Conditions: Raynaud Phenomenon Secondary to Systemic Sclerosis
Keywords: systemic sclerosis raynaud phenomenon
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate the effect of iloprost on the symptomatic relief of Raynaud's Phenomenon attacks in subjects with symptomatic Raynaud's Phenomenon secondary to Systemic Sclerosis.

Detailed description:

Arms:
arm 1: Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line. Study drug will be initiated at a starting dose 0.5 ng/kg/min up to 2.0 ng/kg/min. arm 2: Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line. Study drug will be initiated at a starting dose 0.5 ng/kg/min up to 2.0 ng/kg/min.

Interventions: intervention 1: Placebo IV infusion intervention 2: Iloprost Injection, for intravenous use
Intervention descriptions: intervention 1: Study drug will be initiated at a starting dose of 0.5 ng/kg/min up to 2.0 ng/kg/min. Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line. intervention 2: Study drug will be initiated at a starting dose of 0.5 ng/kg/min up to 2.0 ng/kg/min. Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line.

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Phase 2 Pilot Study Evaluating Intravenous Iloprost in Subjects 
With Symptomatic Raynaud’s Phenomenon Secondary to Systemic 
Sclerosis 
 
Investigational Product: Iloprost Injection, for intravenous use  
Protocol Number: ES-201 
 
 
Sponsor: 
Eicos Sciences, Inc. 
200 Four Falls Corporate Center, Suite 107 
West Conshohocken, PA 19428-2958 
USA 
Telephone: 301-968-2390 
 
 
Version Number: 4.0 
Original Protocol: 04 October 2018 
Amendment 1: 05 December 2018 
Amendment 2: 30 January 2019 
Amendment 3: 01 March 2019 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Eicos Sciences, Inc. except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical study for Eicos Sciences, Inc. You are 
allowed to disclose the contents of this document only to your Institutional Review Board and 
study personnel directly involved with conducting this protocol. Persons to whom the 
information is disclosed must be informed that the information is confidential and proprietary to 
Eicos Sciences, Inc. and that it may not be further disclosed to third parties. 


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SIGNATURE PAGE 
STUDY TITLE: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Pilot Study Evaluating Intravenous Iloprost in Subjects With Symptomatic Raynaud’s 
Phenomenon Secondary to Systemic Sclerosis 
We, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
Date 
Eicos Sciences, Inc., a CiVi Biopharma, Inc. Affiliated Company 
Eicos Sciences, Inc., a CiVi Biopharma, Inc. Affiliated Company 
Eicos Sciences, Inc., a CiVi Biopharma, Inc. Affiliated Company 
Eicos Sciences, Inc., a CiVi Biopharma, Inc. Affiliated Company 
01 Mar 2019
01 Mar 2019
01 Mar 2019
02 Mar 2019
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Eicos Sciences, Inc. to study personnel under my supervision. I will discuss this material with 
them to ensure they are fully informed about the study product and study procedures. I will let 
them know that this information is confidential and proprietary to Eicos Sciences, Inc. and that it 
may not be further disclosed to third parties. I understand that the study may be terminated or 
enrollment suspended at any time by Eicos Sciences, Inc., with or without cause, or by me if it 
becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Declaration of Helsinki, Institutional Review Board Regulations, and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS 
TITLE:  A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Pilot Study 
Evaluating Intravenous Iloprost in Subjects With Symptomatic Raynaud’s Phenomenon 
Secondary to Systemic Sclerosis 
PROTOCOL NUMBER:  ES-201 
INVESTIGATIONAL PRODUCT:  Iloprost Injection, for intravenous use 
PHASE:  Phase 2 
INDICATION(S):  Symptomatic Raynaud’s phenomenon (RP) secondary to systemic sclerosis 
(SSc) 
OBJECTIVES: 
The primary objective is to evaluate the efficacy of iloprost compared to placebo on the change in 
the weekly frequency of symptomatic RP attacks from baseline in subjects with symptomatic RP 
secondary to SSc. 
The exploratory objectives are the following: 
• To evaluate the efficacy of iloprost compared to placebo on the severity of RP attack 
symptoms 
• To evaluate the efficacy of iloprost compared to placebo on the Raynaud’s Condition Score 
• To evaluate the efficacy of iloprost compared to placebo on hand function as assessed by the 
Cochin Hand Function Scale (CHFS) 
• To evaluate the safety and tolerability of iloprost 
• To evaluate the efficacy of iloprost compared to placebo on symptomatic RP attack duration 
• To evaluate the efficacy of iloprost compared to placebo on the worst pain associated with 
symptomatic RP 
• To evaluate the efficacy of iloprost compared to placebo on the patient assessment of overall 
improvement in symptomatic RP 
• To evaluate the pharmacokinetics (PK) of iloprost in subjects with symptomatic RP secondary 
to SSc 
POPULATION: 
The population for this study is male and female subjects 18 years of age with a diagnosis of SSc 
as defined by the 2013 American College of Rheumatology criteria/European League Against 
Rheumatism (EULAR) criteria. During the 5-day eligibility period, eligible subjects will have a 
minimum of 10 symptomatic RP attacks, documented in the electronic patient-reported outcomes 
(ePRO) diary, occurring over at least 3 separate days of the 5-day eligibility period.  


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INCLUSION AND EXCLUSION CRITERIA: 
Inclusion criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female subjects must be 18 years of age. 
2. Subjects must have a diagnosis of SSc as defined by the 2013 American College of 
Rheumatology criteria/EULAR criteria. 
3. Subjects must have a diagnosis or history of RP, self-reported or reported by a physician, with 
at least a 2-phase color change in finger(s) of pallor, cyanosis, and/or reactive hyperemia in 
response to cold exposure or emotion. 
4. Subjects must have a minimum of 10 symptomatic RP attacks, documented in the ePRO diary, 
occurring over at least 3 separate days of the 5-day eligibility period. 
o Note: A symptomatic Raynaud’s attack for this study is defined as at least 1 color change 
of the subject’s finger(s) (blue, white, or red) associated with at least 1 symptom (pain, 
numbness, tingling, and/or discomfort of the finger[s]). The attack is considered over when 
the color changes back to pre-attack color (normal) and the symptoms return to the 
subject’s pre-attack level.  
5. Female subjects of childbearing potential (defined as female subjects who have experienced 
menarche and who are not permanently sterile or postmenopausal; postmenopausal is defined 
as 12 consecutive months with no menses without an alternative medical cause) and male 
subjects must agree to use contraception for the duration of the study.  
6. Subjects must be willing and able to comply with the study requirements and give informed 
consent for participation in the study. 
Exclusion criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Female subjects who are pregnant or breastfeeding. 
2. Subjects with systolic blood pressure <85 mmHg (sitting position) at screening. 
3. Subjects with an estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening as 
determined by the Modification of Diet in Renal Disease equation. 
4. Subjects with Child-Pugh Class B or Class C liver disease or an alanine aminotransferase 
and/or aspartate aminotransferase value >3 × the upper limit of normal at screening. 
5. Subjects with gangrene, digital ulcer infection, or requirement of cervical or digital 
sympathectomy within 30 days of screening. 
6. Subjects with intractable diarrhea or vomiting. 
7. Subjects with a risk of clinically significant bleeding events including those with coagulation 
or platelet disorders. 
8. Subjects with a history of major trauma or hemorrhage in the past 4 weeks. 


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9. Subjects with clinically significant chronic intermittent bleeding such as active gastric antral 
vascular ectasia or active peptic ulcer disease. 
10. Subjects who have had any cerebrovascular events (eg, transient ischemic attack or stroke) 
within 6 months of screening. 
11. Subjects with a history of myocardial infarction or unstable angina within 6 months of 
screening. Subjects should not have a planned coronary procedure during their participation 
in the study. 
12. Subjects with acute or chronic congestive heart failure (New York Heart Association Class III 
[moderate] or Class IV [severe]). 
13. Subjects with a history of life-threatening cardiac arrhythmias. 
14. Subjects with a history of hemodynamically significant aortic or mitral valve disease. 
15. Subjects with more than mild restrictive or congestive cardiomyopathy uncontrolled by 
medication or implanted device. 
16. Subjects with known pulmonary hypertension, pulmonary arterial hypertension, or pulmonary 
veno-occlusive disease. 
17. Subjects with a history of significant restrictive lung disease defined as forced vital capacity 
<45% predicted and diffusing capacity of the lungs for carbon monoxide <40% predicted 
(uncorrected for hemoglobin). 
18. Subjects with a history of cervical or digital sympathectomy within 6 months of screening. 
19. Subjects with scleroderma renal crisis within 6 months of screening. 
20. Subjects with a concomitant life-threatening disease with a life expectancy <12 months. 
21. Subjects who have a clinically significant disorder, that in the opinion of the Investigator, 
could contraindicate the administration of study drug, affect compliance, interfere with study 
evaluations, or confound the interpretation of study results. 
22. Subjects who have taken or are currently taking any parenteral, inhaled, or oral prostacyclin 
or prostacyclin receptor agonists (eg, epoprostenol, treprostinil, iloprost, and selexipag) within 
8 weeks of screening. 
23. Subjects must not initiate dosing of oral, topical, or intravenous (IV) vasodilators (eg, calcium 
channel blockers, phosphodiesterase-5 inhibitors [eg, sildenafil, tadalafil, or vardenafil], 
nitrates, and fluoxetine), or if currently receiving any vasodilator, must have been stably 
medicated (no dose adjustments) for at least 2 weeks prior to screening. 
24. Subjects with any history of acetaminophen intolerability (eg, allergic reaction to 
acetaminophen). 
25. Subjects with any malignancy that requires treatment during the study period, that has required 
treatment within 1 year of screening, or that is currently not in remission. 
26. Subjects who have used any investigational medication or device for any indication within 
30 days or 5 half-lives (whichever is longer) of screening. 


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STUDY DESIGN AND DURATION: 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate the 
effect of iloprost on the symptomatic relief of RP attacks in subjects with symptomatic RP 
secondary to SSc. The study will be piloting an initial evaluation of iloprost, testing the study 
endpoints and logistics of study operations that include, among other things, an ePRO diary for 
the evaluation of subject response to the treatment as well as the infusion workflow for this 
multiday treatment. Subjects are allowed to continue receiving stable standard of care therapies 
for the management of symptomatic RP (eg, calcium channel blockers, angiotensin-converting 
enzyme inhibitors, statins, fluoxetine, and low dose acetylsalicylic acid) or may participate 
without the use of background standard of care therapies.  
The study will enroll up to a maximum of 40 subjects. Subject enrollment may be halted by the 
Sponsor at any time for any reason.  
The study consists of an up to 30-day screening period during which subjects will complete a daily 
ePRO diary to record information regarding all symptomatic RP attacks (eg, severity of symptoms, 
duration, and hand function). The up to 30-day screening period consists of a 5-day eligibility 
period and an up to 25-day baseline ePRO diary completion period: 
• During the 5-day eligibility period, eligible subjects will have a minimum of 10 symptomatic 
RP attacks, documented in the ePRO diary, occurring over at least 3 separate days of the 5-day 
eligibility period.  
• During the baseline ePRO diary completion period, eligible subjects must complete the daily 
ePRO diary for a minimum of 10 days (up to a maximum of 25 days) until the day of 
randomization. It may be necessary to extend the baseline ePRO diary completion period 
beyond 10 days in order to accommodate the preferred Monday to Friday dosing schedule. 
The ePRO symptomatic RP attack data from this time period will be used for the calculation 
of the baseline frequency of symptomatic RP attacks. 
Eligible subjects will be given the option to participate in a PK substudy. Subjects who participate 
in the substudy will provide plasma samples for PK analysis. The samples will be analyzed for 
iloprost concentrations using validated liquid chromatography mass spectrometry methods.  
Subjects will be randomized in a 1:1 ratio to iloprost injection for IV use or placebo. 
Randomization will be stratified based on the use of phosphodiesterase inhibitors at screening. 
Study drug administration will begin on Day 1, and subjects will receive study drug for 
5 consecutive days (eg, Monday through Friday) as an IV infusion over 6 hours each day via a 
peripheral line (NovaCath™ Integrated IV Catheter System) or a peripherally inserted central 
catheter (PICC) using an infusion pump. 
Subjects must have a systolic blood pressure 85 mmHg (sitting position) prior to study drug 
administration each day of administration. On Day 1, study drug will be initiated at a starting dose 
of 0.5 ng/kg/min, and dose increases will occur every 30 minutes (5 minutes) in increments of 
0.5 ng/kg/min up to 2.0 ng/kg/min or the individual tolerated dose. If dose-limiting adverse events 
(eg, headache, flushing, jaw pain, myalgia, nausea, or vomiting) occur that cannot be tolerated by 
the subject, then the dose will be reduced in a step wise manner by 0.5 ng/kg/min every 30 minutes 
(5 minutes), until a tolerated dose is determined. If symptomatic hypotension or a dose-limiting 
adverse event occurs during administration of iloprost at the starting dose (ie, 0.5 ng/kg/min), the 


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infusion will be reduced to 0.25 ng/kg/min. If the dose of 0.25 ng/kg/min is not tolerated due to 
symptomatic hypotension or a dose-limiting adverse event occurs, the study drug will be 
discontinued and reinitiation of the infusion can be attempted after the event has resolved or been 
treated. Blood pressure and heart rate will be monitored 15 minutes (5 minutes) prior to and after 
all dose changes. If the subject experiences symptomatic hypotension or any other adverse event 
that cannot be tolerated, as determined by the Investigator, during administration of study drug, 
the dose will be reduced or the infusion will be stopped until the symptoms resolve, at which point 
the study drug should be reinitiated at a previously tolerated dose. The maximum tolerated dose 
will be maintained for the remaining 6-hour daily period. At the end of the 6-hour infusion period, 
the dose will be stopped. Subjects will be monitored for up to 1 hour after completion of study 
drug infusion (ie, vital signs will be obtained 15 minutes [5 minutes] and 1 hour [15 minutes] 
after completion of the infusion). 
On Days 2 to 5, the infusion will be started using the highest infusion rate tolerated on the previous 
day without up- or down-titration, unless the subject does not tolerate the infusion or adverse 
events occur that cannot be tolerated by the subject and necessitate a reduction in the dose. Vital 
signs will be measured prior to study drug administration and at 15 minutes (5 minutes) prior to 
and after all dose changes during the infusion. Additionally, vital signs will be monitored at 
15 minutes (5 minutes) and 1 hour (15 minutes) after completion of the 6-hour infusion.  
During the treatment period (Days 1 to 5), while subjects receive study drug, the ePRO diary will 
not be completed. No study assessments will be performed on the 2 days following the end of 
treatment (Days 6 and 7, eg, Saturday and Sunday) to allow the subject to rest and return to a 
schedule of normal daily living activity following the 5 days of infusions.  
Subjects will be contacted via telephone on Day 8 to ensure they resume completion of the daily 
ePRO diary; subjects will complete the diary from Day 8 through Day 21. On Day 22, subjects 
will return to the clinic for post-treatment evaluations. A follow-up visit will occur 30 days after 
the last administration of study drug (Day 35).  
Subjects who discontinue study drug early will remain in the study (unless the subject withdraws 
consent) and complete the daily ePRO diary from Day 8 to Day 21 including clinical laboratory 
assessments on the remaining missed infusion days as well as post-treatment study assessments. 
The total duration of the study for a subject will be up to approximately 9 weeks.  
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Iloprost injection for IV use and matching placebo will be supplied in vials packaged in a blinded 
study drug kit (10 vials per kit). The iloprost and placebo vials will be identical, except 100 mcg 
of iloprost will be added to the active study drug vials. The drug product must be diluted with 
sodium chloride 0.9% in a drug reservoir (IV bag) prior to use.  
Subjects will receive the study drug IV infusions for 5 consecutive days (eg, Monday to Friday). 
Study drug will be administered after dilution as an IV infusion over 6 hours each day via a 
peripheral line (NovaCath Integrated IV Catheter System) or a PICC using an infusion pump. 
(Note: In some instances where the site chooses to use a PICC, it may be necessary to confirm 
placement of the PICC with an x-ray). 


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EFFICACY VARIABLES:  
The primary efficacy parameter is the change in the weekly frequency of symptomatic RP attacks 
from baseline. 
The exploratory efficacy parameters include changes from baseline to the end of the efficacy 
follow-up in the following: 
• Severity of RP attacks as determined by the severity of RP attack symptoms (pain, numbness, 
tingling, and/or discomfort) (using a Numeric Rating Scale [NRS])  
• Raynaud’s Condition Score  
• Hand function as assessed by the CHFS  
• Duration of symptomatic RP attacks  
• NRS for worst pain associated with symptomatic RP  
• Patient assessment of overall improvement in symptomatic RP  
PHARMACOKINETIC VARIABLES: 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of iloprost: 
• Steady state plasma concentration just before infusion is stopped 
• Area under the plasma concentration versus time curve (AUC) from time of dosing to the last 
time point with measurable concentration  
• AUC from time 0 extrapolated to infinity  
• Percentage of AUC obtained by extrapolation  
• Plasma terminal elimination half-life  
• Plasma clearance  
• Volume of distribution  
SAFETY VARIABLES: 
Safety parameters will include all adverse events, physical examination findings, vital sign 
measurements (heart rate and blood pressure), 12-lead electrocardiogram findings, and standard 
clinical laboratory measurements (chemistry and hematology). 
STATISTICAL ANALYSES: 
All efficacy analyses are intended to provide an initial description of the clinical profile of iloprost 
and to inform the design and logistics of future studies.  
The modified Intent-to-Treat (mITT) Population is defined as all randomized subjects who initiate 
infusion of study drug. The mITT Population is the primary efficacy analysis population. 


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The Per-Protocol (PP) Population is defined as subjects in the mITT Population who complete at 
least Day 21 without any major protocol deviations. The PP Population will be used for sensitivity 
analyses of the primary efficacy variable. 
The Safety Population is defined as all randomized subjects who initiate infusion of study drug. 
The Safety Population will be used for all safety analyses. 
Primary efficacy analysis 
The baseline weekly frequency of symptomatic RP attacks is defined as the average number of 
weekly symptomatic RP attacks occurring during the 10- to 25-day baseline ePRO diary 
completion period. The double-blind weekly symptomatic RP attacks is defined as the average 
number of weekly symptomatic RP attacks during Days 8 to 21. The primary efficacy parameter 
is the change in the weekly frequency of symptomatic RP attacks from baseline (ie, the mean 
number of weekly symptomatic RP attacks during Days 8 to 21 compared to during the 10- to 
25-day baseline ePRO diary completion period). 
The primary analysis will be performed based on an analysis of covariance model, including 
randomized treatment group and randomized stratification (ie, use of phosphodiesterase inhibitors 
at screening) as factors and baseline weekly frequency of symptomatic RP attacks as a covariate. 
The treatment comparisons will be estimated together with the 95% confidence interval and 
p-value. The site effect will be explored as necessary. For subjects in the mITT Population with 
intermittent missingness during the baseline or double-blind intervals, multiple imputation will be 
used assuming data are missing at random; for those subjects with truncated follow-up, methods 
will be used assuming missingness is not at random. 
The primary analysis is formally based on a 3-category decision guideline for future clinical study 
evaluation of iloprost. Specifically, the decision guideline for this study is based on whether the 
difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is less than X, is from X to Y, or is at least Y, where X is 
the threshold that would be exceeded with 90% probability when the true difference between 
iloprost and placebo in the change in the weekly frequency of symptomatic RP attacks from 
baseline is 6.65, and where Y is the threshold that would be exceeded with only 2.5% probability 
when the true difference between iloprost and placebo in the change in the weekly frequency of 
symptomatic RP attacks from baseline is 0. 
Note that these categories based on the thresholds X and Y should not be interpreted as providing 
strict decision rules, but rather as guidelines that will be factored into a broader scientific and 
clinical assessment of the benefit-to-risk profile of IV iloprost. This broader assessment will 
include consideration of safety, supportive efficacy endpoints, and relevant information external 
to this study.  


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The decision guidelines for this study include the following: 
• If the difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is less than X, then iloprost is not plausibly more 
efficacious than placebo; its utility in this indication should be reconsidered unless the 
endpoints support further development. 
• If the difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is between X and Y, then iloprost is plausibly more 
efficacious than placebo. 
• If the difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is at least Y, then iloprost would be statistically 
significantly more effective than placebo, with the strength of evidence meeting the standard 
requirement of a 0.025 one-sided (0.05 two-sided) false-positive error rate. 
Sample size determination 
The study will enroll up to a maximum of 40 subjects.  
If 12.0 is the standard deviation of the change from baseline in the weekly frequency of 
symptomatic Raynaud attacks, then with 20 patients per arm, X is 1.785 and Y is 7.438. 
The operating characteristics for this 3-category decision guideline, when 12.0 is the standard 
deviation of the change from baseline in the weekly frequency of symptomatic Raynaud attacks 
and the sample size is 20 patients per arm, are as follows: 
1. Regarding the false-positive error rate of the screening procedure, if IV iloprost truly provides 
no improvement in the change from baseline in the weekly frequency of symptomatic Raynaud 
attacks, then the probability of bringing IV iloprost forward to a Phase 3 study is 32%. 
However, there is only a 2.5% chance of reaching the false positive conclusion that IV iloprost 
provides a statistically significant improvement in efficacy relative to a placebo control.    
2. The false-negative error rate is low. If the true difference between IV iloprost and the placebo 
control groups in the change from baseline in the weekly frequency of symptomatic Raynaud 
attacks is 6.65, then there is only a 10% chance that IV iloprost would be discarded, and thus 
a 90% chance that it would be evaluated in a subsequent confirmatory Phase 3 study; 
furthermore, the probability that IV iloprost will have a statistically significant improvement 
in efficacy (at one-sided p<0.025) relative to the placebo control is 21%. 
Exploratory efficacy analysis 
Descriptive analyses based on point estimates and confidence intervals will be used for 
exploratory endpoints. 
Analysis of pharmacokinetics  
The PK Population will include all subjects in the PK substudy who receive study drug and for 
whom at least 1 PK parameter can be determined and who have at least 1 value above the lower 
limit of quantification. 


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Descriptive statistics (sample size, mean, standard deviation, minimum, median, maximum, and 
coefficient of variation [CV]) will be used to summarize PK concentrations and parameters. 
Geometric mean and geometric CV will also be used to summarize specific parameters. 
Additional PK/pharmacodynamic analysis may be performed as an exploratory analysis, if 
applicable.  
Analysis of safety  
All safety analyses will be performed on the Safety Population. Subjects will be analyzed by the 
treatment received. 
Safety measures will be summarized descriptively. Qualitative variables will be summarized using 
counts and percentages by treatment group at each study visit. A treatment-emergent adverse event 
(TEAE) is defined as an adverse event with a start date and time on or after the administration of 
study drug. Treatment-emergent adverse events will be summarized by Medical Dictionary for 
Regulatory Activities system organ class (SOC) and preferred term. Tables will be provided for 
overall incidence and incidence by SOC and preferred term for TEAEs, drug-related TEAEs, 
TEAEs by maximum severity, serious adverse events, and TEAEs leading to treatment 
discontinuation. Laboratory and vital signs parameters will be presented using descriptive 
statistics for observed values at each visit and changes from baseline, as appropriate. 
DATA MONITORING COMMITTEE:  
The Data Monitoring Committee (DMC) is responsible for safeguarding the interests of study 
subjects and for enhancing the integrity and credibility of the study. To address this mission, the 
DMC will have ongoing access to efficacy and safety data, and to information regarding the 
quality of study conduct. 
STEERING COMMITTEE:  
The Steering Committee is responsible for providing overall guidance to Eicos Sciences, Inc. on 
study protocol development, execution of the study, analysis, and reporting of the study. 
SITES:  Up to 20 sites in the United States  
SPONSOR: 
Eicos Sciences, Inc. 
200 Four Falls Corporate Center, Suite 107 
West Conshohocken, PA 19428-2958 
USA 
Telephone: 301-968-2390 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 13 
List of Tables ................................................................................................................................ 18 
List of Abbreviations and Definition of Terms............................................................................. 19 
1 Introduction and Background Information ............................................................................. 21 
1.1 
Overview of Systemic Sclerosis .................................................................................... 21 
1.1.1 Raynaud’s Phenomenon in Systemic Sclerosis ................................................. 21 
1.1.2 Digital Ulcers in Systemic Sclerosis ................................................................. 21 
1.1.3 Current Management of Raynaud’s Phenomenon and Digital Ulcers in 
Systemic Sclerosis ............................................................................................. 22 
1.2 
Overview of Iloprost ..................................................................................................... 22 
1.2.1 Regulatory Status of Iloprost ............................................................................. 23 
1.2.2 Rationale for Iloprost for the Treatment of Symptomatic Raynaud’s 
Phenomenon Secondary to Systemic Sclerosis ................................................. 23 
1.2.3 Summary of Iloprost Mechanism of Action ...................................................... 23 
1.2.4 Clinical Pharmacology ...................................................................................... 24 
1.2.5 Summary of Iloprost Clinical Experience in Systemic Sclerosis ...................... 24 
1.3 
Rationale ........................................................................................................................ 26 
2 Study Objectives ..................................................................................................................... 27 
2.1 
Primary Objective ......................................................................................................... 27 
2.2 
Exploratory Objectives .................................................................................................. 27 
3 Study Description.................................................................................................................... 28 
3.1 
Summary of Study Design ............................................................................................ 28 
3.2 
Study Indication ............................................................................................................ 29 
4 Selection and Withdrawal of Subjects .................................................................................... 30 
4.1 
Inclusion Criteria ........................................................................................................... 30 
4.2 
Exclusion Criteria .......................................................................................................... 30 
4.3 
Withdrawal Criteria ....................................................................................................... 32 
4.3.1 Discontinuation of Study Drug ......................................................................... 32 


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4.3.2 Withdrawal of Subjects From the Study ........................................................... 32 
5 Study Treatments .................................................................................................................... 33 
5.1 
Treatment Groups .......................................................................................................... 33 
5.2 
Rationale for Dosing ..................................................................................................... 33 
5.3 
Randomization and Blinding ......................................................................................... 33 
5.4 
Breaking the Blind ........................................................................................................ 33 
5.5 
Drug Supplies ................................................................................................................ 34 
5.5.1 Formulation and Packaging ............................................................................... 34 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 34 
5.5.3 Study Drug Administration ............................................................................... 34 
5.5.3.1 Common adverse events associated with iloprost intravenous 
infusion ............................................................................................... 36 
5.5.4 Treatment Compliance ...................................................................................... 36 
5.5.5 Storage and Accountability ............................................................................... 36 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 37 
5.6.1 Excluded Medications and/or Procedures ......................................................... 37 
5.6.2 Restricted Medications and/or Procedures ........................................................ 37 
5.6.3 Allowed Medications ........................................................................................ 37 
5.6.4 Documentation of Prior and Concomitant Medication Use .............................. 37 
6 Study Procedures .................................................................................................................... 38 
6.1 
Informed Consent .......................................................................................................... 38 
6.2 
Screening Period (Days -30 to -1) ................................................................................. 38 
6.2.1 Eligibility Period (Days -30 to -26 [Visit 1]) .................................................... 38 
6.2.2 Baseline Electronic Patient-Reported Outcomes Diary Completion Period 
(Days -25 to -1) ................................................................................................. 39 
6.3 
Treatment Period (Days 1 to 5 [Visits 2 to 6]) .............................................................. 39 
6.3.1 Day 1 (Visit 2) ................................................................................................... 39 
6.3.2 Days 2 to 5 (Visits 3 to 6) ................................................................................. 40 
6.4 
Post-Treatment Period (Days 8 and 22 [Visits 7 and 8]) .............................................. 41 
6.4.1 Day 8 (Visit 7) – Telephone Call ...................................................................... 41 
6.4.2 Day 22 (Visit 8) ................................................................................................. 41 
6.5 
Follow-up Visit (Day 35 [Visit 9]) ................................................................................ 41 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................... 41 


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7 Efficacy and Pharmacokinetic Assessments ........................................................................... 43 
7.1 
Efficacy Endpoints ........................................................................................................ 43 
7.1.1 Primary Efficacy Endpoint ................................................................................ 43 
7.1.2 Exploratory Efficacy Endpoints ........................................................................ 43 
7.2 
Efficacy Assessments .................................................................................................... 43 
7.2.1 Raynaud’s Phenomenon Attacks ....................................................................... 43 
7.2.2 Electronic Patient-Reported Outcomes Diary ................................................... 43 
7.2.2.1 Severity of Raynaud’s phenomenon attack symptoms (using a 
Numeric Rating Scale) ........................................................................ 43 
7.2.2.2 Raynaud’s Condition Score ................................................................ 44 
7.2.2.3 Cochin Hand Function Scale .............................................................. 44 
7.2.2.4 Duration of Raynaud’s phenomenon attacks ...................................... 44 
7.2.2.5 Overall patient improvement .............................................................. 44 
7.3 
Pharmacokinetic Assessments ....................................................................................... 44 
8 Safety Assessments ................................................................................................................. 46 
8.1 
Adverse Events .............................................................................................................. 46 
8.1.1 Adverse (Drug) Reaction .................................................................................. 47 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 47 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 47 
8.1.4 Adverse Events of Special Interest .................................................................... 48 
8.2 
Serious Adverse Events ................................................................................................. 48 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 49 
8.4 
Pregnancy Reporting ..................................................................................................... 50 
8.5 
Expedited Reporting ...................................................................................................... 50 
8.6 
Special Situation Reports .............................................................................................. 51 
8.7 
Clinical Laboratory Evaluations .................................................................................... 51 
8.8 
Vital Signs ..................................................................................................................... 52 
8.9 
Electrocardiograms ........................................................................................................ 52 
8.10 Physical Examinations .................................................................................................. 52 
8.11 Height and Weight ........................................................................................................ 52 
8.12 Demographics and Medical/Surgical History ............................................................... 52 
8.13 Digital Ulcers ................................................................................................................ 52 
9 Statistics .................................................................................................................................. 53 


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9.1 
Analysis Populations ..................................................................................................... 53 
9.1.1 Modified Intent-to-Treat Population ................................................................. 53 
9.1.2 Per-Protocol Population .................................................................................... 53 
9.1.3 Safety Population .............................................................................................. 53 
9.2 
Statistical Methods ........................................................................................................ 53 
9.2.1 Analysis of Efficacy .......................................................................................... 53 
9.2.1.1 Primary efficacy analysis .................................................................... 53 
9.2.1.2 Sample size determination .................................................................. 54 
9.2.1.3 Exploratory efficacy analysis .............................................................. 55 
9.2.2 Analysis of Pharmacokinetics ........................................................................... 55 
9.2.3 Analysis of Safety ............................................................................................. 55 
9.2.4 Interim Analysis ................................................................................................ 56 
9.2.5 Data Monitoring Committee ............................................................................. 56 
9.2.6 Steering Committee ........................................................................................... 56 
10 Data Management and Record Keeping ................................................................................. 57 
10.1 Data Management ......................................................................................................... 57 
10.1.1 Data Handling ................................................................................................... 57 
10.1.2 Computer Systems ............................................................................................. 57 
10.1.3 Data Entry ......................................................................................................... 57 
10.1.4 Medical Information Coding ............................................................................. 57 
10.1.5 Data Validation ................................................................................................. 57 
10.2 Record Keeping ............................................................................................................. 57 
10.3 End of Study .................................................................................................................. 58 
11 Investigator Requirements and Quality Control ..................................................................... 59 
11.1 Ethical Conduct of the Study ........................................................................................ 59 
11.2 Institutional Review Board ............................................................................................ 59 
11.3 Informed Consent .......................................................................................................... 59 
11.4 Study Monitoring Requirements ................................................................................... 59 
11.5 Disclosure of Data ......................................................................................................... 60 
11.6 Retention of Records ..................................................................................................... 60 
11.7 Publication Policy ......................................................................................................... 60 
11.8 Financial Disclosure ...................................................................................................... 61 


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12 Study Administrative Information .......................................................................................... 62 
12.1 Protocol Amendments ................................................................................................... 62 
13 References ............................................................................................................................... 63 
Appendix A:  Schedule of Procedures .......................................................................................... 66 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 68 
Appendix C:  Study Drug Intravenous Infusion Pump Rate......................................................... 69 


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LIST OF TABLES 
Table 1. 
Iloprost Dose Titration ................................................................................................ 36 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ACE 
Angiotensin-converting enzyme 
AESI 
Adverse events of special interest 
AUC 
Area under the plasma concentration versus time curve 
cAMP 
Cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
CHFS 
Cochin Hand Function Scale 
CRA 
Clinical Research Associate 
CV 
Coefficient of variation 
DMC 
Data Monitoring Committee 
DU 
Digital ulcer 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
ePRO 
Electronic patient-reported outcomes 
ET 
Early termination 
EULAR 
European League Against Rheumatism 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IP receptor 
Prostacyclin receptor 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
Intravenous(ly) 
mITT 
Modified Intent-to-Treat 
NRS 
Numeric Rating Scale 
PAH 
Pulmonary arterial hypertension 
PAOD 
Peripheral arterial occlusive disease 
PDE5 
Phosphodiesterase-5 
PICC 
Peripherally inserted central catheter/line 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
RP 
Raynaud’s phenomenon 
SAE 
Serious adverse event 
SOC 
System organ class 


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Abbreviation 
Definition 
SSc 
Systemic sclerosis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-emergent adverse event 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1 
Overview of Systemic Sclerosis 
Systemic sclerosis (SSc) is a heterogeneous disease whose pathogenesis is characterized by 
3 hallmarks: small vessel vasculopathy, production of autoantibodies, and fibroblast dysfunction 
leading to increased deposition of extracellular matrix.1 The pathogenesis of SSc involves 
autoimmune mechanisms, which contribute to vascular damage, mainly to small arteries and 
arterioles, and excessive accumulation of collagen and other extracellular matrix components in 
the skin and internal organs.  
Systemic sclerosis is an orphan disease. Incidence rates and prevalence estimates are fairly similar 
for Europe, the United States, Australia, and Argentina, suggesting a prevalence of 150 to 
300 cases per million with a lower prevalence noted in Scandinavia, Japan, the United Kingdom, 
Taiwan, and India.2 The data consistently report prevalence estimates that equate to less than 
100,000 persons in the United States.  
The clinical manifestations and the prognosis of SSc vary, with the majority of patients having 
skin thickening and variable involvement of cardiovascular, gastrointestinal, musculoskeletal, and 
pulmonary systems.3 Subsets of SSc can be discerned, (eg, limited cutaneous SSc, diffuse 
cutaneous SSc, and without skin involvement [sine SSc]).1  
1.1.1 
Raynaud’s Phenomenon in Systemic Sclerosis 
Vascular dysfunction is one of the earliest manifestations of SSc and is thought to be a major factor 
in its pathogenesis.4,5,6 Occlusive vasculopathy is the hallmark lesion of all forms of SSc and is 
seen in different organs involved, such as skin, lungs, kidneys, etc.7,8 
Raynaud’s phenomenon (RP) is the most common manifestation of vascular abnormalities in SSc 
and is a universal feature of SSc disease, affecting more than 95% of patients.9,10,11  
Raynaud’s phenomenon is characterized by abnormal functioning of the cutaneous vessels 
involved in the thermal regulation of blood flow. The distinctive features of RP include pain, 
numbness, tingling, and discoloration of digits due to vasospasms (typically occurring after 
exposure to cold temperatures or stress). Hand impairment is nearly universal in SSc patients. 
Raynaud’s phenomenon secondary to SSc is also associated with significant disability and 
psychological impact.12 In addition to pain, annoyance, and functional disability of RP attacks, 
many patients with SSc report that they change their daily routine to accommodate their RP and 
may have significant anxiety associated with their disease, often expressing fears of digital 
ulcers (DUs) and auto-amputation. 
1.1.2 
Digital Ulcers in Systemic Sclerosis 
Digital ulcers are a frequent external manifestation of vasculopathy in SSc.13 Many factors are 
implicated in the pathogenesis of DUs in the setting of SSc. These include 1) impaired afferent 
vasomotion (highlighted by the intimal hyperplasia of arterioles), 2) disrupted microvasculature 
including capillary and lymphatic, 3) leucocyte and platelet activation and adherence to injured 
endothelium, and 4) hemorheological alterations typical of SSc.8 The disease is also characterized 
by insufficient angiogenesis and defective vasculogenesis contributing further to tissue ischemia.14 


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Ischemic DUs are generally due to aberrant vasculopathy and usually occur on the pulp of the 
fingers. Digital ulcers are defined as a denuded area of de-epithelized tissue.15 Ulcers can also 
occur over bony prominences such as proximal or metacarpophalangeal joints with 
well-demarcated borders and may be caused by traumatic and ischemic causes. The majority of 
the published data has focused on ischemic DUs. Digital ulcers occur in up to 58% of patients with 
limited or diffuse SSc and often occur early in the disease course.16,17,18 A 30% annual incidence 
of SSc DUs has been reported in the literature, suggesting ~20,000 adult patients experience DUs 
secondary to SSc yearly in the United States (based on current United States Census data).19 Of 
those patients who experience a DU, more than half have persistent or recurrent DUs for at least 
6 months.16,17,18,19  
Several studies have shown that the lesions heal slowly, lead to substantial pain and functional 
disability, and are associated with complications such as scarring, loss of distal tissue, infection, 
gangrene, and amputation. These symptoms lead to reduced quality of life, an increased frequency 
of hospitalization, and decreased survival.9,17,20,21 
1.1.3 
Current Management of Raynaud’s Phenomenon and Digital Ulcers in Systemic 
Sclerosis 
Currently, there are no Food and Drug Administration (FDA) approved therapies to treat RP or 
DUs secondary to SSc. Management of RP or DUs in SSc includes nonpharmacologic, 
pharmacologic, and surgical interventions. Multiple pharmacologic agents are used in clinical 
practice to counteract RP and prevent/reduce the burden of DUs (eg, calcium channel blockers, 
angiotensin receptor blockers, angiotensin-converting enzyme [ACE] inhibitors, alpha-adrenergic 
blockers, and serotonin inhibitors), although many lack supportive data and none are approved for 
such use in the United States. Management of SSc vascular diseases includes vasodilators 
(including medications approved for pulmonary arterial hypertension [PAH] such as prostacyclin 
analogs, endothelin receptor antagonists, phosphodiesterase-5 (PDE5) inhibitors, and soluble 
guanylate cyclase stimulators). Phosphodiesterase-5 inhibitors, prostacyclin analogs (iloprost), 
and bosentan have been endorsed by the 2016 updated European League Against Rheumatism 
(EULAR) recommendations for the treatment of SSc.22 None of these drugs are approved for SSc 
RP or DU in the United States. 
In general, immunosuppressive therapies are not effective for vasculopathy associated with SSc, 
as highlighted in PAH and scleroderma renal crisis.23 
In addition to the above strategies aimed at specific intervention, established SSc DUs often require 
treatments for secondary effects, such as use of opioids and other analgesics for pain and 
aggressive use of systemic and local antibiotics for infection.24 Efforts to promote healing are often 
unsatisfactory, and surgical intervention resulting in permanent tissue loss may be necessary. Thus, 
there remains a clear, unmet medical need for a pharmacological therapy that will treat and affect 
the natural course of DUs in SSc. 
1.2 
Overview of Iloprost 
Iloprost, a stable analog of prostacyclin, has been used for over a decade as an inhaled formulation 
to treat PAH (both within and outside of the United States) and as an intravenous (IV) formulation 
for occlusive arterial diseases (outside of the United States) due to its pharmacological effects on 
vascular cells and platelets.25,26 Iloprost is a potent prostacyclin receptor (IP receptor) agonist. 
Pharmacology studies have shown that iloprost increases the cyclic adenosine monophosphate 


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(cAMP) levels in human platelets of various species through stimulation of adenylate cyclase, 
leading to inhibition of platelet aggregation. In addition, iloprost has been shown to cause 
vasodilation through stimulation of the IP receptor on smooth muscle cells. The commercially 
approved forms of iloprost (Ilomedin® and Ventavis®) consist of 2 diastereoisomers that contrast 
in conformation of a methyl group at the carbon 16 position. The current commercial formulation 
uses a fixed racemic mixture of 16(S) and 16(R) diastereoisomers (47:53). The 16(S) is 
substantially more potent than the 16(R) in vasodilating and inhibiting collagen-induced platelet 
aggregation.  
1.2.1 
Regulatory Status of Iloprost 
The inhaled formulation of iloprost received marketing authorization in the European Union in 
September 2003, and Schering AG began commercializing the product (Ventavis) in early 2004.  
Ventavis is indicated for the treatment of PAH to improve a composite endpoint consisting of 
exercise tolerance, symptoms, and lack of deterioration. Studies establishing effectiveness 
predominately included patients with New York Heart Association Functional Class III to IV 
symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective 
tissue diseases (23%).  
The IV formulation of iloprost was first approved in the early 1990s in Europe and has since 
received marketing approvals in 30 European and non-European countries under the tradename 
Ilomedin. The approved indications for Ilomedin in the European Union include 1) treatment of 
patients with severe peripheral arterial occlusive disease (PAOD), particularly those at risk of 
amputation and in whom surgery or angioplasty is not possible; 2) treatment of advanced 
thromboangitis obliterans (Buerger’s disease) with critical limb ischemia in cases where 
revascularization is not indicated; 3) treatment of patients with severe disabling RP unresponsive 
to other therapies; and 4) treatment of moderate or severe primary and secondary PAH, such as 
New York Heart Association functional classes III and IV. 
1.2.2 
Rationale for Iloprost for the Treatment of Symptomatic Raynaud’s Phenomenon 
Secondary to Systemic Sclerosis  
Iloprost is a synthetic analog of prostacyclin. Iloprost may improve outcomes and restore function 
lost due to SSc by enhancing cutaneous blood flow, reducing microvascular inflammation, 
reducing/reversing fibrosis, and decreasing platelet aggregation.27,28,29,30,31,32 
1.2.3 
Summary of Iloprost Mechanism of Action  
Iloprost is thought to dilate systemic arterial vascular beds through stimulation of the IP receptor 
on smooth muscle cells. Iloprost has been shown to inhibit vasoconstriction induced by 
arachidonic acid and phenylephrine.33,34 Pharmacology studies have shown that iloprost also 
increases the cAMP levels in human platelets of various species through stimulation of adenylate 
cyclase, leading to inhibition of platelet aggregation and adhesion.30,31 Iloprost is thought to have 
anti-inflammatory and immunomodulating effects. It reduces neutrophil adhesion and chemotaxis, 
and has been shown to down-regulate the intracellular expression of interleukin-6 and tumor 
necrosis factor-alpha in human monocytes.35,36 Iloprost has been suggested to possess antifibrotic 
effects, as it has been shown to prevent bleomycin-induced fibrosis and reverse established right 
ventricular fibrosis in animal models.28,32  


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1.2.4 
Clinical Pharmacology 
Pharmacokinetic (PK) studies have been conducted with iloprost in healthy volunteers and in a 
variety of patient populations using different formulations and routes of administration. The PK 
and systemic exposures associated with these formulations and routes of administration are very 
well characterized in the literature. A vast majority of the clinical pharmacology and clinical 
studies published in the literature are with the IV formulation of iloprost.  
In PK studies in animals, there was no evidence of interconversion of the 2 diastereoisomers of 
iloprost. In human PK studies, the 2 diastereoisomers were not individually assayed.  
Iloprost has a short half-life of 20 to 30 minutes and has linear PK following IV administration at 
doses of 1 to 3 ng/kg/min. Approximately 60% of iloprost is bound to plasma protein (75% to 
albumin). The total plasma clearance of iloprost in healthy individuals is 20 mL/min/kg.37  
In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the 
biotransformation of iloprost. Iloprost is metabolized principally via β-oxidation of the carboxyl 
side chain. The main metabolite is tetranor-iloprost, which is found in the urine in free and 
conjugated form. In animal experiments, tetranor-iloprost was pharmacologically inactive. 
Clearance in normal subjects was approximately 20 mL/min/kg. A mass-balance study using IV 
and orally administered [3H]-iloprost in healthy subjects (n=8) showed recovery of 81% of total 
radioactivity over 14 hours postdose, with 68% and 12% recoveries in urine and feces, 
respectively. In patients with liver cirrhosis, the mean clearance in Child-Pugh B subjects (n=5) 
was approximately 10 mL/min/kg. For patients requiring intermittent dialysis (n=7), the mean area 
under the plasma concentration time curve from time 0 to 4 hours was 230 pg*h/mL compared to 
54 pg*h/mL for patients with renal failure (n=8) not requiring intermittent dialysis and 48 pg*h/mL 
for normal healthy volunteers. Dialysis did not affect iloprost plasma concentrations.25  
Iloprost PK has been investigated in patients suffering from renal insufficiency who are not on 
dialysis with serum creatinine >2 mg/dL and patients on dialysis.38 This study demonstrated that 
the PK profile for iloprost in patients with renal failure, not on dialysis, was similar to that observed 
in PAOD patients and healthy volunteers. Patients on dialysis have a reduced clearance of iloprost 
by a factor of 4. The iloprost dosing regimen requires titration, so more careful titration should be 
considered for patients on dialysis.38,39  
Iloprost PK has also been investigated in patients suffering from liver cirrhosis. The study 
demonstrated that iloprost clearance was reduced by a factor of 2 in patients suffering from hepatic 
dysfunction compared with healthy subjects. The iloprost dosing regimen requires titration, so 
more careful titration should be considered for patients with liver impairment. However, apart 
from a reduction of the starting dose (of approximately 50%) for titration, special 
recommendations are not necessary for patients with impaired liver function.40 
1.2.5 
Summary of Iloprost Clinical Experience in Systemic Sclerosis 
Several proof-of-concept studies have been conducted evaluating the effects of IV iloprost in 
patients with SSc. These studies evaluated the effects of iloprost in SSc patients with RP and DUs.  
Two placebo-controlled studies that support the Eicos Sciences, Inc. development program were 
published by Fredrick M Wigley, MD and sponsored by Berlex Laboratories and the Scleroderma 
Society.41,42   


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The first study evaluated the effect of treatment with IV iloprost in patients with RP and ischemic 
ulcers secondary to SSc. In this double-blind, placebo-controlled, randomized, parallel-group 
study, 35 patients with SSc-associated RP were randomized to receive iloprost (0.5 to 
2.0 ng/kg/min) or placebo by continuous infusion for 6 hours on 5 consecutive days. Patients were 
examined every 2 weeks for a follow-up period of 10 weeks. The study evaluated patient diaries 
recording RP symptoms and attacks. Digital cutaneous lesions including digital ischemic 
ulcerations, fissures, and paronychia were counted, described, and photographed at entry and on 
each follow-up assessment. 41 
Of the 35 patients enrolled, 34 completed the 5 days of infusion. One patient discontinued 
treatment on Day 2 due to chest and thigh pain of uncertain etiology. Thirty-three patients 
completed 10 weeks of follow-up; 1 patient in the placebo group withdrew at the 8-week follow-up 
due to a new DU. A total of 11 patients, 7 treated with iloprost and 4 receiving placebo, had 
cutaneous finger lesions (DUs, fissures, or paronychia) at baseline. At the Week 10 study visit, 
6 of the 7 patients treated with iloprost had complete healing of all lesions compared to none of 
the 4 patients taking placebo (p=0.015). Digital tip ulcers were present in 4 patients in each 
treatment group. All of the iloprost patients had complete healing at Weeks 6, 8, and 10 compared 
to none of the 4 patients receiving placebo (p=0.029). One of the placebo patients reported partial 
healing of DUs. Of the patients with no lesions at baseline, 3 of 11 patients receiving iloprost and 
3 of 13 patients receiving placebo developed new lesions. The total number of DUs that developed 
was less in iloprost (11 DUs) compared to placebo (29 DUs). At least 1 adverse event was reported 
in all 18 patients receiving iloprost and by 10 of the 17 patients receiving placebo. The most 
common adverse events reported in the iloprost group were headache, nausea, vomiting, and jaw 
or thigh pain.41 
The second study evaluated the effect of IV iloprost in treating patients with RP secondary to SSc. 
In a follow-up, multicenter (12 sites), double-blind, placebo-controlled, randomized, 
parallel-group study, 131 SSc patients with RP were randomized to receive iloprost (0.5 to 
2.0 ng/kg/min) or placebo by continuous infusion for 6 hours on 5 consecutive days. The study 
follow-up period was 9 weeks and patients were re-examined at 3, 6, and 9 weeks after completion 
of the infusion. The study evaluated patient diaries recording RP symptoms and attacks. 
Physicians’ assessment of overall treatment effect was recorded. Digital cutaneous lesions were 
recorded on Days 1 and 5 of infusion and at Weeks 3, 6, and 9 of the follow-up period. The protocol 
defined a healing response as a reduction in number of finger lesions from baseline of at least 50%. 
Data for cutaneous lesions were analyzed for the subset of patients who successfully completed 
5 days of infusion and had at least 6 weeks of follow-up.42 
A total of 131 patients (64 iloprost and 67 placebo) enrolled and 126 successfully completed the 
5-day infusion. Of these, 114 patients (56 iloprost and 58 placebo) completed at least 6 weeks of 
follow-up. A total of 17 patients (8 iloprost and 9 placebo) withdrew from the study. The patients 
receiving iloprost had a decreased RP severity score at Weeks 3, 6, and 9. The treatment difference 
was greater at Weeks 1 to 3 (p=0.006) and Weeks 4 to 6 (p=0.05) than at Weeks 7 to 9 (p=0.09). 
A comparison of the changes over the entire study period (Weeks 1 to 9) showed a greater mean 
decrease in the iloprost group (-34.8%) than the placebo group (-19.7%) (p=0.01). In the subset of 
patients with digital cutaneous lesions at baseline, the mean decrease in RP severity score remained 
the same as those in the entire group given iloprost (-34.5%), but the effect was less in those who 
received placebo in this subset (-9.9%) (p=0.01).42  


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Patients receiving iloprost had a greater decrease in frequency of RP attacks than those receiving 
placebo at every follow-up assessment. The mean decrease in attack frequency per week during 
the entire study was 39.1% in patients receiving iloprost compared to 22.2% in patients receiving 
placebo (p=0.005). In the subset of patients with digital cutaneous lesions, there was a mean 
decrease in attack frequency during the entire follow-up period of 36% in patients receiving 
iloprost and 14.1% in patients receiving placebo (p=0.064).42   
A total of 73 patients (35 iloprost and 38 placebo) had digital cutaneous lesions at baseline. A 
greater number of patients receiving iloprost had at least a 50% reduction from baseline in the total 
number of lesions at all times during the 9-week follow-up period. The group receiving iloprost 
had a greater proportion of patients who completely healed (no remaining original lesions and no 
new lesions) at all times during the study compared to placebo (p>0.20 at Week 9). The most 
common adverse events reported by patients receiving iloprost were headache, flushing, nausea, 
jaw pain, diarrhea, and vomiting. The side effects were reversible and controlled by a reduction of 
the infusion rate of iloprost.42  
In addition to the 2 studies summarized above, there is a large amount of published data in Europe 
on the successful use of intermittent or continuous iloprost for management of DUs secondary to 
SSc.43,44,45,46,47,48 
1.3 
Rationale  
Intravenous iloprost has market authorization in Europe and Australia and is the standard of care 
treatment for RP and DUs in Europe. However, this treatment is not currently available within the 
United States. In clinical practice, there is a high unmet need for effective pharmacologic therapies 
for patients with symptomatic RP secondary to SSc. This Phase 2 pilot study will be piloting an 
initial evaluation of iloprost, testing the study endpoints and logistics of study operations that 
include, among other things, an electronic patient-reported outcomes (ePRO) diary for the 
evaluation of subject response to the treatment as well as the infusion workflow for this multiday 
treatment to prepare for a Phase 3 study. There are several significant feasibility challenges to 
studying symptomatic RP secondary to SSc. First, the population is very small,2,49 estimated at 
~70,000 adult patients with SSc in the United States (based on United States Census from 
04 July 2016). For patients with SSc, RP is a problem throughout the year, but the symptoms have 
been reported to be reduced by about 50% in the summer months.50 To ensure recruitment and 
limit the impact of seasonal variation in temperature on the incidence of attacks, this study will be 
conducted during the winter and spring months.  


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to evaluate the efficacy of iloprost compared to placebo on the change in 
the weekly frequency of symptomatic RP attacks from baseline in subjects with symptomatic RP 
secondary to SSc. 
2.2 
Exploratory Objectives 
The exploratory objectives are the following: 
• To evaluate the efficacy of iloprost compared to placebo on the severity of RP attack symptoms 
• To evaluate the efficacy of iloprost compared to placebo on the Raynaud’s Condition Score 
• To evaluate the efficacy of iloprost compared to placebo on hand function as assessed by the 
Cochin Hand Function Scale (CHFS) 
• To evaluate the safety and tolerability of iloprost 
• To evaluate the efficacy of iloprost compared to placebo on symptomatic RP attack duration 
• To evaluate the efficacy of iloprost compared to placebo on the worst pain associated with 
symptomatic RP 
• To evaluate the efficacy of iloprost compared to placebo on the patient assessment of overall 
improvement in symptomatic RP 
• To evaluate the PK of iloprost in subjects with symptomatic RP secondary to SSc 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate the 
effect of iloprost on the symptomatic relief of RP attacks in subjects with symptomatic RP 
secondary to SSc. The study will be piloting an initial evaluation of iloprost, testing the study 
endpoints and logistics of study operations that include, among other things, an ePRO diary for 
the evaluation of subject response to the treatment as well as the infusion workflow for this 
multiday treatment. Subjects are allowed to continue receiving stable standard of care therapies 
for the management of symptomatic RP (eg, calcium channel blockers, ACE inhibitors, statins, 
fluoxetine, and low dose acetylsalicylic acid) or may participate without the use of background 
standard of care therapies.  
The study will enroll a maximum of 40 subjects. Subject enrollment may be halted by the Sponsor 
at any time for any reason. 
The study consists of an up to 30-day screening period during which subjects will complete a daily 
ePRO diary to record information regarding all symptomatic RP attacks (eg, severity of symptoms, 
duration, and hand function). The up to 30-day screening period consists of a 5-day eligibility 
period and an up to 25-day baseline ePRO diary completion period: 
• During the 5-day eligibility period, eligible subjects will have a minimum of 10 symptomatic 
RP attacks, documented in the ePRO diary, occurring over at least 3 separate days of the 5-day 
eligibility period.  
• During the baseline ePRO diary completion period, eligible subjects must complete the daily 
ePRO diary for a minimum of 10 days (up to a maximum of 25 days) until the day of 
randomization. It may be necessary to extend the baseline ePRO diary completion period 
beyond 10 days in order to accommodate the preferred Monday to Friday dosing schedule. The 
ePRO symptomatic RP attack data from this time period will be used for the calculation of the 
baseline frequency of symptomatic RP attacks. 
Eligible subjects will be given the option to participate in a PK substudy. Subjects who participate 
in the substudy will provide plasma samples for PK analysis. The samples will be analyzed for 
iloprost concentrations using validated liquid chromatography mass spectrometry methods.  
Subjects will be randomized in a 1:1 ratio to iloprost injection for IV use or placebo. 
Randomization will be stratified based on the use of phosphodiesterase inhibitors at screening. 
Study drug administration will begin on Day 1, and subjects will receive study drug for 
5 consecutive days (eg, Monday through Friday) as an IV infusion over 6 hours each day via a 
peripheral line (NovaCath™ Integrated IV Catheter System) or a peripherally inserted central 
catheter (PICC) using an infusion pump. 
Subjects must have a systolic blood pressure 85 mmHg (sitting position) prior to study drug 
administration each day of administration. On Day 1, study drug will be initiated at a starting dose 
of 0.5 ng/kg/min, and dose increases will occur every 30 minutes (5 minutes) in increments of 
0.5 ng/kg/min up to 2.0 ng/kg/min or the individual tolerated dose. If dose-limiting adverse events 
(eg, headache, flushing, jaw pain, myalgia, nausea, or vomiting) occur that cannot be tolerated by 
the subject, then the dose will be reduced in a step wise manner by 0.5 ng/kg/min every 30 minutes 
(5 minutes), until a tolerated dose is determined. If symptomatic hypotension or a dose-limiting 


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adverse event occurs during administration of iloprost at the starting dose (ie, 0.5 ng/kg/min), the 
infusion will be reduced to 0.25 ng/kg/min. If the dose of 0.25 ng/kg/min is not tolerated due to 
symptomatic hypotension or a dose-limiting adverse event occurs, the study drug will be 
discontinued and reinitiation of the infusion can be attempted after the event has resolved or been 
treated. Blood pressure and heart rate will be monitored 15 minutes (5 minutes) prior to and after 
all dose changes. If the subject experiences symptomatic hypotension or any other adverse event 
that cannot be tolerated, as determined by the Investigator, during administration of study drug, 
the dose will be reduced or the infusion will be stopped until the symptoms resolve, at which point 
the study drug should be reinitiated at a previously tolerated dose. The maximum tolerated dose 
will be maintained for the remaining 6-hour daily period. At the end of the 6-hour infusion period, 
the dose will be stopped. Subjects will be monitored for up to 1 hour after completion of study 
drug infusion (ie, vital signs will be obtained 15 minutes [5 minutes] and 1 hour [15 minutes] 
after completion of the infusion). 
On Days 2 to 5, the infusion will be started using the highest infusion rate tolerated on the previous 
day without up- or down-titration, unless the subject does not tolerate the infusion or adverse 
events occur that cannot be tolerated by the subject and necessitate a reduction in the dose. Vital 
signs will be measured prior to study drug administration and at 15 minutes (5 minutes) prior to 
and after all dose changes during the infusion. Additionally, vital signs will be monitored at 
15 minutes (5 minutes) and 1 hour (15 minutes) after completion of the 6-hour infusion. 
During the treatment period (Days 1 to 5), while subjects receive study drug, the ePRO diary will 
not be completed. No study assessments will be performed on the 2 days following the end of 
treatment (Days 6 and 7, eg, Saturday and Sunday) to allow the subject to rest and return to a 
schedule of normal daily living activity following the 5 days of infusions.  
Subjects will be contacted via telephone on Day 8 to ensure they resume completion of the daily 
ePRO diary; subjects will complete the diary from Day 8 through Day 21. On Day 22, subjects 
will return to the clinic for post-treatment evaluations. A follow-up visit will occur 30 days after 
the last administration of study drug (Day 35). 
Subjects who discontinue study drug early will remain in the study (unless the subject withdraws 
consent) and complete the daily ePRO diary from Day 8 to Day 21 including clinical laboratory 
assessments on the remaining missed infusion days as well as post-treatment study assessments. 
The total duration of the study for a subject will be up to approximately 9 weeks. 
A Data Monitoring Committee (DMC) and a Steering Committee will be utilized in the study. See 
Section 9.2.6 for details. 
3.2 
Study Indication 
The indication of this study is symptomatic RP secondary to SSc. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female subjects must be 18 years of age. 
2. Subjects must have a diagnosis of SSc as defined by the 2013 American College of 
Rheumatology criteria/EULAR criteria. 
3. Subjects must have a diagnosis or history of RP, self-reported or reported by a physician, with 
at least a 2-phase color change in finger(s) of pallor, cyanosis, and/or reactive hyperemia in 
response to cold exposure or emotion. 
4. Subjects must have a minimum of 10 symptomatic RP attacks, documented in the ePRO diary, 
occurring over at least 3 separate days of the 5-day eligibility period. 
o Note: A symptomatic Raynaud’s attack for this study is defined as at least 1 color change 
of the subject’s finger(s) (blue, white, or red) associated with at least 1 symptom (pain, 
numbness, tingling, and/or discomfort of the finger[s]). The attack is considered over when 
the color changes back to pre-attack color (normal) and the symptoms return to the 
subject’s pre-attack level. 
5. Female subjects of childbearing potential (defined as female subjects who have experienced 
menarche and who are not permanently sterile or postmenopausal; postmenopausal is defined 
as 12 consecutive months with no menses without an alternative medical cause) and male 
subjects must agree to use contraception for the duration of the study.  
6. Subjects must be willing and able to comply with the study requirements and give informed 
consent for participation in the study. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Female subjects who are pregnant or breastfeeding. 
2. Subjects with systolic blood pressure <85 mmHg (sitting position) at screening. 
3. Subjects with an estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening as 
determined by the Modification of Diet in Renal Disease equation. 
4. Subjects with Child-Pugh Class B or Class C liver disease or an alanine aminotransferase 
and/or aspartate aminotransferase value >3 × the upper limit of normal at screening. 
5. Subjects with gangrene, DU infection, or requirement of cervical or digital sympathectomy 
within 30 days of screening. 
6. Subjects with intractable diarrhea or vomiting. 
7. Subjects with a risk of clinically significant bleeding events including those with coagulation 
or platelet disorders. 
8. Subjects with a history of major trauma or hemorrhage in the past 4 weeks. 


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9. Subjects with clinically significant chronic intermittent bleeding such as active gastric antral 
vascular ectasia or active peptic ulcer disease. 
10. Subjects who have had any cerebrovascular events (eg, transient ischemic attack or stroke) 
within 6 months of screening. 
11. Subjects with a history of myocardial infarction or unstable angina within 6 months of 
screening. Subjects should not have a planned coronary procedure during their participation in 
the study. 
12. Subjects with acute or chronic congestive heart failure (New York Heart Association Class III 
[moderate] or Class IV [severe]). 
13. Subjects with a history of life-threatening cardiac arrhythmias. 
14. Subjects with a history of hemodynamically significant aortic or mitral valve disease. 
15. Subjects with more than mild restrictive or congestive cardiomyopathy uncontrolled by 
medication or implanted device. 
16. Subjects with known pulmonary hypertension, PAH, or pulmonary veno-occlusive disease. 
17. Subjects with a history of significant restrictive lung disease defined as forced vital capacity 
<45% predicted and diffusing capacity of the lungs for carbon monoxide <40% predicted 
(uncorrected for hemoglobin). 
18. Subjects with a history of cervical or digital sympathectomy within 6 months of screening. 
19. Subjects with scleroderma renal crisis within 6 months of screening. 
20. Subjects with a concomitant life-threatening disease with a life expectancy <12 months. 
21. Subjects who have a clinically significant disorder, that in the opinion of the Investigator, could 
contraindicate the administration of study drug, affect compliance, interfere with study 
evaluations, or confound the interpretation of study results. 
22. Subjects who have taken or are currently taking any parenteral, inhaled, or oral prostacyclin or 
IP receptor agonists (eg, epoprostenol, treprostinil, iloprost, and selexipag) within 8 weeks of 
screening. 
23. Subjects must not initiate dosing of oral, topical, or IV vasodilators (eg, calcium channel 
blockers, PDE5 inhibitors [eg, sildenafil, tadalafil, or vardenafil], nitrates, and fluoxetine), or 
if currently receiving any vasodilator, must have been stably medicated (no dose adjustments) 
for at least 2 weeks prior to screening. 
24. Subjects with any history of acetaminophen intolerability (eg, allergic reaction to 
acetaminophen). 
25. Subjects with any malignancy that requires treatment during the study period, that has required 
treatment within 1 year of screening, or that is currently not in remission. 
26. Subjects who have used any investigational medication or device for any indication within 
30 days or 5 half-lives (whichever is longer) of screening. 


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4.3 
Withdrawal Criteria 
Subjects should be listed as having withdrawn consent only when the subject no longer wishes to 
participate in the study and no longer authorizes the Investigators to make efforts to continue to 
obtain their outcome data.  
Every effort should be made to encourage subjects to remain in the study and complete the ePRO 
diary for the entire duration of the study. Subjects will be educated on the continued scientific 
importance of their data, even if they discontinue study drug. Ideally, if subjects withdraw their 
consent, it should be done in writing. 
Withdrawn subjects will not be replaced. 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records.  
4.3.1 
Discontinuation of Study Drug 
A subject in this clinical study may discontinue study drug for any of the following reasons: 
• Subject requests to discontinue study drug 
• Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol 
• Any serious adverse event (SAE), clinically significant adverse event, severe laboratory 
abnormality, intercurrent illness, or other medical condition which indicates to the Investigator 
that continued participation is not in the best interest of the subject 
• Pregnancy 
• Requirement of prohibited concomitant medication 
• Subject fails to comply with protocol requirements or study-related procedures 
Unless the subject withdraws consent, subjects who discontinue study drug early will remain in 
the study for further acquisition of endpoint measurements through Day 21 including clinical 
laboratory assessments on the remaining missed infusion days as well as post-treatment study 
assessments. The reason for subject discontinuation of study drug must be documented in the 
electronic case report form (eCRF). 
4.3.2 
Withdrawal of Subjects From the Study 
Participation of a subject in this clinical study may be discontinued for any of the following 
reasons: 
• Subject withdraws consent or requests discontinuation from the study for any reason 
• Death of the subject 
• Termination of the study by the Sponsor or the regulatory authority 
In circumstances where a subject discontinues the study prior to Day 21, study staff should make 
every effort to complete the full panel of assessments scheduled for the early termination (ET) 
visit. The reason for subject withdrawal from the study must be documented in the eCRF. 


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Subjects will be randomized by Interactive Response Technology (IRT) in a 1:1 ratio to the 
following treatment groups: 
• Iloprost injection for IV use  
• Placebo injection for IV use 
5.2 
Rationale for Dosing 
Intravenous iloprost for the treatment of RP is well established in European guidelines and 
practice. The dosing in this study is based on the iloprost dosing titration algorithm that has been 
used in proof-of-concept studies in subjects with SSc 41,42,51 and current labeling outside the 
United States (Ilomedin).26  
5.3 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Subjects will be randomized to 1 of 
the 2 treatment groups listed in Section 5.1.  
Randomization will be stratified based on the use of phosphodiesterase inhibitors at screening. 
Individual treatment assignments will be blinded to the Sponsor, Investigator, study personnel, and 
subjects throughout the course of the study. All individuals directly involved in the conduct of the 
study, including data management personnel, will remain blinded to treatment assignments.  
5.4 
Breaking the Blind 
It is not expected that emergency unblinding will be needed due to the short half-life of iloprost 
and the lack of a known antidote. Furthermore, adverse events due to iloprost typically resolve 
quickly once treatment with iloprost has been stopped. However, at all times, study personnel will 
attempt to safeguard the integrity of the blinding in order to minimize bias in the conduct of the 
study. 
Breaking of the blind should not occur except in the case of a medical emergency and should only 
occur after discussion with the Medical Monitor. In such a case, the Investigator may access this 
information by contacting the Sponsor or its designee. If the blind is broken for an individual 
subject, the blinding should be preserved for the remainder of the subjects throughout the duration 
of the study. In such a case, study personnel may be notified of that individual subject’s treatment 
assignment without jeopardizing study blinding for the overall study. 
If the blind is broken for a subject, the subject will be encouraged to continue his/her randomized 
intervention unless it would be medically contraindicated to do so; this decision will be based on 
Investigator consultation with the Medical Monitor. All subjects should be encouraged to continue 
study visits to the end of the study whether or not they remain on his/her randomized intervention. 


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5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
Iloprost injection for IV use and matching placebo will be supplied in vials packaged in a blinded 
study drug kit (10 vials per kit). The iloprost and placebo vials will be identical, except 100 mcg 
of iloprost will be added to the active study drug vials. The drug product must be diluted with 
sodium chloride 0.9% in a drug reservoir (IV bag) prior to use.  
Study drug will be packaged according to current Good Manufacturing Practice (GMP) and Good 
Clinical Practice (GCP) guidelines. 
Study drug will be labeled according to the requirements of local law and legislation, as well as 
current GMP and GCP guidelines. Proof labels, detailing actual label text, will be available in the 
study files. 
5.5.2 
Study Drug Preparation and Dispensing 
Dilution of drug product for use in the infusion pump is as follows: A total of 1 mL volume (0.5 mL 
withdrawn from 2 vials) should be withdrawn into a sterile syringe using aseptic technique. The 
iloprost in the sterile syringe should be transferred to a drug reservoir containing 99 mL of sodium 
chloride to make a 1000 ng/mL (1 mcg/mL) concentration. 
The drug reservoir should always be dispensed in a pump drug reservoir with instructions for use 
as described in the Pharmacy Manual. 
5.5.3 
Study Drug Administration 
Study drug will be administered at the site by personnel who are trained on how to prepare the 
study drug solution, how to prepare the IV site, and how to administer the IV infusion via a 
peripheral line or a PICC using an infusion pump. Prior to the first infusion, the NovaCath 
Integrated IV Catheter System will be inserted into a small peripheral vein in the hand or arm using 
aseptic technique by a trained healthcare professional. If the subject’s peripheral veins do not 
support the placement of a peripheral line, a trained healthcare professional will insert a PICC. 
(Note: In some instances where the site chooses to use a PICC, it may be necessary to confirm 
placement of the PICC with an x-ray). When possible, the same NovaCath Integrated IV Catheter 
System or PICC will be used for the 5 days of treatment. Refer to the Infusion and/or Pharmacy 
Manual for additional information regarding infusion preparation and administration. 
Subjects will receive the study drug IV infusions for 5 consecutive days (eg, Monday to Friday). 
Study drug will be administered after dilution as an IV infusion over 6 hours each day via a 
peripheral line (NovaCath Integrated IV Catheter System) or a PICC using an infusion pump.  
Prior to study drug administration, subjects will be premedicated with a single dose of 
2 acetaminophen extended-release tablets, 650 mg (each). 
Subjects must have a systolic blood pressure 85 mmHg (sitting position) prior to study drug 
administration each day of administration. 
First infusion 
On Day 1, study drug will be initiated at a starting dose of 0.5 ng/kg/min, and dose increases will 
occur every 30 minutes (5 minutes) in increments of 0.5 ng/kg/min up to 2.0 ng/kg/min or the 


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individual tolerated dose. If dose-limiting adverse events (eg, headache, flushing, jaw pain, 
myalgia, nausea, or vomiting) occur that cannot be tolerated by the subject, then the dose will be 
reduced in a step wise manner by 0.5 ng/kg/min every 30 minutes (5 minutes), until a tolerated 
dose is determined. If symptomatic hypotension or a dose-limiting adverse event occurs during 
administration of iloprost at the starting dose (ie, 0.5 ng/kg/min), the infusion will be reduced to 
0.25 ng/kg/min. If the dose of 0.25 ng/kg/min is not tolerated due to symptomatic hypotension or 
a dose-limiting adverse event occurs, the study drug will be discontinued and reinitiation of the 
infusion can be attempted after the event has resolved or been treated. Blood pressure and heart 
rate will be monitored 15 minutes (5 minutes) prior to and after all dose changes. If the subject 
experiences symptomatic hypotension or any other adverse event that cannot be tolerated, as 
determined by the Investigator, during administration of study drug, the dose will be reduced or 
the infusion will be stopped until the symptoms resolve, at which point the study drug should be 
reinitiated at a previously tolerated dose. The maximum tolerated dose will be maintained for the 
remaining 6-hour daily period. At the end of the 6-hour infusion period, the dose will be stopped. 
Subjects will be monitored for up to 1 hour after completion of study drug infusion (ie, vital signs 
will be obtained 15 minutes [5 minutes] and 1 hour [15 minutes] after completion of the 
infusion). 
Infusions 2 to 5 
On Days 2 to 5, the infusion will be started using the highest infusion rate tolerated on the previous 
day without up- or down-titration, unless the subject does not tolerate the infusion or adverse 
events occur that cannot be tolerated by the subject and necessitate a reduction in the dose. Vital 
signs will be measured prior to study drug administration and at 15 minutes (5 minutes) prior to 
and after all dose changes during the infusion. Additionally, vital signs will be monitored at 
15 minutes (5 minutes) and 1 hour (15 minutes) after completion of the 6-hour infusion. 
Table 1 outlines the dose titration schedule. 


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Table 1. Iloprost Dose Titration 
Titration and 
Maintenance 
Time Point 
Dose 
Instructions 
Starting dose 
0 min; Day 1 
0.5 ng/kg/min 
Reduce the dose to 0.25 ng/kg/min if the subject 
does not tolerate the 0.5 ng/kg/min starting dose. 
Up-titration 
(5 minutes) 
30 min; Day 1 
1.0 ng/kg/min 
Reduce the dose to 0.5 ng/kg/min (starting dose) 
if the subject does not tolerate the 1.0 ng/kg/min 
dose. 
60 min; Day 1 
1.5 ng/kg/min 
Reduce the dose to 1.0 ng/kg/min if the subject 
does not tolerate the 1.5 ng/kg/min dose. 
90 min; Day 1 
2.0 ng/kg/min 
Reduce the dose to 1.5 ng/kg/min if the subject 
does not tolerate the 2.0 ng/kg/min dose. 
120 min; Day 1 
(Hours 2 to 6) 
2.0 ng/kg/min, or 
highest tolerated dose 
Reduce dose in a step-wise manner if the subject 
experiences dose-limiting adverse events. 
Maintenance 
Days 2 to 5 
2.0 ng/kg/min, or 
highest dose tolerated 
on previous day 
The highest tolerated dose will be administered 
for the remaining days without up- or 
down-titration, unless the subject does not 
tolerate the infusion or adverse events occur that 
necessitate a reduction in dose (in 0.5 ng/kg/min 
increments) and subsequent up-titration is 
allowed to the Day 1 high tolerated dose. 
A lower starting dose may be initiated on Day 3 
to Day 5 if the subject does not tolerate the 
previous days’ highest tolerated dose as a starting 
dose. 
Refer to Appendix C for the study drug IV infusion pump rate.   
5.5.3.1 
Common adverse events associated with iloprost intravenous infusion 
Investigators should be aware that the following adverse events are commonly experienced with 
iloprost IV infusion: headache, flushing, jaw pain, myalgia, nausea, and vomiting. These adverse 
events may be dose-limiting and Investigators should closely monitor subjects and reduce the dose 
in a step-wise manner as described in Table 1. 
5.5.4 
Treatment Compliance 
Study drug will be administered at the site by trained site staff. Dosing compliance will be recorded 
by the Investigator or designee at the investigational site. 
5.5.5 
Storage and Accountability 
The fully diluted drug product, ready for use, can be used immediately as a 6-hour continuous 
infusion with an infusion pump per the conditions of use as outlined in the Infusion and/or 
Pharmacy Manual. The Day 1 dose preparation should not occur until randomization on Day 1. 
Records will be maintained indicating the receipt and dispensation of all study drug supplies. At 
the conclusion of the study, the Clinical Research Associate (CRA) will conduct a review of the 
study drug inventory. If no study drug remains, this will be indicated in the Drug Accountability 
Log. 


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5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
The following medications are not permitted within 8 weeks of screening or during the study: any 
parenteral, inhaled, or oral prostacyclin or IP receptor agonists (eg, epoprostenol, treprostinil, 
iloprost, and selexipag). 
5.6.2 
Restricted Medications and/or Procedures 
Use of oral, topical, or IV vasodilators (eg, calcium channel blockers, PDE5 inhibitors [eg, 
sildenafil, tadalafil, or vardenafil], nitrates, and fluoxetine) is permitted only if the subject is 
currently receiving a stably medicated regimen (no dose adjustments for at least 2 weeks prior to 
screening). Initiation of any vasodilators within 2 weeks prior to screening is not permitted.  
5.6.3 
Allowed Medications 
Supportive medications to treat mild side effects of the study drug infusion (eg, headache) are 
allowed at the Investigator’s discretion. All concomitant medications must be recorded on the 
eCRF. 
5.6.4 
Documentation of Prior and Concomitant Medication Use 
All prior and concomitant medications and treatments received by the subject will be recorded on 
the appropriate eCRF as follows: 
• Premedicated with acetaminophen extended-release tablets, 650 mg (each) 
• Within 8 weeks of screening and throughout the duration of the study for any parenteral, 
inhaled, or oral prostacyclin or IP receptor agonists  
• Within 2 weeks of screening and throughout the duration of the study for oral, topical, or IV 
vasodilators  
• Within 2 weeks of screening and throughout the duration of the study for all other medications 
The medication name, route of administration, dose, frequency, indication, and duration of the 
treatment or procedure (start and stop dates) will be recorded. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before any 
protocol-specific procedures are carried out. See Section 11.3 for details on informed consent. 
6.2 
Screening Period (Days -30 to -1) 
The study consists of an up to 30-day screening period during which subjects will complete a daily 
ePRO diary to record information regarding all symptomatic RP attacks (eg, severity of symptoms, 
duration, and hand function). The up to 30-day screening period consists of a 5-day eligibility 
period and an up to 25-day baseline ePRO diary completion period. 
6.2.1 
Eligibility Period (Days -30 to -26 [Visit 1]) 
During the 5-day eligibility period, eligible subjects will have a minimum of 10 symptomatic RP 
attacks, documented in the ePRO diary, occurring over at least 3 separate days of the 5-day 
eligibility period.  
Subjects are allowed a 1-time rescreening at least 2 weeks from the last screening assessment. The 
following procedures will be performed at screening: 
• Obtain signed informed consent form (ICF). 
• Record demographics and medical/surgical history.  
• Assess DUs as part of the subject’s medical history. 
o Note: Investigator assessment of the DU will consist of location, status, and healing. 
• Assess inclusion/exclusion criteria. 
• Perform physical examination. 
• Obtain height and weight. 
• Obtain vital signs (heart rate and blood pressure). 
• Perform 12-lead electrocardiogram (ECG). 
• Perform clinical laboratory assessments (chemistry and hematology). 
• Perform urine pregnancy test on women of childbearing potential. 
• Distribute ePRO diary. 
• Complete the daily ePRO diary. 
o Note: Completion of the daily ePRO diary begins the day after signing informed consent. 
• Assess adverse events. 
• Record prior/concomitant medications. 


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6.2.2 
Baseline Electronic Patient-Reported Outcomes Diary Completion Period 
(Days -25 to -1) 
During the baseline ePRO diary completion period, eligible subjects must complete the daily ePRO 
diary for a minimum of 10 days (up to a maximum of 25 days) until the day of randomization. It 
may be necessary to extend the baseline ePRO diary completion period beyond 10 days in order 
to accommodate the preferred Monday to Friday dosing schedule. The ePRO symptomatic RP 
attack data from this time period will be used for the calculation of the baseline frequency of 
symptomatic RP attacks. 
6.3 
Treatment Period (Days 1 to 5 [Visits 2 to 6])  
Eligible subjects will return to the site for study drug infusion on 5 consecutive days. 
6.3.1 
Day 1 (Visit 2) 
The following procedures will be performed at Day 1 (Visit 2): 
• Assess inclusion/exclusion criteria. 
o Note: Eligible subjects will have a minimum of 10 symptomatic RP attacks, documented 
in the ePRO diary, occurring over at least 3 separate days of the 5-day eligibility period. 
• Obtain weight. 
• Obtain vital signs (heart rate and blood pressure). 
o Note: Vital signs will be measured prior to study drug administration and at 15 minutes 
(5 minutes) prior to and after all dose changes during the infusion. Additionally, vital 
signs will be monitored at 15 minutes (5 minutes) and 1 hour (15 minutes) after 
completion of the 6-hour infusion. 
o Note: The arm used for IV infusion should not be used for blood pressure monitoring. 
o Note: Subjects must have a systolic blood pressure 85 mmHg (sitting position) prior to 
study drug administration.  
• Perform urine pregnancy test on women of childbearing potential prior to study drug 
administration. 
• Contact the IRT system to randomize the subject and obtain study drug assignment. 
• Premedicate with a single dose of 2 acetaminophen extended-release tablets, 650 mg (each), 
15 to 60 minutes prior to study drug administration. 


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• Insert NovaCath Integrated IV Catheter System or PICC. 
o Note: Prior to the first infusion, the NovaCath Integrated IV Catheter System will be 
inserted into a small peripheral vein in the hand or arm using aseptic technique by a trained 
healthcare professional. If the subject’s peripheral veins do not support the placement of a 
peripheral line, a trained healthcare professional will insert a PICC. (Note: In some 
instances where the site chooses to use a PICC, it may be necessary to confirm placement 
of the PICC with an x-ray.) When possible, the same NovaCath Integrated IV Catheter 
System or PICC will be used for the 5 days of treatment. 
• Prepare and administer study drug infusion. See Section 5.5.3. 
• Assess adverse events. 
• Record concomitant medications. 
6.3.2 
Days 2 to 5 (Visits 3 to 6) 
The following procedures will be performed at Days 2 to 5 (Visits 3 to 6): 
• Obtain vital signs (heart rate and blood pressure). 
o Note: Vital signs will be measured prior to study drug administration and at 15 minutes 
(5 minutes) prior to and after all dose changes during the infusion. Additionally, vital 
signs will be monitored at 15 minutes (5 minutes) and 1 hour (15 minutes) after 
completion of the 6-hour infusion. 
o Note: The arm used for IV infusion should not be used for blood pressure monitoring. 
o Note: Subjects must have a systolic blood pressure 85 mmHg (sitting position) prior to 
study drug administration each day of study drug administration. 
• Collect blood samples for PK analysis for subjects participating in the PK substudy on Day 2 
only at the time points indicated in Section 7.3. The arm used for IV infusion should not be 
used to draw blood samples. 
• On Day 5 only, perform clinical laboratory assessments (chemistry and hematology) 1 hour 
postinfusion (within 45 minutes to 3 hours postinfusion is allowed). The arm used for IV 
infusion should not be used to draw blood samples. 
• Premedicate with a single dose of 2 acetaminophen extended-release tablets, 650 mg (each), 
15 to 60 minutes prior to study drug administration. 
• Administer study drug infusion. See Section 5.5.3. 
• Assess adverse events. 
• Record concomitant medications. 


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6.4 
Post-Treatment Period (Days 8 and 22 [Visits 7 and 8]) 
6.4.1 
Day 8 (Visit 7) – Telephone Call 
The following procedures will be performed via the telephone call on Day 8 (Visit 7): 
• Remind subjects to resume completion of the daily ePRO diary. Subjects will complete the 
diary from Day 8 to Day 21. 
• Assess adverse events. 
• Record concomitant medications. 
6.4.2 
Day 22 (Visit 8) 
The following procedures will be performed at Day 22 (+5 days) (Visit 8): 
• Obtain vital signs (heart rate and blood pressure). 
• Assess DUs. 
o Note: Investigator assessment of the DU will consist of location, status, and healing. 
• Assess adverse events. 
• Record concomitant medications. 
6.5 
Follow-up Visit (Day 35 [Visit 9]) 
The following procedures will be performed at the follow-up visit (Day 35 [+7 days], Visit 9) 
30 days after the last dose of study drug: 
• Obtain vital signs (heart rate and blood pressure). 
• Perform clinical laboratory assessments (chemistry and hematology). 
• Assess DUs. 
o Note: Investigator assessment of the DU will consist of location, status, and healing. 
• Assess adverse events. 
• Record concomitant medications. 
6.6 
Early Termination Visit and Withdrawal Procedures 
In circumstances where a subject discontinues the study prior to Day 21, an ET visit will be 
performed. The following procedures will be performed at this visit: 
• Obtain vital signs (heart rate and blood pressure). 
• Perform clinical laboratory assessments (chemistry and hematology). 
• Assess DUs. 
o Note: Investigator assessment of the DU will consist of location, status, and healing. 
• Complete the daily ePRO diary. 


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• Assess adverse events. 
• Record concomitant medications. 
• Contact the IRT system to record subject’s withdrawal from the study. 


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7 
EFFICACY AND PHARMACOKINETIC ASSESSMENTS 
7.1 
Efficacy Endpoints 
7.1.1 
Primary Efficacy Endpoint 
The primary efficacy parameter is the change in the weekly frequency of symptomatic RP attacks 
from baseline. 
7.1.2 
Exploratory Efficacy Endpoints 
The exploratory efficacy parameters include changes from baseline to the end of the efficacy 
follow-up in the following: 
• Severity of RP attacks as determined by the severity of RP attack symptoms (pain, numbness, 
tingling, and/or discomfort) (using a Numeric Rating Scale [NRS])  
• Raynaud’s Condition Score  
• Hand function as assessed by the CHFS  
• Duration of symptomatic RP attacks  
• NRS for worst pain associated with symptomatic RP  
• Patient assessment of overall improvement in symptomatic RP  
7.2 
Efficacy Assessments  
7.2.1 
Raynaud’s Phenomenon Attacks 
A symptomatic Raynaud’s attack for this study is defined as at least 1 color change of the subject’s 
finger(s) (blue, white, or red) associated with at least 1 symptom (pain, numbness, tingling, and/or 
discomfort of the finger[s]). The attack is considered over when the color changes back to 
pre-attack color (normal) and the symptoms return to the subject’s pre-attack level. 
7.2.2 
Electronic Patient-Reported Outcomes Diary  
Subjects will be provided with an ePRO diary at Visit 1 and trained on its use. Subjects will be 
asked to complete the ePRO diary at the time points indicated in Appendix A. Questionnaires 
allow for documentation of frequency, severity, and duration of symptomatic RP attacks, as well 
as assessment of hand function. Specific questionnaires include the severity of RP attack 
symptoms (using NRS), Raynaud’s Condition Score, CHFS, and overall patient improvement. 
7.2.2.1 
Severity of Raynaud’s phenomenon attack symptoms (using a Numeric Rating Scale) 
Raynaud’s phenomenon attacks are associated with significant discomfort (pain, numbness, 
tingling, and/or discomfort). Subjects will be asked to rate the severity of RP attack symptoms 
(pain, numbness, tingling, and/or discomfort) using an 11-point NRS.  
Intensity will be assessed as follows: 0 = no pain/numbness/tingling/discomfort, 1 to 3 = mild 
pain/numbness/tingling/discomfort, 4 to 6 = moderate pain/numbness/tingling/discomfort, and 
7 to 10 = severe pain/numbness/tingling/discomfort. 


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7.2.2.2 
Raynaud’s Condition Score 
The Raynaud’s Condition Score asks subjects to rate their difficulty with Raynaud’s condition on 
a given day from “No difficulty (0)” to “Extreme difficulty (10).” Subjects will be asked to 
consider the number of attacks they have had on that day and how long each attack lasted. Subjects 
will also be asked to consider how much pain, numbness, or other symptoms the Raynaud’s caused 
in their fingers (including painful sores) and how much the Raynaud’s alone affected the use of 
their hands that day.  
7.2.2.3 
Cochin Hand Function Scale 
Raynaud’s phenomenon attacks have a significant impact on hand function.12 The CHFS is an 
18-item self-administered instrument that assesses hand function as it relates to daily activities. 
The CHFS has been validated for use in subjects with SSc.21  
7.2.2.4 
Duration of Raynaud’s phenomenon attacks 
Subjects will be asked to document the duration of each symptomatic RP attack within their ePRO 
diaries. For each attack, the subject will record the duration in minutes. Refer to Section 7.2.1 for 
the definition of a symptomatic RP attack.  
7.2.2.5 
Overall patient improvement 
At Day -1, subjects will be asked to rate their overall symptomatic RP in the last week. At Day 21, 
subjects will be asked to rate their overall symptomatic RP compared to the start of the study. 
7.3 
Pharmacokinetic Assessments 
Eligible subjects will be given the option to participate in a PK substudy. Subjects who participate 
in the substudy will provide plasma samples for PK analysis. The samples will be analyzed for 
iloprost concentrations using validated liquid chromatography mass spectrometry methods. The 
actual PK sampling times will be captured on the eCRF. The actual dosing time will also be 
captured on the eCRF. 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of iloprost: 
• Steady state plasma concentration just before infusion is stopped 
• Area under the plasma concentration versus time curve (AUC) from time of dosing to the last 
time point with measurable concentration  
• AUC from time 0 extrapolated to infinity  
• Percentage of AUC obtained by extrapolation  
• Plasma terminal elimination half-life  
• Plasma clearance  
• Volume of distribution  
Plasma PK samples will not be obtained from the arm used for IV infusion. Plasma PK samples 
will be obtained only from subjects in the PK substudy at the following time points:  


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Day 2:  
• Predose (5 minutes) 
• 6 hours (5 minutes) postdose, just before infusion is stopped 
• 6 hours and 15 minutes (5 minutes) postdose 
• 6 hours and 30 minutes (5 minutes) postdose 
• 6 hours and 45 minutes (5 minutes) postdose 
• 7 hours (5 minutes) postdose 


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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
Since symptomatic RP attacks (as defined in Section 7.2.1) are recorded as efficacy assessments, 
these will not be treated as adverse events. However, if an event results in hospitalization or 
amputation, the event will then be reported as an SAE. If subjects have non-RP-related pain during 
a symptomatic RP attack, that event will be captured as an adverse event. 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
All adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of informed consent until Day 35. During study drug infusions (Day 1 
to Day 5) treatment-emergent adverse events (TEAEs) are expected (see Section 5.5.3.1). 
Treatment-emergent adverse events should be captured in relation to the dose, dose rate, and/or 
need for dose reduction. Subjects should be instructed to report any adverse event that they 
experience to the Investigator, whether or not they think the event is due to study treatment. 
Beginning at screening until Day 35, Investigators should make an assessment for adverse events 
at each visit and record the event on the appropriate adverse event eCRF.  
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure itself.  
Any medical condition already present at screening should be recorded as medical history and not 
be reported as an adverse event, unless the medical condition or signs or symptoms present at 
baseline change in severity, frequency, or seriousness at any time during the study. In this case, it 
should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at the date of screening and significantly worsen during 
the study should be reported as adverse events, as described below. The Investigator will exercise 
his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant. Clinically significant abnormal laboratory 
values occurring during the clinical study will be followed until repeat tests return to normal, 
stabilize, or are no longer clinically significant. Abnormal test results that are determined to be an 
error should not be reported as an adverse event.  


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Laboratory abnormalities or other abnormal clinical findings (eg, ECG abnormalities) should be 
reported as an adverse event if any of the following are applicable: 
• If an intervention is required as a result of the abnormality 
• If action taken with study drug is required as a result of the abnormality 
• Based on the clinical judgment of the Investigator 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
8.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
Assessment of severity 
Mild – An event that is easily tolerated, causing minimal discomfort, and generally not interfering 
with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality assessment 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal relationship 
and another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 


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The following factors should also be considered: 
• The temporal sequence from study drug administration- 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
Each report 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 drug- 
The other drugs the subject is taking or the treatment the subject receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• Known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology and PK of the study drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
8.1.4 
Adverse Events of Special Interest 
The Investigator will monitor each subject for clinical and laboratory evidence for predefined 
adverse events of special interest (AESIs) throughout the subject’s participation in this study.  
The Investigator will assess and record any additional information on the AESI in detail on an 
adverse event form which must be submitted within 24 hours of awareness of the event. 
For this study, hypotension will be considered an AESI. 
During the course of the study, additional AESIs may be identified by the Sponsor. 
Adverse events of special interest must be recorded in the eCRF. 
8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening adverse event. 


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o Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
• Requires hospitalization or prolongation of existing hospitalization. 
o Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will 
not be recorded as an SAE under this criterion, nor will hospitalization for a procedure 
scheduled or planned before signing of informed consent, or elective treatment of a pre-
existing condition that did not worsen from baseline. However, unexpected complications 
and/or prolongation of hospitalization that occur during elective surgery should be recorded 
as adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (ie, no place to stay, live too far away to come for hospital visits, respite 
care) will not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• An important medical event. 
o Note: Important medical events that do not meet any of the above criteria may be 
considered an SAE when, based upon appropriate medical judgment, they may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalizations, or the development of drug dependency. 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to Medpace Clinical Safety within 24 hours of the 
knowledge of the occurrence.  
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at 
Medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (phone 
number listed below), and fax/email the completed paper SAE form to Medpace (contact 
information listed in Section 8.6) within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming available. 


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Follow-up reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs.  
8.4 
Pregnancy Reporting 
A pregnancy is not considered to be an adverse event or SAE. However, if a subject becomes 
pregnant during the study or within the safety follow-up period defined in the protocol, the 
Investigator should report the pregnancy to Medpace Clinical Safety within 24 hours of knowledge 
of the event. Medpace Clinical Safety will then provide the Investigator/site the Exposure In Utero 
(EIU) form for completion. The Investigator/site must complete the EIU form and fax/email it 
back to Medpace Clinical Safety.  
If the female partner of a male subject becomes pregnant while the subject is receiving study drug 
or within the safety follow-up period defined in the protocol (30 days after last study drug 
infusion), the Investigator should notify Medpace Clinical Safety as described above.  
The pregnancy should be followed (up to 1 year) until the outcome of the pregnancy is known, 
whenever possible. Once the outcome of the pregnancy is known, the EIU form should be 
completed and faxed/emailed to Medpace Clinical Safety. If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should also follow the 
procedures for reporting an SAE. 
8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the FDA, and 
in any case no later than 7 days after knowledge by the Sponsor/designee of such a case. Relevant 
follow-up information will subsequently be communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to an investigational medicinal product. 


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8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
• Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgment should always be applied. In 
cases of a discrepancy in the drug accountability, overdose will be established only when it is 
clear that the subject has taken an additional dose(s) or the Investigator has reason to suspect 
that the subject has taken an additional dose(s).  
• Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information, and may be accompanied by harmful physical and/or psychological effects.  
• Abuse: Is defined as persistent or sporadic, intentional, excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
• Medication error: Is defined as any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product by a healthcare professional, subject, or consumer, 
respectively. The administration or consumption of the unassigned treatment and 
administration of an expired product are always reportable as medication errors. Cases of 
subjects missing doses of an investigational product are not considered reportable as 
medication error. 
• Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations form 
will only be completed if a complaint is associated with an adverse drug reaction.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All adverse events associated with these Special Situation 
Reports should be reported as adverse events or SAEs as well as recorded on the adverse event 
eCRF and/or the SAE eCRF. Details of the signs and symptoms, clinical management, and 
outcome should be provided, when available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
email: medpace-safetynotification@medpace.com 
8.7 
Clinical Laboratory Evaluations 
A detailed list of clinical laboratory analytes performed during this study is included in 
Appendix B. Samples for clinical laboratories will be collected at the visits indicated in 
Appendix A. The arm used for IV infusion should not be used to draw blood samples. 
A urine pregnancy test for female subjects of childbearing potential only will be performed at the 
visits indicated in Appendix A. 


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8.8 
Vital Signs 
Vital signs include heart rate and blood pressure and will be assessed at the visits indicated in 
Appendix A. A resting blood pressure and heart rate will be measured indirectly by using an 
oscillometric device on the same arm. The arm used for IV infusion should not be used for blood 
pressure monitoring. 
On dosing days (Days 1 to 5), vital signs will be measured prior to study drug administration and 
at 15 minutes (5 minutes) prior to and after all dose changes during the infusion. Additionally, 
vital signs will be monitored 15 minutes (5 minutes) and 1 hour (15 minutes) after completion 
of the 6-hour infusion. 
8.9 
Electrocardiograms 
A 12-lead ECG will be performed at screening.  
8.10 
Physical Examinations 
A complete physical examination will be performed at screening. The physical examination will 
consist of an examination of the following systems: general appearance, skin, eyes, ears, nose, 
throat, neck (including thyroid), lymph nodes, chest, heart (including any auscultated cardiac 
murmurs), abdomen, extremities, and neurologic. 
8.11 
Height and Weight 
Height will be measured at screening only. Weight will be assessed at screening and the first 
in-clinic visit (Day 1) and used with the dose rate card (Appendix C) to determine the starting flow 
rate for each subject. 
8.12 
Demographics and Medical/Surgical History 
Demographic information, including day, month, and year of birth; race; ethnicity; and gender will 
be collected for all subjects at screening. 
Medical history information, including relevant details regarding illness and allergies, date(s) of 
onset, status of current condition, and smoking/alcohol use, will be collected at screening. 
Additional information to be collected includes past surgical and medical procedures.  
8.13 
Digital Ulcers 
Digital ulcers will be assessed at screening and captured as part of the medical history at this visit. 
New DUs will be captured as an adverse event/SAE. In all cases, subjects that present with DUs 
will be followed until the end of the study (Day 22, Day 35, or ET). Investigator assessment of the 
DU will consist of location, status, and healing. 


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9 
STATISTICS 
9.1 
Analysis Populations 
9.1.1 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) Population is defined as all randomized subjects who initiate 
infusion of study drug. The mITT Population is the primary efficacy analysis population. 
9.1.2 
Per-Protocol Population 
The Per-Protocol (PP) Population is defined as all subjects in the mITT Population who complete 
at least Day 21 without any major protocol deviations. The PP Population will be used for 
sensitivity analyses of the primary efficacy variable. 
9.1.3 
Safety Population 
The Safety Population is defined as all randomized subjects who initiate infusion of study drug. 
The Safety Population will be used for all safety analyses. 
9.2 
Statistical Methods 
9.2.1 
Analysis of Efficacy 
All efficacy analyses are intended to provide an initial description of the clinical profile of iloprost 
and to inform the design and logistics of future studies. 
9.2.1.1 
Primary efficacy analysis 
The baseline weekly frequency of symptomatic RP attacks is defined as the average number of 
weekly symptomatic RP attacks occurring during the 10- to 25-day baseline ePRO diary 
completion period. The double-blind weekly symptomatic RP attacks is defined as the average 
number of weekly symptomatic RP attacks during Days 8 to 21. The primary efficacy parameter 
is the change in the weekly frequency of symptomatic RP attacks from baseline (ie, the mean 
number of weekly symptomatic RP attacks during Days 8 to 21 compared to during the 
10- to 25-day baseline ePRO diary completion period). 
The primary analysis will be performed based on an analysis of covariance model, including 
randomized treatment group and randomized stratification (ie, use of phosphodiesterase inhibitors 
at screening) as factors and baseline weekly frequency of symptomatic RP attacks as a covariate. 
The treatment comparisons will be estimated together with the 95% confidence interval and 
p-value. The site effect will be explored as necessary. For subjects in the mITT Population with 
intermittent missingness during the baseline or double-blind intervals, multiple imputation will be 
used assuming data are missing at random; for those subjects with truncated follow-up, methods 
will be used assuming missingness is not at random. 
The primary analysis will be performed on the mITT Population. Sensitivity analyses for the 
primary endpoint will include comparable analyses performed on the PP Population. 
The primary analysis is formally based on a 3-category decision guideline for future clinical study 
evaluation of iloprost. Specifically, the decision guideline for this study is based on whether the 
difference between iloprost and placebo in the mean change in the weekly frequency of 


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symptomatic RP attacks from baseline is less than X, is from X to Y, or is at least Y, where X is 
the threshold that would be exceeded with 90% probability when the true difference between 
iloprost and placebo in the change in the weekly frequency of symptomatic RP attacks from 
baseline is 6.65, and where Y is the threshold that would be exceeded with only 2.5% probability 
when the true difference between iloprost and placebo in the change in the weekly frequency of 
symptomatic RP attacks from baseline is 0. 
Note that these categories based on the thresholds X and Y should not be interpreted as providing 
strict decision rules, but rather as guidelines that will be factored into a broader scientific and 
clinical assessment of the benefit-to-risk profile of IV iloprost. This broader assessment will 
include consideration of safety, supportive efficacy endpoints, and relevant information external 
to this study.  
The decision guidelines for this study include the following: 
• If the difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is less than X, then iloprost is not plausibly more 
efficacious than placebo; its utility in this indication should be reconsidered unless the 
endpoints support further development. 
• If the difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is between X and Y, then iloprost is plausibly more 
efficacious than placebo. 
• If the difference between iloprost and placebo in the mean change in the weekly frequency of 
symptomatic RP attacks from baseline is at least Y, then iloprost would be statistically 
significantly more effective than placebo, with the strength of evidence meeting the standard 
requirement of a 0.025 one-sided (0.05 two-sided) false-positive error rate. 
The study (and other information that emerges during the conduct of this study) will provide 
important insights through consideration of the following:  
• Estimated benefit-to-risk profile of IV iloprost 
• Possible refinements in the dose/schedule of IV iloprost 
• Approaches to improve adherence to the IV iloprost regimen 
• Modifications to defining eligibility criteria to enhance enrichment 
• Approaches to achieving timely accrual of study participants at centers with the established 
ability to provide high quality implementation of the study  
• Modifications to the use of an electronic diary to collect patient reported outcome data 
9.2.1.2 
Sample size determination 
The study will enroll up to a maximum of 40 subjects. Subject enrollment may be halted by the 
Sponsor at any time for any reason. 
If 12.0 is the standard deviation of the change from baseline in the weekly frequency of 
symptomatic Raynaud attacks, then with 20 patients per arm, X is 1.785 and Y is 7.438. 


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The operating characteristics for this 3-category decision guideline, when 12.0 is the standard 
deviation of the change from baseline in the weekly frequency of symptomatic Raynaud attacks 
and the sample size is 20 patients per arm, are as follows: 
1. Regarding the false-positive error rate of the screening procedure, if IV iloprost truly provides 
no improvement in the change from baseline in the weekly frequency of symptomatic Raynaud 
attacks, then the probability of bringing IV iloprost forward to a Phase 3 trial is 32%. However, 
there is only a 2.5% chance of reaching the false positive conclusion that IV iloprost provides 
a statistically significant improvement in efficacy relative to a placebo control.    
2. The false-negative error rate is low. If the true difference between IV iloprost and the placebo 
control groups in the change from baseline in the weekly frequency of symptomatic Raynaud 
attacks is 6.65, then there is only a 10% chance that IV iloprost would be discarded, and thus 
a 90% chance that it would be evaluated in a subsequent confirmatory Phase 3 study; 
furthermore, the probability that IV iloprost will have a statistically significant improvement 
in efficacy (at one-sided p<0.025) relative to the placebo control is 21%. 
9.2.1.3 
Exploratory efficacy analysis 
Descriptive analyses based on point estimates and confidence intervals will be used for exploratory 
endpoints. 
9.2.2 
Analysis of Pharmacokinetics 
The PK Population will include all subjects in the PK substudy who receive study drug and for 
whom at least 1 PK parameter can be determined and who have at least 1 value above the lower 
limit of quantification. 
Descriptive statistics (sample size, mean, standard deviation, minimum, median, maximum, and 
coefficient of variation [CV]) will be used to summarize PK concentrations and parameters. 
Geometric mean and geometric CV will also be used to summarize specific parameters. 
Additional PK/pharmacodynamic analysis may be performed as an exploratory analysis, if 
applicable.  
9.2.3 
Analysis of Safety 
All safety analyses will be performed on the Safety Population. Subjects will be analyzed by the 
treatment received. 
Safety measures will be summarized descriptively. Qualitative variables will be summarized using 
counts and percentages by treatment group at each study visit. A TEAE is defined as an adverse 
event with a start date and time on or after the administration of study drug. Treatment-emergent 
adverse events will be summarized by Medical Dictionary for Regulatory Activities system organ 
class (SOC) and preferred term. Tables will be provided for overall incidence and incidence by 
SOC and preferred term for TEAEs, drug-related TEAEs, TEAEs by maximum severity, SAEs, 
and TEAEs leading to treatment discontinuation.  
Laboratory and vital signs parameters will be presented using descriptive statistics for observed 
values at each visit and changes from baseline, as appropriate. Abnormal physical examination 
findings will be presented in a by-subject data listing. Descriptive statistics will be provided for 
ECG data. Details of any abnormalities will be included in subject listings. 


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9.2.4 
Interim Analysis 
No interim analysis is planned for the study.  
9.2.5 
Data Monitoring Committee 
A DMC consisting of 3 members, including 1 SSc expert and 1 prostacyclin PAH expert, will be 
responsible for safeguarding the interests of study subjects and for enhancing the integrity and 
credibility of the study. To address this mission, the DMC will have ongoing access to efficacy 
and safety data, and to information regarding the quality of study conduct. A separate DMC 
Charter will be prepared. 
9.2.6 
Steering Committee 
The purpose of the Steering Committee is to provide objective and independent scientific and 
medical input on the design, execution, analysis, and reporting of the study. The Steering 
Committee will consist of members with medical specialties or scientific expertise 
(eg, statisticians) pertinent to the population under study. There will be 7 voting external members 
of the Steering Committee who are independent of Eicos Sciences, Inc. The Steering Committee 
statisticians and Sponsor representatives will be nonvoting members. A separate Steering 
Committee Charter will be prepared. 


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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data have 
been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations (CFR) 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Medical Dictionary for Regulatory Activities (latest) for medical history and adverse events 
• World Health Organization Drug Dictionary for prior and concomitant medications 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. For this study, the 
end of study will be Visit 35, unless the subject terminates early. 


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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of subjects. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements 
(if applicable), written information given to the subjects, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB prior to participation of subjects in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject 
recruitment, and any other written information regarding this study to be provided to a subject or 
subject’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. The ICF will be provided to the subject in 
his/her native language, as necessary. 
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each subject before any study-specific activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of the signed ICF will be given to the subject. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor, in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 


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the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the CRA and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.   
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor and share their 
proposed publication with Medpace and the Sponsor at least 60 days prior to submitting for 
publication, upon which, the Sponsor has 60 days to review and propose edits or additional delay. 
The Sponsor reserves the right to deny publication rights until mutual agreement on the content, 
format, interpretation of data in the manuscript, and journal selected for publication are achieved. 


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11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 


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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for subject safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 


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13 
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39 . 
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Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with 
Raynaud phenomenon secondary to systemic sclerosis. A multicenter, 
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Foti R, Visalli E, Amato G, et al. Long-term clinical stabilization of scleroderma patients 
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44. 
Garcia de la Peña Lefebvre P, Nishishinya MB, Pereda CA, et al. Efficacy of Raynaud’s 
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systematic literature review. Rheumatol Int. 2015;35(9):1447-1459. 
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Casigliani Rabl S, Della Rossa A, Pepe P, et al. Long-term cyclic intravenous iloprost in 
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Kawald A, Burmester GR, Huscher D, et al. Low versus high-dose iloprost therapy over 
21 days in patients with secondary Raynaud's phenomenon and systemic sclerosis: a 
randomized, open, single-center study. J Rheumatol. 2008;35(9):1830-1837. 
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Zachariae H, Halkier-Sørensen L, Bjerring P, et al. Treatment of ischaemic digital ulcers 
and prevention of gangrene with intravenous iloprost in systemic sclerosis. Acta Derm 
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48. 
Caramaschi P, Biasi D, Canestrini S, et al. Evaluation of finger skin temperature in 
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50. 
Watson HR, Robb R, Belcher G, et al. Seasonal variation of Raynaud’s Phenomenon 
secondary to systemic sclerosis. J Rheumatol. 1999;26(8):1734-1737. 
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Torley HI, Madhok R, Capell HA, et al. A double blind, randomised, multicentre 
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1991;50(11):800-804. 


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APPENDIX A:  SCHEDULE OF PROCEDURES 
 
Screening Perioda 
Treatment Visits 
Post-Treatment 
Visits 
Follow-up Visit 
ET Visitd 
Eligibility 
Periodb 
Baseline ePRO 
Completion 
Periodc 
Visit 
1 
NA 
2 
3, 4, 5, 6 
7e 
8 
9 
 
Time point 
Days -30 to -26 
Days -25 to -1 
Day 1 
Days 2 to 5 
Day 8 
Day 22 
Day 35 
 
Window 
 
 
 
 
 
+5 days 
+7 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/surgical historyf 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
Xg 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
Height and weighth 
X 
 
X 
 
 
 
 
 
Vital signs (HR and BP)  
X 
 
Xi 
Xi 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
Clinical laboratory 
assessmentsj 
X 
 
 
Xk 
 
 
X 
X 
PKl 
 
 
 
Xm 
 
 
 
 
Urine pregnancy testn 
X 
 
Xo 
 
 
 
 
 
Distribute ePRO diaryp 
X 
 
 
 
 
 
 
 
ePRO diary completionq 
X 
X 
 
 
X 
 
 
X 
Randomization 
 
 
Xr 
 
 
 
 
 
Insertion of NovaCath™ 
Integrated IV Catheter 
System or PICCs 
 
 
X 
 
 
 
 
 
Premedicate with 
acetaminophent 
 
 
X 
X 
 
 
 
 
Administer study drug 
infusionu 
 
 
X 
X 
 
 
 
 
Digital ulcer assessmentf 
X 
 
 
 
 
X 
X 
X 
Adverse eventsv 
X 
 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medication 
X 
 
X 
X 
X 
X 
X 
X 
a. 
The study consists of an up to 30-day screening period during which subjects will complete a daily ePRO diary to record information regarding all symptomatic RP attacks 
(eg, severity of symptoms, duration, and hand function). The up to 30-day screening period consists of a 5-day eligibility period and an up to 25-day baseline ePRO diary 


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completion period. Subjects are allowed a 1-time rescreening at least 2 weeks from the last screening assessment.  
b. 
During the 5-day eligibility period, eligible subjects will have a minimum of 10 symptomatic RP attacks, documented in the ePRO diary, occurring over at least 3 separate 
days of the 5-day eligibility period. 
c. 
During the baseline ePRO diary completion period, eligible subjects must complete the daily ePRO diary for a minimum of 10 days (up to a maximum of 25 days) until the 
day of randomization. It may be necessary to extend the baseline ePRO diary completion period beyond 10 days in order to accommodate the preferred Monday to Friday 
dosing schedule. The ePRO symptomatic RP attack data from this time period will be used for the calculation of the baseline frequency of symptomatic RP attacks. 
d. 
In circumstances where a subject discontinues the study prior to Day 21, an ET visit will be performed. Contact the IRT system to record the subject’s withdrawal from the 
study. 
e. 
Subjects will be contacted via telephone on Day 8 to ensure they resume completion of the daily ePRO diary; subjects will complete the diary from Day 8 through Day 21. 
f. 
Digital ulcers will be assessed at screening and captured as part of the medical history at this visit. New DUs will be captured as an adverse event/SAE. In all cases, 
subjects that present with DUs will be followed until the end of the study. Investigator assessment of the DU will consist of location, status, and healing.  
g. 
Eligible subjects will have a minimum of 10 symptomatic RP attacks, documented in the ePRO diary, occurring over at least 3 separate days of the 5-day eligibility period. 
h. 
Height will be collected at screening only. 
i. 
Vital signs will be measured prior to study drug administration and at 15 minutes (5 minutes) prior to and after all dose changes during the infusion. Additionally, vital 
signs will be monitored at 15 minutes (5 minutes) and 1 hour (15 minutes) after completion of the 6-hour infusion. Subjects must have a systolic BP 85 mmHg (sitting 
position) prior to study drug administration each day of administration. The arm used for IV infusion should not be used for blood pressure monitoring. 
j. 
Includes chemistry and hematology. The arm used for IV infusion should not be used to draw blood samples. 
k. 
On Day 5 only, perform clinical laboratory assessments (chemistry and hematology) 1 hour postinfusion (within 45 minutes to 3 hours postinfusion is allowed). 
l. 
Eligible subjects will be given the option to participate in a PK substudy. Subjects who participate in the substudy will provide plasma samples for PK analysis on Day 2 at 
the time points indicated in Section 7.3. The arm used for IV infusion should not be used to draw blood samples. 
m. Day 2 only. 
n. 
For women of childbearing potential only. 
o. 
Prior to study drug administration. 
p. 
Subjects will be provided with an ePRO diary at Visit 1 and trained on its use. Subjects will start the daily ePRO diary the day after signing informed consent. Specific 
questionnaires include the severity of RP attack symptoms (using NRS), Raynaud’s Condition Score, CHFS, and overall patient improvement. 
q. 
Subjects will complete the daily ePRO diary during the eligibility period and baseline ePRO diary completion period as outlined above. Subjects will not complete the 
ePRO diary during Days 1 to 7, but will resume reporting at Day 8 and continue until Day 21. The CHFS and overall patient improvement will only be completed on 
Day -1 and Day 21. 
r. 
Contact the IRT system to randomize the subject and obtain study drug assignment.  
s. 
Prior to the first infusion, the NovaCath™ Integrated IV Catheter System will be inserted into a small peripheral vein in the hand or arm using aseptic technique by a 
trained healthcare professional. If the subject’s peripheral veins do not support the placement of a peripheral line, a trained healthcare professional will insert a PICC. 
(Note: In some instances where the site chooses to use a PICC, it may be necessary to confirm placement of the PICC with an x-ray). When possible, the same NovaCath 
Integrated IV Catheter System or PICC will be used for the 5 days of treatment. 
t. 
Subjects will be premedicated with a single dose of 2 acetaminophen extended-release tablets, 650 mg (each), 15 to 60 minutes prior to study drug administration.  
u. 
To be administered for 5 consecutive days (eg, Monday through Friday) as an IV infusion over 6 hours each day via a peripheral line or a PICC using an infusion pump. 
Study drug will be initiated at a dose of 0.5 ng/kg/min and will be increased every 30 minutes (5 minutes) in increments of 0.5 ng/kg/min to 2.0 ng/kg/min or the 
individual tolerated dose. Refer to Section 5.5.3 for further details. 
v. 
All adverse events will be collected from the time of informed consent until Day 35. 
BP = blood pressure; CHFS = Cochin Hand Function Scale; DU = digital ulcer; ECG = electrocardiogram; ePRO = electronic patient-reported outcomes; ET = early 
termination; HR = heart rate; IRT = Interactive Response Technology; IV = intravenous; NRS = Numeric Rating Scale; PICC = peripherally inserted central catheter/line; 
PK = pharmacokinetic(s); RP = Raynaud’s phenomenon; SAE = serious adverse event. 


Eicos Sciences, Inc. 
Clinical Study Protocol ES-201 
Confidential & Proprietary 
 
Version 4.0, 01 March 2019 
68
APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Bicarbonate 
Aspartate aminotransferase 
Calcium 
Blood urea nitrogen 
Estimated glomerular filtration rate 
Chloride 
Glucose 
Creatinine 
Potassium 
Sodium 
Total bilirubin 
Total protein 
 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count and differential [1] 
Mean corpuscular volume 
1. Manual microscopic review is performed only if white blood cell count 
and/or differential values are out of reference range. 
 
Pregnancy test 
Urine pregnancy test (for women of childbearing potential only) 


Eicos Sciences, Inc. 
Clinical Study Protocol ES-201 
Confidential & Proprietary 
 
Version 4.0, 01 March 2019 
69
APPENDIX C:  STUDY DRUG INTRAVENOUS INFUSION PUMP RATE  
Subject Weight 
Study Drug Intravenous Infusion Pump Rate (mL/hr) 
0.25 ng/kg/min 
0.5 ng/kg/min 
(Starting Dose) 
1.0 ng/kg/min 
1.5 ng/kg/min 
2.0 ng/kg/min 
30 to 39.9 kg 
0.45 
0.9 
1.8 
2.7 
3.6 
40 to 49.9 kg 
0.6 
1.2 
2.4 
3.6 
4.8 
50 to 59.9 kg 
0.75 
1.5 
3.0 
4.5 
6.0 
60 to 69.9 kg 
0.9 
1.8 
3.6 
5.4 
7.2 
70 to 79.9 kg 
1.05 
2.1 
4.2 
6.3 
8.4 
80 to 89.9 kg 
1.2 
2.4 
4.8 
7.2 
9.6 
90 to 99.9 kg 
1.35 
2.7 
5.4 
8.1 
10.8 
100 to 109.9 kg 
1.5 
3.0 
6.0 
9.0 
12.0 
If the subject weight 110 kg, contact the Medical Monitor to discuss the dosing strategy. 
 
 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Phase 2 Pilot Study Evaluating Intravenous Iloprost in Subjects 
With Symptomatic Raynaud’s Phenomenon Secondary to Systemic 
Sclerosis  
 
 
Investigational Product: Iloprost Injection, for intravenous use 
Protocol Number: ES-201 
Protocol Version: 4.0, 01 March 2019 
 
 
 
Sponsor: 
Eicos Sciences, Inc. 
200 Four Falls Corporate Center, Suite 107 
West Conshohocken, PA 19428-2958  
USA 
Telephone: 301-968-2390 
 
SAP Version: 2.0, 26 June 2019 
 
 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of Eicos Sciences, Inc. except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical study for Eicos Sciences, Inc. You are 
allowed to disclose the contents of this document only to your Institutional Review Board and 
study personnel directly involved with conducting this protocol. Persons to whom the 
information is disclosed must be informed that the information is confidential and proprietary to 
Eicos Sciences, Inc. and that it may not be further disclosed to third parties. 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 2 
Version Date:  26 June 2019 
SIGNATURE PAGE 
 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Pilot Study 
Evaluating Intravenous Iloprost in Subjects With Symptomatic Raynaud’s Phenomenon 
Secondary to Systemic Sclerosis  
 
Protocol Number: ES-201 
We, the undersigned, have reviewed and approve this Statistical Analysis Plan. 
Signature 
Date 
 
 
______________________________________________ 
Medpace, Inc. 
 
 
___________________________ 
 
 
 
 
_________________________________ 
Medpace, Inc. 
___________________________ 
 
 
 
 
______________________________________________ 
Medpace, Inc. 
___________________________ 
 
 
 
 
 
Eicos Sciences, Inc. 
 
 
 
 
 
______________________________________________ 
Eicos Sciences, Inc. 
___________________________ 
PPD
PPD
PPD
PPD
PPD


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 3 
Version Date:  26 June 2019 
 
 
 
 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 4 
Version Date:  26 June 2019 
VERSION HISTORY 
Version  
Date 
Description 
1.0 
25 MAR 2019 
Original signed version 
2.0 
26 JUN 2019 
1. Updated imputation method for primary endpoint; 
2. Add imputation method for date of Systemic Sclerosis 
diagnosis and Raynaud's Phenomenon diagnosis. 
 
 
 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 5 
Version Date:  26 June 2019 
TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................. 8 
2 
Overview ................................................................................................................................. 8 
2.1 Objectives ......................................................................................................................... 8 
2.2 Trial Design ...................................................................................................................... 8 
3 
Study Endpoints ..................................................................................................................... 13 
3.1 Efficacy Variables .......................................................................................................... 13 
3.1.1 Primary efficacy variable ..................................................................................... 13 
3.1.2 Exploratory efficacy variables .............................................................................. 13 
3.2 Pharmacokinetic Variables ............................................................................................. 15 
3.3 Safety Variables ............................................................................................................. 15 
3.3.1 Adverse Events ..................................................................................................... 15 
3.3.2 Safety Laboratory Evaluations ............................................................................. 16 
3.3.3 Vital Signs ............................................................................................................ 16 
3.3.4 Other Safety Variables ......................................................................................... 16 
4 
Analysis Populations ............................................................................................................. 16 
4.1.1 Modified Intent-to-Treat Population .................................................................... 16 
4.1.2 Safety Population ................................................................................................. 16 
4.1.3 Per-Protocol Population ....................................................................................... 16 
4.1.4 PK Population ....................................................................................................... 17 
5 
General Considerations for Data Analysis ............................................................................ 17 
5.1 Baseline Determination .................................................................................................. 17 
5.2 Evaluation of Site Effect ................................................................................................ 17 
5.3 Handling of Dropouts and Missing Data........................................................................ 17 
5.3.1 Missing or Incomplete Dates ................................................................................ 17 
5.3.2 Multiple Imputation for Efficacy Endpoints ........................................................ 18 
5.3.3 Missing or Incomplete PK Data ........................................................................... 18 
6 
Analysis of Disposition and Subject Characteristics ............................................................. 18 
6.1 Disposition and Analysis Populations ............................................................................ 18 
6.2 Protocol Deviations ........................................................................................................ 19 
6.3 Demographics and Baseline Characteristics .................................................................. 19 
6.4 Concomitant Medications .............................................................................................. 19 
6.5 Study and Drug Exposure .............................................................................................. 20 
7 
Analysis of Efficacy .............................................................................................................. 20 
7.1 Primary Efficacy Analysis ............................................................................................. 20 
7.2 Exploratory Efficacy Analyses....................................................................................... 21 
7.3 Subgroup Analysis ......................................................................................................... 21 
7.4 Sensitivity Analyses ....................................................................................................... 21 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 6 
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8 
Pharmacokinetic Analysis ..................................................................................................... 21 
9 
Analysis of Safety .................................................................................................................. 22 
9.1 Adverse Events ............................................................................................................... 22 
9.2 Clinical Laboratory Evaluations..................................................................................... 23 
9.3 Vital Signs ...................................................................................................................... 23 
9.4 ECG Parameters ............................................................................................................. 24 
9.5 Physical Examination ..................................................................................................... 24 
10 Data Monitoring Committee .................................................................................................. 24 
11 Steering Committee ............................................................................................................... 24 
12 Interim Analysis .................................................................................................................... 24 
13 Sample Size and Power Considerations ................................................................................ 24 
14 Programming Specifications.................................................................................................. 25 
 
 
 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
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Version Date:  26 June 2019 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ACE 
Angiotensin-converting enzyme 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
CHFS 
Cochin Hand Function Scale 
ePRO  
Electronic patient-reported outcomes  
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
NRS 
Numeric Rating Scale 
PGI-S 
Patient Global Impression of Severity 
PGI-C 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
PT 
Preferred Term 
RP 
Raynaud’s Phenomenon 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SSc 
Systemic sclerosis 
TEAE 
Treatment emergent adverse event 
WHO 
World Health Organization 
 
 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 8 
Version Date:  26 June 2019 
1 
INTRODUCTION 
The purpose of this document is to provide a description of the statistical methods and procedures 
to be implemented for the analysis of data from Eicos Sciences, Inc. protocol number ES-201.  If 
circumstances arise during the study such that more appropriate analytic procedures become 
available, the statistical analysis plan (SAP) may be revised.  Any revisions to the SAP (both 
alternative and additional methods) will be made prior to database lock and reasons for such 
revisions will be described in the final Clinical Study Report (CSR). 
2 
OVERVIEW 
2.1 
Objectives 
The primary objectives are the following: 
• To pilot the use of the electronic patient-reported outcomes (ePRO) diary for the 
evaluation of subject response to the treatment as well as the study drug infusion workflow 
for this multiday treatment. 
• To assess whether there is a signal for efficacy of iloprost compared to placebo on the 
change in the weekly frequency of symptomatic Raynaud’s phenomenon (RP) attacks 
from baseline in subjects with symptomatic RP secondary to systemic sclerosis (SSc). 
• To provide an early assessment of intravenous iloprost safety 
The exploratory objectives are to obtain preliminary evidence regarding the biological activity, 
efficacy, safety and tolerability of iloprost compared to placebo regarding the following measures: 
• Severity of RP attack symptoms 
• Raynaud’s Condition Score 
• Hand function as assessed by the Cochin Hand Function Scale (CHFS) 
• Symptomatic RP attack duration 
• Worst pain associated with symptomatic RP 
• Patient assessment of overall improvement in symptomatic RP 
• Pharmacokinetics (PK) of iloprost in subjects with symptomatic RP secondary to SSc 
2.2 
Trial Design 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate 
the effect of iloprost on the relief of symptomatic RP attacks in subjects with SSc. The study will 
be piloting an initial evaluation of intravenous iloprost, testing the study endpoints and logistics 
of study operations that include, among other things, an ePRO diary for the evaluation of subject 
response to the treatment as well as the study drug infusion workflow for this multiday treatment. 
Subjects are allowed to continue receiving stable standard of care therapies for the management 
of symptomatic RP (eg, calcium channel blockers, angiotensin-converting enzyme inhibitors, 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 9 
Version Date:  26 June 2019 
statins, fluoxetine, and low dose acetylsalicylic acid) or may participate without the use of 
background standard of care therapies.   
The study will enroll up to 40 subjects. Subject enrollment may be halted by the Sponsor at any 
time for any reason. 
The study consists of an up to 30-day screening period during which subjects will complete a 
daily ePRO diary to record information regarding all symptomatic RP attacks (eg, severity of 
symptoms, duration, and hand function). The up to 30-day screening period consists of a 5-day 
eligibility period and an up to 25-day baseline ePRO diary completion period: 
• During the 5-day eligibility period, eligible subjects will have a minimum of 10 
symptomatic RP attacks, documented in the ePRO diary, occurring over at least 3 
separate days of the 5-day eligibility period.  
• During the baseline ePRO diary completion period, eligible subjects must complete the 
daily ePRO diary for a minimum of 10 days (up to a maximum of 25 days) until the day 
of randomization. It may be necessary to extend the baseline ePRO diary completion 
period beyond 10 days in order to accommodate the preferred Monday to Friday dosing 
schedule. The ePRO symptomatic RP attack data from this time period will be used for 
the calculation of the baseline frequency of symptomatic RP attacks. 
Eligible subjects will be given the option to participate in a PK substudy. Subjects who 
participate in the substudy will provide plasma samples for PK analysis. The samples will be 
analyzed for iloprost concentrations using validated liquid chromatography mass spectrometry 
methods.  
Subjects will be randomized in a 1:1 ratio to iloprost injection for IV use or placebo. 
Randomization will be stratified based on the use of phosphodiesterase inhibitors at screening. 
Study drug administration will begin on Day 1, and subjects will receive study drug for 5 
consecutive days (eg, Monday through Friday) as a continous IV infusion over 6 hours each day 
via a peripheral line (NovaCath™ Integrated IV Catheter System) or a peripherally inserted central 
catheter (PICC) using an infusion pump. Iloprost is associated with high rates (~>80%) of 
headaches during the daily infusions which is associated with reduced tolerability and may unmask 
subjects who are assigned to the active agent. Prior to study drug administration, subjects will be 
premedicated with a single dose of 2 acetaminophen extended-release tablets, 650 mg (each) to 
help maintain blinding and to improve study drug infusion tolerability.    
Subjects must have a systolic blood pressure ≥85 mmHg (sitting position) prior to study drug 
administration each day of administration. On Day 1, study drug will be initiated at a starting 
dose of 0.5 ng/kg/min, and dose increases will occur every 30 minutes (5 minutes) in 
increments of 0.5 ng/kg/min up to 2.0 ng/kg/min or the individual tolerated dose. If dose-limiting 
adverse events (eg, headache, flushing, jaw pain, myalgia, nausea, or vomiting) occur that cannot 
be tolerated by the subject, then the dose will be reduced in a step wise manner by 0.5 ng/kg/min 
every 30 minutes (5 minutes), until a tolerated dose is determined. If symptomatic hypotension 
or a dose-limiting adverse event occurs during administration of study drug  at the starting dose 
(ie, 0.5 ng/kg/min), the study drug infusion will be reduced to 0.25 ng/kg/min. If the dose of 0.25 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
Version Number: 2.0 
Page 10 
Version Date:  26 June 2019 
ng/kg/min is not tolerated due to symptomatic hypotension or a dose-limiting adverse event 
occurs the study drug will be discontinued and reinitiation of the study drug infusion can be 
attempted after the event has resolved or been treated. Blood pressure and heart rate will be 
monitored 15 minutes (5 minutes) prior to and after all dose changes. If the subject experiences 
symptomatic hypotension or any other adverse event that cannot be tolerated, as determined by 
the Investigator, during administration of study drug, the dose will be reduced or the study drug 
infusion will be stopped until the symptoms resolve, at which point the study drug should be 
reinitiated at a previously tolerated dose. The maximum tolerated dose will be maintained for the 
remaining 6-hour daily period. At the end of the 6-hour study drug infusion period, the dose will 
be stopped. Subjects will be monitored for up to 1 hour after completion of study drug infusion 
(ie, vital signs will be obtained 15 minutes [5 minutes] and 1 hour [15 minutes] after 
completion of the study drug infusion). 
On Days 2 to 5, the study drug infusion will be started using the highest study drug infusion rate 
tolerated on the previous day without up- or down-titration, unless the subject does not tolerate 
the study drug infusion or adverse events occur that cannot be tolerated by the subject and 
necessitate a reduction in dose. Vital signs will be measured prior to study drug administration 
and at 15 minutes (5 minutes) prior to and after all dose changes during the study drug infusion. 
Additionally, vital signs will be monitored at 15 minutes (5 minutes) and 1 hour (15 minutes) 
after completion of the 6-hour study drug infusion.  
During the treatment period (Days 1 to 5), while subjects receive study drug, the ePRO diary will 
not be completed. No study assessments will be performed on the 2 days following the end of 
treatment (Days 6 and 7, eg, Saturday and Sunday) to allow the subject to rest and return to a 
schedule of normal daily living activity following the 5 days of study drug infusions.  
Subjects will be contacted via telephone on Day 8 to ensure they resume completion of the daily 
ePRO diary; subjects will complete the diary from Day 8 through Day 21. On Day 22, subjects 
will return to the clinic for post-treatment evaluations. A follow-up visit will occur 30 days after 
the last administration of study drug (Day 35).  
Subjects who discontinue study drug early will remain in the study (unless the subject withdraws 
consent) and complete the daily ePRO diary from Day 8 to Day 21 including clinical laboratory 
assessments on the remaining missed study drug infusion days as well as post-treatment study 
assessments. 
The total duration of the study for a subject will be up to approximately 9 weeks. 
A detailed schedule of procedures is provided below: 


 
Statistical Analysis Plan 
 
 
          Protocol Number: ES-201 
Version Number: 2.0                                               Page 11                                                                                                Version Date:  26 June 2019 
 
Screening Perioda 
Treatment Visits 
Post-Treatment 
Visits 
Follow-up Visit 
ET Visitd 
Eligibility 
Periodb 
Baseline ePRO 
Completion 
Periodc 
Visit 
1 
NA 
2 
3, 4, 5, 6 
7e 
8 
9 
 
Time point 
Days -30 to -26 
Days -25 to -1 
Day 1 
Days 2 to 5 
Day 8 
Day 22 
Day 35 
 
Window 
 
 
 
 
 
+5 days 
+7 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/surgical historyf 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
Xg 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
Height and weighth 
X 
 
X 
 
 
 
 
 
Vital signs (HR and BP)  
X 
 
Xi 
Xi 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
Clinical laboratory 
assessmentsj 
X 
 
 
Xk 
 
 
X 
X 
PKl 
 
 
 
Xm 
 
 
 
 
Urine pregnancy testn 
X 
 
Xo 
 
 
 
 
 
Distribute ePRO diaryp 
X 
 
 
 
 
 
 
 
ePRO diary completionq 
X 
X 
 
 
X 
 
 
X 
Randomization 
 
 
Xr 
 
 
 
 
 
Insertion of NovaCath™ 
Integrated IV Catheter 
System or PICCs 
 
 
X 
 
 
 
 
 
Premedicate with 
acetaminophent 
 
 
X 
X 
 
 
 
 
Administer study drug 
infusionu 
 
 
X 
X 
 
 
 
 
Digital ulcer assessmentf 
X 
 
 
 
 
X 
X 
X 
Adverse eventsv 
X 
 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medication 
X 
 
X 
X 
X 
X 
X 
X 
a. 
The study consists of an up to 30-day screening period during which subjects will complete a daily ePRO diary to record information regarding all symptomatic RP attacks 
(eg, severity of symptoms, duration, and hand function). The up to 30-day screening period consists of a 5-day eligibility period and an up to 25-day baseline ePRO diary 
completion period. Subjects are allowed a 1-time rescreening at least 2 weeks from the last screening assessment.  
b. 
During the 5-day eligibility period, eligible subjects will have a minimum of 10 symptomatic RP attacks, documented in the ePRO diary, occurring over at least 3 separate 
days of the 5-day eligibility period. 
c. 
During the baseline ePRO diary completion period, eligible subjects must complete the daily ePRO diary for a minimum of 10 days (up to a maximum of 25 days) until the 


 
Statistical Analysis Plan 
 
 
          Protocol Number: ES-201 
Version Number: 2.0                                               Page 12                                                                                                Version Date:  26 June 2019 
day of randomization. It may be necessary to extend the baseline ePRO diary completion period beyond 10 days in order to accommodate the preferred Monday to Friday 
dosing schedule. The ePRO symptomatic RP attack data from this time period will be used for the calculation of the baseline frequency of symptomatic RP attacks. 
d. 
In circumstances where a subject discontinues the study prior to Day 21, an ET visit will be performed. Contact the IRT system to record the subject’s withdrawal from the 
study. 
e. 
Subjects will be contacted via telephone on Day 8 to ensure they resume completion of the daily ePRO diary; subjects will complete the diary from Day 8 through Day 21. 
f. 
Digital ulcers will be assessed at screening and captured as part of the medical history at this visit. New DUs will be captured as an adverse event/SAE. In all cases, 
subjects that present with DUs will be followed until the end of the study. Investigator assessment of the DU will consist of location, status, and healing.  
g. 
Eligible subjects will have a minimum of 10 symptomatic RP attacks, documented in the ePRO diary, occurring over at least 3 separate days of the 5-day eligibility period. 
h. 
Height will be collected at screening only. 
i. 
Vital signs will be measured prior to study drug administration and at 15 minutes (5 minutes) prior to and after all dose changes during the infusion. Additionally, vital 
signs will be monitored at 15 minutes (5 minutes) and 1 hour (15 minutes) after completion of the 6-hour infusion. Subjects must have a systolic BP 85 mmHg (sitting 
position) prior to study drug administration each day of administration. The arm used for IV infusion should not be used for blood pressure monitoring. 
j. 
Includes chemistry and hematology. The arm used for IV infusion should not be used to draw blood samples. 
k. 
On Day 5 only, perform clinical laboratory assessments (chemistry and hematology) 1 hour postinfusion (within 45 minutes to 3 hours postinfusion is allowed). 
l. 
Eligible subjects will be given the option to participate in a PK substudy. Subjects who participate in the substudy will provide plasma samples for PK analysis on Day 2 at 
the time points indicated in the protocol Section 7.3. The arm used for IV infusion should not be used to draw blood samples. 
m. Day 2 only. 
n. 
For women of childbearing potential only. 
o. 
Prior to study drug administration. 
p. 
Subjects will be provided with an ePRO diary at Visit 1 and trained on its use. Subjects will start the daily ePRO diary the day after signing informed consent. Specific 
questionnaires include the severity of RP attack symptoms (using NRS), Raynaud’s Condition Score, CHFS, and overall patient improvement. 
q. 
Subjects will complete the daily ePRO diary during the eligibility period and baseline ePRO diary completion period as outlined above. Subjects will not complete the 
ePRO diary during Days 1 to 7, but will resume reporting at Day 8 and continue until Day 21. The CHFS and overall patient improvement will only be completed on 
Day - 1 and Day 21. 
r. 
Contact the IRT system to randomize the subject and obtain study drug assignment.  
s. 
Prior to the first infusion, the NovaCath™ Integrated IV Catheter System will be inserted into a small peripheral vein in the hand or arm using aseptic technique by a 
trained healthcare professional. If the subject’s peripheral veins do not support the placement of a peripheral line, a trained healthcare professional will insert a PICC. 
(Note: In some instances where the site chooses to use a PICC, it may be necessary to confirm placement of the PICC with an x-ray). When possible, the same NovaCath 
Integrated IV Catheter System or PICC will be used for the 5 days of treatment. 
t. 
Subjects will be premedicated with a single dose of 2 acetaminophen extended-release tablets, 650 mg (each), 15 to 60 minutes prior to study drug administration.  
u. 
To be administered for 5 consecutive days (eg, Monday through Friday) as an IV infusion over 6 hours each day via a peripheral line or a PICC using an infusion pump. 
Study drug will be initiated at a dose of 0.5 ng/kg/min and will be increased every 30 minutes (5 minutes) in increments of 0.5 ng/kg/min to 2.0 ng/kg/min or the 
individual tolerated dose. Refer to protocol Section 5.5.3 for further details. 
v. 
All adverse events will be collected from the time of informed consent until Day 35. 
BP = blood pressure; CHFS = Cochin Hand Function Scale; DU = digital ulcer; ECG = electrocardiogram; ePRO = electronic patient-reported outcomes; ET = early 
termination; HR = heart rate; IRT = Interactive Response Technology; IV = intravenous; NRS = Numeric Rating Scale; PICC = peripherally inserted central catheter/line; 
PK = pharmacokinetic(s); RP = Raynaud’s phenomenon; SAE = serious adverse event. 
 
 
 
 
 


 
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3 
STUDY ENDPOINTS 
3.1 
Efficacy Variables 
3.1.1 Primary efficacy variable 
The primary efficacy parameter is the change in the weekly frequency of symptomatic RP attacks 
from baseline. 
A symptomatic RP attack, for this study, is defined as at least 1 color change of the subject’s 
finger(s) (blue, white, or red) associated with at least 1 symptom (pain, numbness, tingling, 
and/or discomfort of the finger(s)). The attack is considered over when the color changes back to 
pre-attack color (normal) and the symptoms return to the subject’s pre-attack level. 
During the baseline ePRO diary completion period, eligible subjects must complete the daily 
ePRO diary for a minimum of 10 days (up to a maximum of 25 days) until the day of 
randomization. It may be necessary to extend the baseline ePRO diary completion period beyond 
10 days in order to accommodate the preferred Monday to Friday dosing schedule. The ePRO 
symptomatic RP attack data from this time period will be used for the calculation of the baseline 
frequency of symptomatic RP attacks.  
The baseline weekly frequency of symptomatic RP attacks is defined as the average number of 
weekly symptomatic RP attacks occurring during the 10- to 25-day baseline ePRO diary 
completion period. The double-blind weekly symptomatic RP attacks is defined as the average 
number of weekly symptomatic RP attacks during Days 8 to 21, inclusive. The primary efficacy 
parameter is the change in the weekly frequency of symptomatic RP attacks from baseline (ie, 
the mean number of weekly symptomatic RP attacks during Days 8 to 21 compared to during the 
10- to 25-day baseline ePRO diary completion period). 
If no data are reported on a particular day, the day will be excluded from the calculation of the 
mean. The weekly frequency is calculated by taking the sum of the attacks over the time period, 
divided by the number of days with data reported (including 0 attacks) in the time period, and 
multiplied by 7. For the double-blind weekly symptomatic RP attacks, as long as data are 
reported for at least one day on or between Days 8 to 21, the endpoint will be calculated in this 
way. For the baseline weekly frequency of symptomatic RP attacks, as long as data are reported 
for at least one day in the baseline ePRO completion period, the baseline will be calculated in 
this way. 
3.1.2 Exploratory efficacy variables 
Severity of RP Attack Symptoms 
Severity of RP attacks is determined by the overall severity of RP attack symptoms (using a 
Numeric Rating Scale pain [NRS]. The symptom (pain, numbness, discomfort or tingling) with 
the worst average baseline value for each patient will be used for evaluating the patient’s overall 


 
Statistical Analysis Plan 
 
Protocol Number: ES-201   
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severity. If more than one symptom have the same value, the priority is pain > numbness > tingling 
> discomfort. 
Raynaud’s phenomenon attacks are associated with significant discomfort (pain, numbness, 
tingling, and/or discomfort). Subjects will be asked to rate the severity of RP attack symptoms 
(pain, numbness, tingling, and/or discomfort) using an 11-point NRS.  
Intensity will be assessed as follows: 0 = no pain/numbness/tingling/discomfort, 1 to 3 = mild 
pain/numbness/tingling/discomfort, 4 to 6 = moderate pain/numbness/tingling/discomfort, and 
7 to 10 = severe pain/numbness/tingling/discomfort. 
The baseline and endpoint severity will be the average severity over the respective time periods.  
Raynaud’s Condition Score 
The Raynaud’s Condition Score asks subjects to rate their difficulty with Raynaud’s condition on 
a given day from “No difficulty (0)” to “Extreme difficulty (10).” Subjects will be asked to 
consider the number of attacks they have had on that day and how long each attack lasted. Subjects 
will also be asked to consider how much pain, numbness, or other symptoms the Raynaud’s caused 
in their fingers (including painful sores) and how much the Raynaud’s alone affected the use of 
their hands that day. 
The baseline and endpoint Raynaud’s Condition Score will be the average score over the respective 
time periods. If the score is not reported for a particular day, it will be excluded from the weekly 
mean derivation; no daily scores will be imputed. 
Cochin Hand Function Scale 
The CHFS is an 18-item self-administered instrument that assesses hand function as it relates to 
daily activities. Each item is scored on a 6-point Likert scale, where 0 = “Yes, without difficulty” 
and 5 = “Impossible”. The total score is the sum of the scores from each item and ranges from 0 
(without difficulty) to 90 (impossible). A higher score indicates more difficulty in hand function 
or greater disability. A total score will be calculated as long as 70% of the items (13 items) are 
completed. If any items are missing, the total score will be calculated as follows: 18 x (sum of the 
non-missing items) / (the number of non-missing items). Baseline will be the value collected at 
Day 1, and the endpoint will be the value collected at Day 21.  
Duration of symptomatic RP Attacks 
Subjects are asked to document the duration of each RP attack within their ePRO diaries. For each 
attack, the subject will record the duration in minutes. The average duration for baseline and 
endpoint will be calculated over the respective time periods. 
Worst pain associated with symptomatic RP 
Subjects will be asked to rate the severity of the worst pain using 11-point NRS within their 
ePRO diaries. The baseline and endpoint worst pain will be the average over the respective time 
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Worst numbness, worst tingling and worst discomfort may also be explored in the same way. 
Patient assessment of overall improvement in symptomatic RP 
At Day -1, subjects will be asked to rate their overall RP in the last week using Patient Global 
Impression of Severity (PGI-S) score (0-10). 
At Day 21, subjects will be asked to rate their overall RP compared to the start of the study, 
using Patient Global Impression of Change (PGI-C) score (Much worse, A little worse, No 
change, A little better, Much better).  
3.2 
Pharmacokinetic Variables 
The following PK parameters will be calculated whenever possible, based on the plasma 
concentrations of iloprost:  
• Steady state plasma concentration just before infusion is stopped, 
• Area under the plasma concentration versus time curve (AUC) from time of dosing to the 
last time point with measurable concentration (AUC0-t), 
• AUC from time 0 extrapolated to infinity (AUC0-inf), 
• Percentage of AUC obtained by extrapolation (AUCextrap%), 
• Terminal elimination constant (λz), 
• Plasma terminal elimination half-life (t1/2), 
• Plasma clearance (CL), calculated as Dose/AUC0-inf, and 
• Volume of distribution (V), calculated as Dose/(λz*AUC0-inf). 
3.3 
Safety Variables 
3.3.1 Adverse Events 
Since RP attacks are recorded as efficacy assessments, these will not be treated as adverse events. 
However, if an event results in hospitalization or amputation, the event will then be reported as an 
SAE. If subjects have non-RP-related pain during an RP attack, that event is captured as an adverse 
event. 
Adverse events, which include clinical laboratory test variables, are monitored and documented 
from the time of informed consent until Day 35.  
Treatment-emergent adverse events (TEAEs) are defined as those AEs that have a start date on 
or after the first administration of study drug or occur prior to the first administration of study 
drug and worsen in severity/grade or relationship to study medication after the first 
administration of study drug. 
Adverse events related to study drug will be those with a causality of possibly, probably, or 
definitely related.  
Hypotension events will be considered as adverse events of special interest (AESI). Additionally, 
AESIs may be identified by the sponsor. AESIs will be recorded in the eCRF. 


 
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3.3.2 Safety Laboratory Evaluations 
Chemistry and hematology will be assessed at Screening, Day 5, Day 35, and Early Termination 
Visit. A urine pregnancy test will be performed for women of childbearing potential at Screening 
and on Day 1 prior to study drug administration.  
3.3.3 Vital Signs 
Vital signs include heart rate and blood pressure and are assessed at each study visit except for 
Day 8. 
On dosing days (Days 1 to 5), vital signs will be measured prior to study drug administration and 
at 15 minutes (5 minutes) prior to and after all dose changes during the study drug infusion. 
Additionally, vital signs will be monitored 15 minutes (5 minutes) and 1 hour (15 minutes) 
after completion of the study drug 6-hour infusion. 
3.3.4 Other Safety Variables 
A 12-lead ECG will be performed at screening. 
A complete physical examination will be performed at Screening. The physical examination will 
consist of an examination of the following systems: general appearance, skin, eyes, ears, nose, 
throat, neck (including thyroid), lymph nodes, chest, heart (including any auscultated cardiac 
murmurs), abdomen, extremities, and neurologic.  
Height will be measured at screening only. Weight will be assessed at screening and the first in-
clinic visit (Day 1). 
4 
ANALYSIS POPULATIONS 
4.1.1 Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) Population is defined as all randomized subjects who 
initiate infusion of study drug. The mITT Population is the primary efficacy analysis population. 
4.1.2 Safety Population 
The Safety Population is defined as all randomized subjects in whom infusion of study drug is 
initiated.  The Safety Population will be used for all safety analyses. 
4.1.3 Per-Protocol Population 
The Per-Protocol (PP) Population will include subjects in the mITT Population who complete all 
scheduled study drug infusions and at least Day 21 follow-up without any major protocol 
deviations. The PP Population will be used for sensitivity analyses of the primary efficacy 
variable.  
Subject data will be reviewed by the clinical team to identify exclusions from the PP Population.  
The list of subjects to be excluded from the PP Population will be finalized prior to database 
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4.1.4 PK Population 
The PK Population will include all subjects in the PK substudy who received study drug and who 
had at least 1 value above the lower limit of quantification. 
5 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
5.1 
Baseline Determination 
For efficacy measurements, baselines are defined in section 3.1. 
For safety measurements, unless otherwise stated, baseline will be the Day 1 value. If the Day 1 
value is missing, the last measurement prior to the first administration of study drug will be the 
baseline value. Baseline for clinical laboratory assessments will be the value at the Screening 
Visit. 
5.2 
Evaluation of Site Effect 
The site effect will be explored using a pooled site. Pooled site will be generated using the 
following procedure: 
• Sites are sorted by the total number of mITT subjects and site ID in ascending order. 
• If the first (smallest) site has less than 6 mITT subjects, it will be pooled with the next 
site on the sorted list (i.e., the smallest of other sites) until the pooled site has at least 6 
mITT subjects. 
• The previous steps are repeated for the rest of the sites until all pooled sites have at least 
6 mITT subjects. If the total number of mITT subjects in the rest of the site(s) is less than 
6, they will then be included in the previous pooled sites. 
5.3 
Handling of Dropouts and Missing Data 
5.3.1 Missing or Incomplete Dates 
Dates will be printed in ISO 8601 date format (YYYY-MM-DD). If only year and month are 
available, date will be displayed as YYYY-MM. If only year, then just YYYY. Dates that are 
missing because they are not applicable for the subjects will be output as “NA”, unless otherwise 
specified. 
For diagnosis/onset dates for Systemic Sclerosis diagnosis and Raynaud's Phenomenon diagnosis, 
the following imputation rules for partial dates will be used for summary (if the imputed date is 
later than the date of screening, the date of screening will be used instead): 
• 
If month and year available but day missing, day will be imputed to the 15th (e.g. 
06/UNK/2009 will be imputed as 06/15/2009) 
• 
If year available but day and month missing, month and day will be imputed to July 1 (e.g. 
UNK/UNK/2010 will be imputed as 07/01/2010). 


 
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Adverse events with missing start dates will be considered as treatment-emergent unless the partial 
date excludes that possibility, e.g. the adverse event month is prior to the treatment infusion month.  
Otherwise, the first day of the month will be used to impute missing start days and January will be 
used to impute missing start months. If the causality for an adverse event is missing, the adverse 
event will be assumed to be related.  
5.3.2 Multiple Imputation for Efficacy Endpoints 
Day 8 to Day 21 
An imputation model will impute missing values between Day 8 and Day 21 as follows:  
• 
For subjects who permanently discontinue before or during Days 8 through 21, missing 
data after their discontinuation will be imputed. The missing data imputation method will 
use data from subjects in the placebo arm.  
• 
For subjects who have only intermittent missingness of Days 8 through 21 values, no 
imputation will be needed. 
Missing data will be imputed 100 times to generate 100 complete data sets using the regression 
method. For each of the 100 imputed datasets, the corresponding endpoint will be constructed, 
and the estimates from the 100 fitted models will be combined. 
5.3.3 Missing or Incomplete PK Data 
For PK substudy, if the actual sampling time is missing, but a valid concentration value has been 
measured, the concentration value will be flagged and the scheduled time point may be used for 
the calculation of PK variables. 
In cases of missing pre-dose, the missing components will be assumed as zero. For the other 
cases, the missing data will not be imputed.  
If one or more below limit of quantification (BLQ) values occur before the first measurable 
concentration, they will be assigned a value of zero. For the BLQ values occur between 
measurable concentrations, they may be assigned a value of lower limit of quantification 
(LLOQ). 
If BLQ values occur after the last measurable concentration in a profile, the BLQ should be 
omitted (set to missing) in the derivation of PK variables, statistical analysis, and the individual 
subject plots. 
6 
ANALYSIS OF DISPOSITION AND SUBJECT CHARACTERISTICS 
6.1 
Disposition and Analysis Populations 
Subject disposition will be provided for all randomized subjects. The number and percentage of 
subjects in each of the following disposition categories will be presented by treatment and in 
total: 


 
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• Subjects who are randomized, 
• Subjects who received at least one infusion of study drug,  
• Subjects who completed treatment per protocol and 
• Subjects who completed the study. 
For subjects who did not complete the study, a summary will be provided for the reason of 
discontinuation. 
The reason for screen failure will be summarized and listed. 
The number and percent of subjects in each of the analysis populations will also be provided. 
The reason for exclusion from the PP population will be listed. 
6.2 
Protocol Deviations 
Protocol deviations as defined in the Medpace Protocol Deviation Plan will be summarized for 
all subjects in the Randomized Population. The number and percentage of subjects with a 
protocol deviation will be summarized for each deviation and overall, by treatment group and 
total, as well as by study site. The deviations will also be listed by site and subject. 
6.3 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be provided for the Safety Population. 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for age, 
baseline weight, baseline body mass index (BMI), and height at Screening will be provided for 
each treatment group and in total. Counts and percentages of subjects for sex, ethnicity, race, 
smoking/alcohol use, and phosphodiesterase inhibitor use at screening will also be presented.  
Medical and surgical history will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT) by treatment group and total. Medical and surgical history will also be listed. 
Digital ulcers assessed at screening will be listed and will include the location, status, and 
healing. 
6.4 
Concomitant Medications 
Medications will be coded using the latest version of the World Health Organization (WHO) 
Drug Dictionary version. Prior medications are any medications stopped prior to the first dose of 
study medication.  Concomitant medications are any medications taken on or after the first dose 
of study medication. The number and percentage of subjects taking each concomitant medication 
will be summarized by preferred term within each anatomical therapeutic chemical (ATC) 
classification for the Safety Population. 
Prior and concomitant medications will be listed. 


 
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6.5 
Study and Drug Exposure 
Study exposure will be calculated as the date of last visit – date of first dose + 1. Study exposure 
will be summarized with descriptive statistics by treatment group and in total. 
The count and percentage of subjects receiving a study drug infusion will be summarized by day 
(Day 1 through Day 5) for each treatment group and in total. Additionally, the count and 
percentage of subjects will be summarized by the highest study drug infusion dose by day for 
each treatment group and in total. 
7 
ANALYSIS OF EFFICACY 
All available efficacy data (weekly frequency of symptomatic RP attacks, severity of 
symptomatic RP attacks, Raynaud’s Condition Score, hand function as assessed by the CHFS, 
the duration of symptomatic RP attacks, worst pain associated with symptomatic RP, overall 
improvement in symptomatic RP on a Likert scale) will be listed for the mITT Population. 
Efficacy measurements will be summarized with descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum) by treatment group (iloprost injection for IV use 
and placebo). Baseline, change from baseline, and percent change from baseline to endpoint will 
be presented for each efficacy measurement for the mITT Population. 
7.1 
Primary Efficacy Analysis 
The primary efficacy parameter is the change in the weekly frequency of symptomatic RP 
attacks from baseline. 
The primary analysis on the primary efficacy parameter will be performed based on an analysis 
of covariance (ANCOVA) model, including randomized treatment group and randomized 
stratification (ie, use of phosphodiesterase inhibitors at screening) as factors and baseline weekly 
RP attacks as a covariate. The treatment comparisons will be estimated together with the 95% 
confidence interval and p-value. The primary analysis will be performed on the mITT 
Population.  
For subjects in the mITT Population with a missing primary efficacy endpoint, multiple 
imputation will be used. 
Normality assumption of the ANCOVA model will be checked and nonparametric model may be 
explored if the assumption is violated. 
Site effect 
Pooled site will be added into the previous ANCOVA model as a factor. The treatment 
comparisons will be estimated with the 95% confidence interval. The patients with missing 
efficacy measurement will be excluded. No imputation will be used. 


 
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7.2 
Exploratory Efficacy Analyses 
The exploratory efficacy parameters include changes from baseline to the end of the efficacy 
follow-up in the following: 
• Severity of RP attacks as determined by the overall severity of RP attack symptoms 
(using a Numeric Rating Scale [NRS]). The symptom (pain, numbness, discomfort or 
tingling) with the worst average baseline value for each patient will be used for 
evaluating the patient’s overall severity. If more than one symptom have the same value, 
the priority is pain > numbness > tingling > discomfort  
• Raynaud’s Condition Score  
• Hand function as assessed by the CHFS  
• Duration of symptomatic RP attacks  
• NRS for worst pain associated with symptomatic RP  
• Patient assessment of overall improvement in symptomatic RP  
Descriptive statistics (n, mean, standard deviation, median, minimum, maximum) will be 
provided by treatment group for the exploratory endpoints on mITT Population. The same 
ANCOVA model utilized in the primary efficacy analyses will be used to analyze the 
exploratory endpoints on mITT Population. The treatment comparisons will be estimated 
together with the 95% confidence interval. No imputation will be needed in the exploratory 
efficacy analyses. 
7.3 
Subgroup Analysis 
The primary efficacy endpoint will be summarized for the mITT population by gender (male, 
female). The ANCOVA model in the primary analysis will be used for each subgroup by gender 
Corresponding forest plot for treatment effect by gender will be provided.  
Stratification factor (ie, use of phosphodiesterase inhibitors at screening) will also be explored 
for subgroup effects. Age and race may be also explored. 
7.4 
Sensitivity Analyses 
The primary analysis will be repeated on the PP Population. No other sensitivity analysis will be 
performed. 
8 
PHARMACOKINETIC ANALYSIS 
The PK parameters of iloprost will be calculated by standard non-compartmental methods 
(NCA) for PK Population. The actual collection times will be used for evaluation of PK data. 
The AUC before end-of-infusion will be calculated as the multiplication of the concentration just 
before end-of-infusion and the corresponding infusion time. AUC after end-of-infusion will be 
calculated using the Linear Up Log Down method (equivalent to the Linear Up/Log Down 
option in WinNonlin® Professional). The total AUC will be sum of the AUC before end-of-
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In order to estimate first-order terminal elimination constant, λz, linear regression of 
concentration in logarithm scale vs. time will be performed using at least 3 data points. Uniform 
weighting will be selected to perform the regression analysis to estimate λz. The λz will not be 
presented for subjects who do not exhibit a terminal elimination phase in their 
concentration-time profiles. 
The constant λz will not be assigned if one of the following happens: 
1. 
Tmax is one of the 3 last data points, 
2. 
The adjusted regression coefficient (R-squared) is less than 0.8, 
3. 
The estimated elimination rate indicates a positive slope, or 
4. 
The terminal elimination phase is not linear (as appears in a semi-logarithmic scale) based 
on visual inspection. 
In the case where the percent of AUC0-inf extrapolated exceeds 20%, the λz will be assigned to 
the subject(s) but the corresponding λZ-related PK parameters (i.e., t1/2, AUC0-inf, CL, and V) will 
be flagged but still included to the calculation of summary statistics with an explanatory 
footnote. In cases where the constant λz is not assigned, the values of associated variables (i.e., 
t1/2, AUC0-inf, AUCextrap%, CL, and V) will not be calculated. 
Descriptive statistics (n, mean, standard deviation, median, minimum, maximum, and coefficient 
of variation [CV]) will be used to summarize PK concentrations and parameters. Geometric 
mean and geometric CV will also be used to summarize specific parameters. The maximum 
plasma concentration and AUCs after dose administration for each cohort will be evaluated using 
a power model for dose proportionality. The power model is described below as:  
y = α x Doseβ,  
where y denotes the PK variables. Dose proportionality implies that β=1 and will be assessed by 
estimating β along with its 90% confidence interval. The exponent, β, in the power model will be 
estimated by regressing the ln-transformed PK variable on ln-transformed dose. 
The power model will be fitted by restricted maximum likelihood (REML) using SAS® Proc 
Mixed. Both the intercept and slope will be fitted as fixed effects. The mean slope will be 
estimated from the power model and the corresponding 90% confidence interval calculated.  
Additional PK/pharmacodynamic modeling may be performed as an exploratory analysis, if 
applicable.  
9 
ANALYSIS OF SAFETY 
The safety parameters include adverse events, physical examination findings, vital sign 
measurements (heart rate and blood pressure), 12-lead electrocardiogram findings, and standard 
clinical laboratory measurements (chemistry and hematology). All safety analyses will be 
performed on the Safety Population. Subjects will be analyzed by treatment received.  
9.1 
Adverse Events 
An overview of adverse events will be provided that includes the number and percentage of 
subjects from the Safety Population by treatment group and in total for the following categories: 


 
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• Any TEAEs, 
• Maximum severity/grade of TEAEs, 
• Study drug-related TEAEs, 
• Maximum severity/grade of study drug-related TEAEs, 
• SAEs, 
• TE-SAEs, 
• Study drug-related TE-SAEs, 
• AESI, 
• TEAEs leading to study drug discontinuation 
• Study drug-related TEAEs leading to study drug discontinuation, and 
• TEAEs leading to death. 
Adverse events will be coded using the latest version of MedDRA. The number and percentage 
of subjects with AEs will be summarized by SOC and PT for each treatment group and in total 
for the following: 
• TEAEs, 
• Study drug-related TEAEs, 
• SAEs, 
• TE-SAEs, 
• Study drug-related TE-SAEs, and 
• TEAEs leading to study drug discontinuation. 
The number and percentage of subjects with TEAEs will be summarized by reported maximum 
severity/grade for each MedDRA preferred term within system organ class for each treatment 
group and in total. 
The number and percentage of subjects with AESIs will be summarized by preferred term within 
system organ class for each treatment group and in total. 
All SAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to death will be 
listed. 
9.2 
Clinical Laboratory Evaluations 
Descriptive statistics for each chemistry and hematology parameter will be presented by 
treatment group for baseline, each visit, and the change from baseline. 
9.3 
Vital Signs 
Vital signs include heart rate and blood pressure. Vital signs parameters will be summarized 
using descriptive statistics for each visit and time point for each treatment group. The change 
from baseline will also be summarized. 


 
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9.4 
ECG Parameters 
The overall interpretation of the ECG at Screening will be summarized with counts and 
percentages for each treatment group and in total. All ECG parameters will be listed. 
9.5 
Physical Examination 
Physical examination data will be listed. 
10 DATA MONITORING COMMITTEE 
A DMC consisting of 3 members including an independent biostatistician, 1 SSc expert, and 1 
prostacyclin PAH expert will be responsible for safeguarding the interests of study subjects and 
for enhancing the integrity and credibility of the study. To address this mission, the DMC will 
have ongoing access to efficacy and safety data, and to information regarding the quality of study 
conduct.  A separate DMC Charter will be prepared. 
11  STEERING COMMITTEE 
The purpose of the Steering Committee is to provide objective and independent scientific and 
medical input on the design, execution, analysis, and reporting of the study. The Steering 
Committee will consist of members with medical specialties or scientific expertise (eg, 
statisticians) pertinent to the population under study. There will be 7 voting external members of 
the Steering Committee who are independent of Eicos Sciences, Inc. The Steering Committee 
statisticians and Sponsor representatives will be nonvoting members. A separate Steering 
Committee Charter will be prepared.  
12 INTERIM ANALYSIS 
No interim analysis is planned for the study.  
13 SAMPLE SIZE AND POWER CONSIDERATIONS 
The study will enroll up to a maximum of 40 subjects. 
The operating characteristics for this 3-category decision guideline (please refer to the protocol), 
when 12.0 is the standard deviation of the change from baseline in the weekly frequency of 
symptomatic Raynaud attacks and the sample size is 20 patients per arm, are as follows: 
1. 
Regarding the false-positive error rate of the screening procedure, if IV iloprost truly 
provides no improvement in the change from baseline in the weekly frequency of symptomatic 
Raynaud attacks, then the probability of bringing IV iloprost forward to a Phase 3 study is 32%. 
However, there is only a 2.5% chance of reaching the false positive conclusion that IV iloprost 
provides a statistically significant improvement in efficacy relative to a placebo control.    
2. 
The false-negative error rate is low. If the true difference between IV iloprost and the 
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Raynaud attacks is 6.65, then there is only a 10% chance that IV iloprost would be discarded, 
and thus a 90% chance that it would be evaluated in a subsequent confirmatory Phase 3 study; 
furthermore, the probability that IV iloprost will have a statistically significant improvement in 
efficacy (at one-sided p<0.025) relative to the placebo control is 21%. 
14 PROGRAMMING SPECIFICATIONS 
Statistical analyses will be performed using SAS® (Cary, NC) version 9.3 or above. All 
available data will be presented in subject data listings, which will be sorted by site number, 
unique subject identifier and where appropriate, visit number and visit/assessment date.  
The programming specifications, including the mock-up validity listings, analysis tables, figures, 
and data listings, as well as the derived database specifications, will be prepared in stand-alone 
documents.