
Concomitant therapy with 
study drug 
 
 
 
 


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7. 
Procedures and variables 
7.1 
Schedule of procedures 
Please refer 7.1.1 to for a schedule of evaluations. 


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7.1.1 
Tabulated overview 
 
Schedule of events 
Assessment 
Window (days) 
Screening 
Baseline 
Week 8 
+/-  7 
Week 16 
+/-  7 
Window 
 
 
 
 
Informed Consent 
X 
 
 
 
Complete Medical History 
X 
 
 
 
Physical Exam 
 
X 
 
X 
Randomization 
 
X 
 
 
Concomitant Medications 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
X 
Liver function tests, Creatinine w/ GFR 
X 
X 
X 
X 
CPK 
 
X 
X 
X 
Fasting lipid panel, C-reactive protein, C3, C4 
 
X 
 
X 
Vascular studies: 
EndoPAT(ischemia and post-NTG)  
Laser Speckle Contrast Imaging (ischemia and post-NTG) 
Brachial FMD (ischemia and post-NTG) 
 
 
X 
X 
X 
 
 
X 
X 
X 
Questionnaires: RCS, Raynauds and Digital Ulcer VAS 
X 
X 
X 
X 
Questionnaires: PROMIS and SHAQ 
X 
X 
X 
X 
Digital Ulcer Count 
X 
X 
 
X 
Biomarker (serum, plasma) and cEPC assessment  
 
X 
 
X 
Nitrite Analysis 
 
X 
 
X 
* VCAM, ICAM, E-selectin, p-selectin, endothelin-1 (ET-1), VEGF, VEGF), angiopoietin -1 and -2, interleukin-2, interleukin-13 
 
 


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7.1.2 
Timing of assessments 
Screening and baseline visits can occur on the same day.   
7.1.2.1 
Visit 0 − Screening 
Screening evaluations will occur after the subject has provided written informed consent.  The 
following evaluations will be performed and information obtained up to 28 days before 
randomization and the start of study drug treatment: 
• Patient information and obtaining of written informed consent 
• Eligibility: Assessment of inclusion and exclusion criteria (see Section 5.1) 
• Demographic data, including age, gender and ethnicity.   
• Complete medical history 
• Liver function tests and creatinine with GFR.   Labs obtained as part of routine clinical 
care up to 28 days prior to screening will be accepted.   
7.1.2.2 
Visit 1 − Baseline (Day 0, Week 0) 
The following assessments will be performed at the Baseline visit (Day 0 of study drug 
treatment): 
• Reconfirmation of eligibility (assessment of inclusion/exclusion criteria; Section 5.1), 
if performed at separate visits 
• Cardiovascular history and assessment or risk factors 
• Physical Exam 
• Assessment of Raynaud and digital ulcer activity and severity (questionnaire) 
• Digital ulcer assessment 
• Questionnaires  
o SHAQ 
o PROMISE-29 
• Vital signs (blood pressure, heart rate, height, weight).   
• Vascular Imaging (to be performed simultaneously) 
o EndoPAT 
o Laser speckle contrast imaging 
o Brachial FMD 
• Pregnancy test (urine) for all women of childbearing potential (see Section 7.5.2) 
• Blood samples for safety (LFTs, creatinine with GFR, CPK) 
• Blood sample for biomarkers  
• Blood sample for nitrite analysis 


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• Recording and assessment of AEs (see Section 7.5.1) 
• Concomitant therapy 
• Randomization to atorvastatin or placebo (see Section 6) 
• Dispense study drug 
7.1.2.3 
Visit 2: 8 weeks  
• Assessment of Raynaud and digital ulcer activity and severity (questionnaire) 
• Digital ulcer assessment 
• Questionnaires  
o SHAQ 
o PROMISE-29 
• Recording and assessment of AEs (see Section 7.5) 
• Blood samples for safety (LFTs, CPK)   
• Pregnancy test ( urine) for all women of childbearing potential (Visit 3 and Visit 5) 
(see Section 7.5.2) 
• Concomitant therapy 
7.1.2.4 
Visit 3: 16 weeks (end of study)  
During the maintenance period of the double-blind treatment period, the following 
assessments will be performed according to the Schedule of evaluations (Section 7.1.1): 
• Physical Exam 
• Assessment of Raynaud and digital ulcer activity and severity (questionnaire) 
• Digital ulcer assessment 
• Questionnaires 
o SHAQ 
o PROMISE-29 
• Vital signs (blood pressure, heart rate, height, weight).   
• Vascular Imaging (to be performed simultaneously) 
o EndoPAT 
o Laser speckle contrast imaging 
o Brachial FMD 
• Pregnancy test (urine) for all women of childbearing potential (see Section 7.5.2) 
• Blood samples for safety (LFTs, creatinine with GFR, CPK) 
• Blood sample for biomarkers  


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• Blood sample for nitrite analysis 
 
7.1.2.5 
Premature discontinuation of study drug treatment 
In the event of premature discontinuation of study drug treatment, subjects must undergo the 
same procedures as outlined for the Week 16 end of study visit if they have completed 8 
weeks or more of therapy.  If subjects discontinue prior to 8 weeks of therapy, then they will 
undergo the same procedures as outlined for Week 8.   All subjects who discontinue study 
drug treatment early will have an additional 30 day safety follow-up visit.  
7.2 
Population characteristics 
7.2.1 
Demographic 
The following demographic data will be recorded:  
• Date of birth (month and year) (age) 
• Sex 
• Ethnicity 
7.2.2 
Medical history 
Medical history findings (ie, previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 
• Pertaining to the study indication and inclusion/exclusion criteria 
• Detailed cardiovascular history and risk factors (including family history of 
cardiovascular events) 
• Medical history related to concomitant therapy 
7.3 
Efficacy 
Primary efficacy outcome measure: 
• Change in microvascular endothelial function as measured by EndoPAT technology.   
Secondary efficacy measures: 
• Change in Raynaud and digital ulcer symptom and severity 
• Change in microcirculatory flow assessed by laser speckle contrast imaging 
• Change in macrovascular function assessed by brachial FMD 
• Health related quality of life (SHAQ and PROMIS) 
• To assess vascular biomarkers in the sera (VEGF, tPA, sE-Selectin, BFGF, VCAM-1, 
ICAM) 
• To assess EPCs. 
• To assess nitrite analysis 
 


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7.4 
Pharmacokinetics / pharmacodynamics 
Pharmacokinetic will not be performed in this study. 
7.5 
Safety 
7.5.1 
Adverse events 
7.5.1.1 Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (ie,any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product. 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal eg, physical examination findings, symptoms, diseases, laboratory, ECG. 
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent will be recorded as medical 
history (eg, seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, will be 
recorded as medical history (eg, allergic pollinosis). 
• Conditionsthat started or deteriorated after signing of informed consent will be 
documented as AEs. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 


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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours 
- The admission is pre-planned  
(ie, elective or scheduled surgery arranged prior to the start of the study) 
- The admission is not associated with an AE  
(eg, social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
d. Results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect 
f. Is another medically important serious event as judged by the investigator 
7.5.1.2 
Classifications for adverse event assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
7.5.1.2.1 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.5.1.1. 
7.5.1.2.2 
Intensity 
The intensity of an AE is classified according to the following categories: 
- Mild 
- Moderate 
- Severe 
Mild is defined as asymptomatic or mild symptoms; intervention not indicated. 
Moderate is defined as moderate symptoms present; only minimal intervention indicated. 
Severe is defined as severe or medically significant symptoms requiring hospitalization or 
urgent intervention. 
 


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7.5.1.2.3 
Causal Relationship/Definitions of Attribution 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information.  The assessment is based on the 
question whether there was a “reasonable causal relationship” to the study treatment in 
question. 
An assessment of “not related” is defined as an adverse event being clearly not related or 
unlikely to be related.   Adverse events can also be attributed as “possible/probable” defined 
as reasonably possible or likely to be related, or “definite” defined as the adverse event is 
clearly related.   
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge): 
- Subject’s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in 
question. 
- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered. 
7.5.1.2.4 
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
- Drug withdrawn 
- Drug interrupted 
- Not applicable 
- Unknown 


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7.5.1.2.5 
Outcome 
The outcome of the AE is to be documented as follows:  
- Recovered, without treatment 
- Recovered, with treatment 
- Still present, no treatment 
- Still present, being treated 
- Residual effect(s) present, no treatment 
- Residual effect(s) present, being treated 
- Subject died 
7.5.1.3 
Assessments and documentation of adverse events 
The investigator has the obligation to report AEs. All non-serious events will be assessed and 
recorded during this trial from the baseline visit and until the end of study visit at week 16, 
whether believed to be related or unrelated to the treatment. The record will include clinical 
symptoms or final diagnosis when available, date of appearance, duration, severity, 
relationship to treatment and outcome. A record will also be kept of the action taken and the 
follow-up until resolution of the AE.  For patients who stop study drug or withdraw before the 
end of the trial (16 week visit), AE will be re-assessed at 30 days after stopping the drug at a 
follow-up study visit.   For all others, adverse events will be followed for 30 days, with 
patients contacted by phone call.   
7.5.1.4 
Reporting of serious adverse events 
The definition of SAEs is given in Section 7.5.1.1. 
Investigator’s notification to the Safety Monitor 
All SAEs occurring during the observation period defined in Section 7.5.1.3 must 
immediately (within 48 hours of the investigator’s awareness) be reported to KAI, NIAMS 
and the internal Safety Officer.  An SAE form must also be completed within 48 hours of the 
investigator awareness and forwarded.   Each SAE must be followed up until resolution or 
stabilization by submission of updated reports.   
Notification of the IRB 
Notification of the University of Pittsburgh IRB about all relevant events (eg, SAEs, 
suspected, unexpected, serious adverse reactions [SUSARs]) will be performed according to  
IRB regulations.   
7.5.1.5 
Adverse events 
7.5.1.6 
Expected adverse events, and events of special safety interest 
Common expected adverse events include: myalgias/arthralgias (> 10%), diarrhea (5-14%), 
nasopharyngitis (4-13%), and dyspepsia (3-6%).   


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There are four significant adverse events associated with the use of atorvastatin which include 
1) increase in fasting blood glucose in patients with diabetes mellitus; 2) hepatotoxicity; 3) 
rhabdomyolysis; and 4) the very rare event of immune-mediated necrotizing myopathy.  
Diabetes mellitus is an exclusion criteria for this study.   
In regards to hepatotoxicity, elevated serum transaminases have been reported in as high as 2-
3% of patients taking a higher dose of atorvastatin (80 mg once daily), although 
postmarketing reports of hepatic failure are rare.   These will be monitored at baseline, week 8 
and week 16.  We will discontinue if hepatic enzymes are > three times the upper limit of 
normal.   
Many patients receiving HMG-CoA reductase inhibitors experience myalgias, and this is an 
expected adverse event.  Patients receiving HMG-CoA reductase inhibitors have developed 
rhabdomyolysis with acute renal failure and/or myopathy.   This risk is dose-related and is 
increased with concurrent use of CYP3A4 inhibitors (eg, clarithromycin, protease inhibitors), 
fibric acid derivatives (eg, gemfibrozil), or niacin (doses ≥1 g/day) (see Drug Interactions), 
which will be monitored.  Serum CPKs will be checked at baseline, week 8 and week 16.  We 
will advise patients not to perform unusual or heavy bouts of exercise in the 24 hours before 
visits.  We will discontinue in any patient in which CPK levels are markedly elevated (> 5 
times ULN) or if myopathy is suspected/diagnosed.   Patients will be instructed to report 
unexplained muscle pain, tenderness, weakness, or brown urine.  If they develop any of these 
symptoms, they will return for an interval visit with repeat CPK and exam at that time.  
Patients receiving HMB-CoA reductase inhibitors have also been rarely reported to develop 
an immune-mediated necrotizing myopathy (IMNM. IMNM presents as proximal muscle 
weakness with elevated CPK levels, which persists despite discontinuation of HMG-CoA 
reductase inhibitor therapy.  Serum CPKs will be checked at baseline, week 8 and week 16.  
We will discontinue in any patient in which CPK levels are markedly elevated (>5 times 
ULN) or if myopathy is suspected/diagnosed.    
 Declaration of an event as serious should only occur when 1 or more of the serious criteria 
(as defined in Section 7.5.1.1) are applicable. 
7.5.1.7 
Expected adverse events 
Expected adverse events are those listed as common (incidence > 2%) in patients treated with 
atorvastatin per the package insert.  These include nasopharyngitis, arthralgia, diarrhea, 
extremity discomfort and urinary tract infection.   
7.5.1.8 
Unxpected adverse events 
An adverse reaction is considered “unexpected” if it is not listed in the package insert for 
atorvastatin (please see Appendix I of the MOOP) 
7.5.1.9 
Pregnancies 
A report of a confirmed pregnancy by serum testing will be submitted within the same 
timelines as an SAE, although a pregnancy per se is not considered an SAE.   
For a study subject, the outcome of the pregnancy should be followed up to completion. 
 


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OTHER PROCEDURES AND VARIABLES 
7.5.2 
Pregnancy testing 
Pregnancy testing is to be performed at the Baseline visit, Week 8 visit and Week 16 visit. In 
the event of pregnancy, a referral to a gynecologist for confirmation of pregnancy will be 
promptly organized.  Further consequences with regard to ongoing participation in the study 
must be discussed with the patient.  
Women of childbearing potential and non-vasectomized male participants must agree to use 
adequate contraception when sexually active.  ‘Adequate contraception’ is defined as any 
combination of at least 2 effective methods of birth control, of which at least one is a physical 
barrier (e.g. condoms with hormonal contraception or implants or combined oral 
contraceptives, certain intrauterine devices).  The exception will be women who have 
undergone tubal ligation and men who have undergone a vasectomy.   
7.5.3 
Vascular Assessments 
Prior to beginning vascular testing, all patients will rest for 15 minutes in a quiet, dark and 
temperature-controlled room (set at 77 degrees Fahrenheit or warmer).  Measurement of 
EndoPAT™, LSCI and brachial FMD will be performed simultaneously.  Measurements will 
be obtained before and after vascular occlusion for all studies to assess endothelial dependent 
vasodilation.  LSCI and brachial FMD will then be performed before and after administration 
of 0.4 mg of sublingual NTG to assess endothelial-independent vasodilation.   
During the acclimation period a pneumatic cuff will be placed on the subject’s right arm.  
Once the acclimation period has ended, a baseline pulse and flow measurements will then be 
obtained for 5 minutes for all modalities.  Following this vaso-occlusion will be induced by 
inflating the pneumatic cuff to a pressure of 280 mmHg or 60 mmHg higher than systolic 
blood pressure (whichever was the highest), for 5 minutes.  After 5 minutes the cuff will be 
rapidly deflated and measurements will be obtained for an additional 5 minutes.  Subjects will 
then receive a single 0.4 mg sublingual spray of NTG.  We will then obtain measurements as 
detailed in the individual vascular studies below over a period of 10 minutes.   
7.5.4 
EndoPAT  
Measurement of microvascular endothelial function will be performed using Peripheral 
Arterial Tonometry (PAT) device (EndoPAT 2000, version 3.3.2, Hamar Medical, Caesavea, 
Israel).  EndoPAT is a well-validated instrument18.  After the vascular assessment acclimation 
period, probes will be placed on the tips of both index fingers.  PAT signal measurement will 
be performed with the digital probe inflation pressure set at 10mmHg below the diastolic 
pressure or 70 mmHg (whichever is lowest) (17).  Baseline pulse amplitude will be recorded 
bilaterally on tips of the index fingers for 5 minutes. Following vaso-occlusion on the right 
the cuff will be deflated and the PAT signal measurement was recorded for an additional 5 
minutes. Mean PAT amplitudes will be measured 90 seconds after the occlusion for a 
duration of 60 seconds. Finally, the ratio of the post-to-pre occlusion PAT amplitude of the 
tested arm, divided by the post-to-pre occlusion ratio of the control arm, will be calculated as 
the Reactive Hyperemia Index (RHI).  


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7.5.5 
Laser Speckle Contrast Imaging 
For assessment of LSCI we will use the PerCam PSI system (Perimed AB, Jarfalla, Sweden), 
which produces a near infrared (780 nm) laser light.  The backscattered light forms a random 
interference (speckle) pattern. Movement, as produced by circulating red blood cells, causes 
the speckle pattern intensity to change, thus allowing for quantification of flow. The PeriCam 
PSI system will be used with the camera placed 20 cm above the SSc patient’s hand, which 
will be immobilized by a fluid support.  A region of interest on the 2nd proximal 
metacarpophalangeal joint will be identified prior to beginning assessments.  Baseline LSCI 
measurements will be obtained continuously beginning five minutes prior to vaso-occlusion 
until 5 minutes after NTG administration. 
7.5.6 
Brachial FMD 
Brachial artery FMD will be performed using the GE Vivid 7 Dimension ultrasound (GE 
Vingmed Ultrasound A/S, Horten, Norway).  Brachial artery diameter will be measured and 
calculated at baseline, 1, 2 and 3 minutes after reactive hyperemia induced by 5-minute 
pneumatic cuff occlusion, and then at 3, 5 and 10 minutes after NTG administration by means 
of averaging 3 measurements. FMD will be calculated as the percent change (%FMD) in 
brachial diameter from the resting state (100*[hyperemic diameter at selected time−resting 
diameter]/resting diameter) for reactive hyperemia. Similarly, vasodilator response to NTG 
will be expressed as percentage change (NTG%) in diameter between baseline and after NTG 
administration.    
7.5.7 
Exploratory Biomarkers 
Samples for exploratory vascular biomarkers will be drawn at the baseline visit and week 16 
(end of study).  Serum biomarkers will include vascular soluble adhesion molecules (VCAM, 
ICAM, E-selectin and p-selectin), endothelin-1 (ET-1), vascular endothelial growth factor 
(VEGF), angiopoietin -1 and -2, inflammatory cytokines (C-reactive protein (CRP), serum 
complement levels, interleukin-2, interleukin-13) and circulating endothelial progenitor cells 
(cEPC).  
We will also assess levels of nitrite and nitrotyrosine at baseline and week 16.   
Circulating EPCs will be assessed at baseline and week 16. 
7.5.8 
Raynaud’s attacks assessment 
Raynaud’s attacks will be assessed using the following individual outcome measures:  in 
Raynaud’s condition score and patient assessment of Raynaud’s phenomenon using the 
VAS19 
The Raynaud’s condition score is a daily patient-assessment of Raynaud’s phenomenon 
activity using a 0-10 ordinal scale. It incorporates the cumulative frequency, duration, severity 
and impact of Raynaud’s phenomenon attacks, reflecting the overall degree that Raynaud’s 
has affected use of the patient’s hands 19. The Raynaud’s condition score, along with details of 
the frequency and duration of Raynaud’s attacks, will be incorporated into the daily diary that 
subjects will be asked to complete for 1 week (7 days) at the time points shown below.  
The patient and physician assessment assesses the severity of Raynaud’s phenomenon in the 
past week using a 0-100 VAS.  


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7.5.9 
Digital ulcer assessment 
Digital ulcers are defined as a full thickness skin lesion with loss of epithelium. Ulcers should 
be > 3mm in maximal diameter. Healing is defined by re-epithelialization with loss of pain 
and exudate. Pitting scars and hyperkeratotic lesions are always excluded. Also, eschar is not 
considered as DU. 
Digital ulcer will be assessed by the following methods: 
• Visual analog score for patient-reported severity of digital ulcers  
• Ulcer count:  
o Total ulcer counts 
o Distal counts: distal (fingertip) – any ulcer including skin area distal to proximal 
interphalangeal (PIP) joint 
• Non-ischemic ulcers over the PIP and MCP will also be evaluated for healing as 
secondary outcomes 
7.5.10 
Patient-Reported Outcomes (PROs) / Health-Related Quality of Life 
(HRQoL) questionnaires 
Two patient-reported outcomes (PROs)—the SHAQand PROMIS-29—will be completed by 
all subjects in the study. In addition, a global for patient and physician should be considered. 
Scleroderma Health Assessment Questionnaire (SHAQ) 
The SHAQ consists of 8 domains from the Health Assessment Questionnaire disability index 
(HAQ-DI), a HRQoL instrument that measures self-reported function in 8 domains of activity 
in 20 weighted responses and a VAS of pain experienced in the past week. It additionally 
measures 5 domains specific to scleroderma using a continuous VAS: Raynaud’s 
phenomenon, digital tip ulcers, lung symptoms, gastrointestinal symptoms, and a global 
patient assessment7. The VAS subscales of the SHAQ were shown to be significantly 
correlated with objective parameters,7 and was responsive to change in a cohort and in a 
Raynaud’s phenomenon trial in SSc.7 20 The SHAQ requires approximately 5 minutes to 
complete. 
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 
The PROMIS-29 is a validated instrument to measure the health status of SSc patients, 
demonstrating moderate to high correlation with other instruments validated in SSc, including 
the SF-36 physical component score and HAQ-DI.21 It incorporates 7 core domains from the 
PROMIS questionnaire, which specifically relate to physical, mental, and social health 
aspects of chronic illness: pain, fatigue, depression, anxiety, sleep, and physical function, as 
well as one 11-point rating scale for pain intensity.21  It contains 8 items with 29 weighted 
responses in total, and requires approximately 5 minutes to complete.  
Frequency of all PROs: Baseline (Visit 1, Day 0), Visit 5 (week 8), Visit 6 (week 10) and 
Visit 8 (week 16) 


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8. 
Statistical methods  
8.1 
General considerations 
An intention to treat analysis will be performed including all who receive one dose of drug. 
Initial analysis will describe the baseline population, sociodemographic and clinical 
characteristics, and compare by treatment group.  Means of continuous measures will be 
conducted using a t-test or Wilcoxon test and discrete measures compared with a chi-square 
test. The goal of all trial analyses is to provide effect size estimates for design of a later phase 
3 clinical trial of statin therapy in early diffuse SSc, if deemed appropriate.   If not mentioned 
otherwise, all statistical tests will be performed with a type I two-sided error rate of α=5%.. 
8.2 
Statistical and analytical plans 
8.2.1 
Demographic and other baseline characteristics 
Demographic variables and baseline characteristics will be summarized by treatment group. 
8.2.2 
Efficacy 
The primary outcome of interest is the change in the EndoPAT measured RHI between 
baseline and week 16 between the atorvastatin and placebo group.  A t-test will be used to 
compare the mean levels between the two groups.  If differences in baseline characteristics 
across treatment groups are identified, multivariable linear regression models will be used to 
estimate the independent effect of treatment after controlling for the possible confounding 
variables. 
 
The secondary outcomes of interest include the following:  
1) Change in RCS  
2) Change in Raynaud VAS 
3) Change in reperfusion peak between the atorvastatin and placebo  groups. 
4) Change in reperfusion nadir between the atorvastatin and placebo groups.  
5) Change in brachial FMD between baseline and week 16 between the atorvastatin and placebo 
group.   
 
A t-test will be used to compare the mean change in RCS and Raynaud VAS between weeks 
16 and baseline in the placebo and atorvastatin therapy groups.   The means of reperfusion 
peak and nadir between groups will be calculated and a 95% confidence interval of the 
difference between means generated.  A t-test will be used to compare the mean change in 
brachial FMD between baseline and week 16 between the two treatment groups.  
 
For all of the above, assumptions of all tests (e.g., normality of residuals) will be evaluated.  If 
violations are identified, transformations will be investigated.  If adequate transformations 
cannot be identified, then nonparametric methods will be used. 
8.2.3 
Safety 
Tables of adverse events and serious adverse events will be created.   These will be 
maintained by the data manager or study statistician and reported twice yearly to the Safety 
Officer.  The internal Safety Officer will be appointed by the Principal Investigator.  These 
tables will include masked treatment group.  This is detailed in the Safety Monitoring Plan. 


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8.3 
Planned interim analyses 
No formal interim analysis of the main study treatment phase is planned given that it is a 
small pilot study.   
8.4 
Determination of sample size 
This is a pilot study.  With a total sample of 30 participants (15 per treatment group), and to 
produce a 95% confidence interval of the difference in means between the two treatment 
groups, the width of the confidence interval would be +/- 0.374.    
 
9. 
Data handing and quality assurance 
9.1 
Data recording 
All data will be entered into the RDMS system. A source document checklist will be used at 
the site to identify the source data for all data points collected.  .  
9.2 
Archiving 
Documents shall be archived safely and securely in such a way that ensures that they are 
readily available if required, and in compliance with the University of Pittsburgh guidelines.  
According to the University of Pittsburgh IRB, all study-related documents will be stored for 
7 years.  The investigator site file is not to be destroyed without approval by NIAMS or the 
Safety Monitor.   
9.3 
Publication Policy 
Following completion of the TAMER study, the investigators will publish the results of this 
research in scientific journals.  The International Committee of Medical Journal Editors 
(ICMJE) member journals has adopted a trials-registration policy as a condition for 
publication.  This policy requires that all clinical trials be registered in a public trials registry 
such as ClinicalTrials.gov, which is sponsored by the National Library of Medicine.  The 
TAMER study will be registered prior to commencement. 
 
As this is a single-center study, there will be no publications committee.  Authorship 
determination will be made in consultation with the co-investigators of the study (Drs. 
Dezfulian, Reis and Wisniewski).   
 
Publication of the results of this trial will be governed by NIAMS publication policies.  Any 
presentation, abstract, or manuscript will be made available for review by the NIAMS 
supporters prior to its submission.   Dr. Domsic will maintain control of all TAMER-
generated specimens and will decide on the scientific merit of any future sub-studies. They 
will adhere to the letter and the spirit of the prevailing NIH and NIAMS guidelines on the 
sharing of research resources produced from federally-funded research. 


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9.4 
Confidentiality  
This is a single-center study, with a relatively small number of subjects.   All personnel 
involved in this study have undergone training and certification on the protection of human 
subjects, confidentiality, HIPAA compliance and research integrity.  This training is 
conducted regularly by the University of Pittsburgh via an internet-based system of education 
in research.  
The only individuals with access to identifiable information and treatment assignment will be 
the data manager and study statistician.   Access to study data will be password protected.  All 
linkage materials are stored separately and maintained in a secure area.   
All blood samples will be collected in a de-identified manner using labels generated through 
the Rheumatic Disease Management System (RDMS) system, which is a Division-wide 
system for rheumatologic research. Linkage codes will be maintained by the data manager in 
the event of emergencies or future need, and these will be kept in a locked filing cabinet 
located in the Scleroderma Center research office. 
10. 
Ethical and legal aspects 
10.1 
Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to abide by GCP guidelines and under the guiding 
principles detailed in the Declaration of Helsinki.  IRB approval has been obtained.  The 
investigator may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to the trial subjects without prior IRB approval.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment will then be submitted to the University of Pittsburgh IRB. Any deviations from 
the protocol will be explained and documented by the investigator.  Protocol deviations will 
also be reported biannually to the Safety Monitor.   
10.2 
Subject information and consent 
The investigator will discuss that written approval of the IRB has been obtained.  Consent 
forms, describing in detail the therapies, procedures, and risks, will be given to the participant, 
and written documentation of informed consent is required prior to starting the study agent(s).  
Consent forms will be IRB-approved, and the participant will be asked to read and review the 
document.  Upon reviewing the document, the study coordinator will explain the research 
study to the participant and answer any questions that may arise.  The participants will sign 
the informed consent document prior to any procedures being done specifically for the study.  
The participants will have sufficient opportunity to discuss the study and process the 
information in the consent process prior to agreeing to participate.  Only if the subject 
voluntarily agrees to sign the informed consent form and has done so, may s/he enter the 
study.  Additionally, the PI will personally sign and date the form.  The subject will receive a 
copy of the signed and dated form.  The signed informed consent statement is to remain in the 
investigator site file.   In the event that informed consent is obtained on the date that baseline 
study procedures are performed, the study record or subject´s clinical record must clearly 
show that informed consent was obtained prior to these procedures. 


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