Clinical trial NCT04195906
Conditions: Calciphylaxis Calcific Uremic Arteriolopathy
Keywords: Calciphylaxis Calcific Uremic Arteriolopathy Wound ESRD
Sponsor: Sanifit Therapeutics S. A.
Start date: 2020-02-12; Completion date: 2022-10-24
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives are to assess the efficacy, safety, and tolerability of SNF472 compared to placebo when added to background care for the treatment of calciphylaxis (CUA).

Detailed description:
The formation and growth of calcified deposits in arterioles and other small blood vessels appears to be fundamental to the development of CUA especially in end stage renal disease patients. This phase 3 double-blind, randomized, placebo-controlled study is designed to assess the effect of SNF472 when added to background care to improve wound healing, as evaluated using Bates-Jensen Wound Assessment Tool (BWAT) scoring and pain as reported by the subject using a VAS scale. The study consists of a double-blind, randomized, placebo controlled period of 12 weeks followed by an open-label period of 12 weeks.. .

Arms: arm 1: Dose: 7 mg/kg SNF472 diluted in 100 mL physiological saline. arm 2: Matching placebo (saline) diluted in 100 mL physiological saline. arm 3: Dose: 7 mg/kg SNF472 diluted in 100 mL physiological saline.
Interventions: intervention 1: Experimental: SNF472 intervention 2: Placebo Comparator: Placebo intervention 3: Experimatenl SNF472 (Open-label)
Intervention descriptions: intervention 1: Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks intervention 2: Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions fo 12 weeks intervention 3: Administered 3 times weekly by intravenous infusion through the hemodialysis machine in conjunction with the subject's hemodialysis sessions for 12 weeks

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Safety of SNF472 When Added to 
Background Care for the Treatment of Calciphylaxis 
SNFCT2017-06 
Development Phase 
Phase 3 
Study Drug 
SNF472 
Indication 
Treatment of calciphylaxis 
Sponsor 
Sanifit Therapeutics S.A. 
EudraCT Number 
2018-001301-90 
IND Number 
116437 
Protocol Version and Date 
Amendment 3, 9 DEC 2021 
Amendment History: 
Date 
Amendment Number 
Region 
20 MAY 2019 
Original Protocol 
Global 
17 SEP 2019 
01 
Global 
30 APR 2020 
1.1 
United Kingdom Specific 
10 DEC 2020 
1.2 
Germany Specific 
10 FEB 2021 
1.3 
Germany Specific 
21 MAY 2021 
02 
Global 
9 DEC 2021 
03 
Global 
This study will be conducted in accordance with the ethical principles that originate from 
the Declaration of Helsinki and that are consistent with International Council for 
Harmonisation (ICH) Guidelines on Good Clinical Practice (GCP), including the archiving of 
essential documents, and regulatory requirements as applicable. 
 
This document is the sole property of Sanifit Therapeutics S.A.
 
 
This document shall be used only for the purpose of the disclosure herein provided. No 
disclosure or publication shall be made without the prior written consent of Sanifit 
Therapeutics S.A. 




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PROTOCOL AMENDMENT 3 - SUMMARY OF CHANGES  
1) SYNOPSIS and Section 5.6.1.1: The central wound rating group BWAT Reviewers will not 
be blinded to the visit order when completing BWAT ratings. BWAT was developed for 
sequential review of wound images and images can be rated with the greatest accuracy 
if BWAT reviewers are able to refer to all of a subject’s images in chronological 
sequence. 
2) Section 5.6.1.2: Clarification that the qualitative reviewers will not be involved in 
confirmation of CUA lesions or BWAT rating. These qualitative reviewers are blinded to 
treatment assignment and visit order in Part 1, and to visit order in Part 2. 
3) Section 8.2.2: Clarification that the independent statistical service provider will provide 
the conditional power and sample size computations to the independent DSMB only. 
The DSMB will review the results and then provide only the sample size 
recommendation to the Sponsor.  
 
 


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PROTOCOL SYNOPSIS 
Study Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and 
Safety of SNF472 When Added to Background Care for the Treatment of Calciphylaxis 
Protocol Number: SNFCT2017-06 
Indication: Treatment of calciphylaxis (calcific uremic arteriolopathy [CUA]) 
Sponsor: Sanifit Therapeutics S.A. 
Number of Subjects and Study Sites: Planned enrollment is approximately 66 subjects from 
approximately 60 sites in multiple countries. Number of subjects may be adjusted up to a 
maximum of 99 based on results of a sample size re-estimation (SSRE). 
Study Objectives 
• To evaluate the efficacy of SNF472 compared with placebo when added to background care 
for the treatment of CUA 
• To evaluate the safety and tolerability of SNF472 compared with placebo when added to 
background care for the treatment of CUA 
Study Design and Methodology 
This Phase 3, global, multicenter study will examine the efficacy and safety of SNF472 in adult 
subjects on maintenance hemodialysis (HD) who have at least one ulcerated CUA lesion 
(wound). The study will include a screening period of up to 5 weeks, a 12-week double-blind, 
randomized, placebo-controlled treatment period (Part 1) followed by a 12-week open-label 
treatment period (Part 2), and a 4-week follow-up period.  
Screening Period: Informed consent will be obtained prior to performing any study procedures. 
Subject eligibility will be evaluated during the screening period, which will be conducted as a 
two-step process. In addition, the subject’s pain medications will be stabilized between 
Screening Visit 1 and Screening Visit 2 to determine the baseline maintenance pain medication 
dose. Completion of screening within 4 weeks or less is preferred but up to 5 weeks is allowed.  
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to receive either 
7 mg/kg of SNF472 or matching placebo in a double-blind manner. Randomization will be 
stratified based on intravenous STS use at the time of randomization (yes/no). 
Double-blind, Randomized, Placebo-Controlled Treatment Period (Part 1): Subjects will 
receive SNF472 or placebo for 12 weeks in addition to background care (in accordance with the 
clinical practices of each site). No changes to the background care regimen, including pain 


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medication, should be made after randomization unless medically indicated in the opinion of 
the Investigator.  
The Schedule of Events for the Screening Period and Part 1 is provided in Table 1. 
Open-label Treatment Period (Part 2): Subjects who complete Part 1 will be eligible to 
participate in Part 2, in which all subjects will receive open-label SNF472 for 12 weeks and 
continue stable background care (in accordance with the clinical practices of each site), 
including pain medication, with no changes unless medically indicated in the opinion of the 
Investigator.  
The Schedule of Events for Part 2 and the follow-up visit is provided in Table 2.  
Follow-Up Period/ Early Termination: Subjects completing the study will return for a follow-up 
visit 4 weeks after the last dose of study drug. Subjects should continue on stable background 
care, including pain medication, during the 4-week follow-up period. with no changes unless 
medically indicated in the opinion of the Investigator. Subjects who discontinue study drug 
during Part 1 or Part 2 will be asked to complete study assessments throughout the respective 
part of the study (Part 1 or Part 2) and complete a follow-up visit.  
Subjects will record all pain medications used in a pain medication diary throughout Screening, 
Part 1, Part 2, and the follow-up period. Diaries should be reviewed with the subject at least 
weekly and pain medications will be recorded in the electronic case report form (eCRF). 
The following assessments will be performed during this study: demographic characteristics, 
medical history, prior/concomitant medications, physical examination, body weight, vital signs, 
electrocardiograms (ECGs), Holter monitoring, blood samples for central laboratory 
assessments (hematology, chemistry, ionized calcium, parathyroid hormone [PTH], high-
sensitivity C-reactive protein [hs-CRP], and serum pregnancy test [females of childbearing 
potential only]), dialysis parameters, record CUA wound care, wound imaging (photos and 
video) and assessment (including Bates-Jensen Wound Assessment Tool [BWAT], qualitative 
wound evaluation, occurrence of new CUA lesions), Pain Visual Analog Scale (VAS), 
Wound-Quality of Life [Wound-QoL] questionnaire, review of subject diary of pain medications, 
adverse events (AEs), HD-related events, and blood samples for pharmacokinetics (PK), 
pharmacodynamics (PD), and biomarkers. No DNA testing will be performed. 
All 13 items comprising the “BWAT total” score will be assessed: size, depth, edges, 
undermining, necrotic tissue type, necrotic tissue amount, exudate type, exudate amount, skin 
color surrounding wound, peripheral tissue edema, peripheral tissue induration, granulation 
tissue, and epithelialization. Endpoints will include the BWAT total score as well as a targeted 
modification of BWAT, the “BWAT-CUA”, which focuses on the following 8 prototypical 
features of CUA lesions: necrotic tissue type, necrotic tissue amount, exudate type, exudate 
amount, skin color surrounding wound, peripheral tissue edema, peripheral tissue induration, 
and granulation tissue. Sites will capture photos and videos of the wounds using the provided 
device and imaging software and will receive training on BWAT and rating of undermining, 
peripheral tissue edema, and peripheral tissue induration. An expert central wound rating 
group blinded to treatment will perform a quality review of the site’s ratings and rate the 
remaining BWAT items based on review of the wound photos and videos, aided by automated 


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measurements from imaging software for the wound size assessment. If a subject has more 
than one CUA lesion, the course of up to 3 of these (primary, secondary, tertiary) will be 
assessed with BWAT. Designation of lesions as primary, secondary, and tertiary will be defined 
based on the total area measured by the wound imaging software at screening. The progress of 
the primary lesion will also be evaluated with a qualitative review by the central wound rating 
group. 
Pain VAS will be electronically administered, requiring the subject to mark a position on a 10-
cm long horizontal line to indicate the worst wound-related pain experienced during the 
previous 24 hours.  
The Wound-QoL questionnaire will also be electronically administered and consists of 17 
questions on impairments that are assessed in reference to the preceding 7 days.  
Safety information from this study will be reviewed by an external independent Data and 
Safety Monitoring Board (DSMB). 
Study Duration 
The planned length of participation in the study for each subject is up to approximately 
33 weeks (from screening through completion of the follow-up visit). This includes: 
• Screening period of up to 5 weeks  
• Part 1 treatment period of 12 weeks  
• Part 2 treatment period of 12 weeks 
• Follow-up period of 4 weeks 
Test Product and Reference Therapy, Dose and Mode of Administration 
The test product, SNF472, will be supplied as a 30mL sterile vial containing 30 mg/mL solution 
(900 mg) in a blinded manner for Part 1 and in an unblinded manner for Part 2. Subjects 
randomized to active treatment for Part 1 will receive 7 mg/kg of SNF472 three times weekly 
(TIW) during dialysis sessions. All subjects will receive 7 mg/kg of SNF472 TIW during dialysis 
sessions for Part 2. 
Placebo will be supplied in a blinded fashion as a physiological saline solution in a 30 mL sterile 
vial that is identical in appearance to the SNF472 test product. Subjects randomized to placebo 
for Part 1 will receive placebo TIW during dialysis sessions.  
In Part 1, weight for dosing calculation will be the subject’s body weight recorded after 
hemodialysis during screening. In Part 2, weight for dosing calculation will be the subject’s 
body weight recorded after hemodialysis at Week 12 Day 5.  
SNF472 solution and placebo will be diluted in physiological saline and infused via the dialysis 
circuit over a period of approximately 2.5 – 3 hours. 


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Summary of Eligibility Requirements  
Inclusion Criteria 
1. ≥18 years of age 
2. Receiving maintenance HD in a clinical setting for at least 2 weeks prior to screening 
3. Clinical diagnosis of CUA by the Investigator including ≥1 CUA lesion with ulceration of 
the epithelial surface. A central wound rating group will review wound images to 
confirm the primary lesion is due to CUA.  
4. CUA wound-related pain shown by a Pain VAS score ≥50 out of 100 
5. Primary lesion that can be clearly photographed for the purpose of protocol-specified 
wound healing assessments 
6. Willing and able to understand and sign the informed consent form and willing to 
comply with all aspects of the protocol 
Exclusion Criteria 
1. Subjects whose primary lesion is due to causes other than CUA 
2. History of treatment with bisphosphonates within 3 months of baseline (Week 1 Day 1) 
3. Severely ill subjects without a reasonable expectation of survival for at least 6 months 
based on the assessment of the Investigator  
4. Subjects with a scheduled parathyroidectomy during the study period 
5. Expectation for kidney transplant within the next 6 months based on Investigator 
assessment or identification of a known living donor 
6. Pregnant or trying to become pregnant, currently breastfeeding, or of childbearing 
potential (including perimenopausal women who have had a menstrual period within 
one year) and not willing to either completely avoid sexual intercourse with a person of 
the opposite sex or use a highly effective method of birth control (specified in 
Section 4.7.4.2) from screening through at least 30 days after last dose of study drug 
7. Significant noncompliance with dialysis treatment evidenced by repeated missed 
dialysis sessions (including if due to hospitalizations where dialysis treatment is 
unavailable) or significant noncompliance with medication regimen, in the judgment of 
the Investigator 
8. Any history of active malignancy within the last year (history of localized basal cell or 
squamous cell carcinoma that has been excised/appropriately treated or a fully excised 
malignant lesion with a low probability of recurrence will not be considered 
exclusionary) 
9. Clinically significant illness other than CUA within 30 days prior to screening that, in the 
judgment of the Investigator, could interfere with interpretation of study results, impair 
compliance with study procedures, or impact the safety of the subject (e.g., unstable 
angina, unstable heart failure, stroke, uncontrolled hypertension, or other illness 
requiring hospitalization) 
10. Participation in an investigational study and receipt of an investigational drug or 
investigational use of a licensed drug (with the exception of intravenous STS) within 
30 days prior to screening. If participating in an investigational study of intravenous STS, 


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all visits of that study must be completed prior to screening for this study. Note: Off-
label use of intravenous STS outside of an investigational study is not restricted. 
11. Past or current participation in another clinical study with SNF472 
12. History or presence of active alcoholism or drug abuse as determined by the 
Investigator within 6 months before screening or concurrent social conditions that, in 
the opinion of the Investigator, would potentially interfere with the subject's study 
compliance 
13. Mental impairment or history of or current significant psychiatric disease that, in the 
opinion of the Investigator, may impair ability to provide informed consent or impact 
compliance with study procedures 
14. Any other condition or circumstance that, in the opinion of the Investigator, may make 
the subject unlikely to complete the study or comply with study procedures and 
requirements, or may pose a risk to the subject's safety and well-being 
15. Subjects whose CUA lesions exhibit significant improvement, in the opinion of the 
Investigator, between the first and second screening visit 
Study Endpoints 
Efficacy Endpoints: 
In Part 1, the primary, secondary, and exploratory efficacy endpoints will compare the placebo 
and SNF472 groups as follows. 
 
Alternate Primary Efficacy Endpoints:  
• Absolute change from baseline to Week 12 in the BWAT-CUA score for the primary 
lesion 
• Absolute change from baseline to Week 12 in Pain VAS score 
Secondary Efficacy Endpoints (assessed hierarchically):  
• Absolute change from baseline to Week 12 in the Wound-QoL score 
• Absolute change from baseline to Week 12 in the BWAT total score for the primary 
lesion 
• Qualitative wound image evaluation for the primary lesion (worsened, equal to, or 
improved relative to baseline) at Week 12  
• Rate of change in opioid use as measured in morphine milligram equivalents (MME) 
from baseline to Week 12 
Exploratory Efficacy Endpoints: 
• Absolute change from baseline to Week 12 in wound size for the primary lesion 
• Absolute change from baseline to Week 12 in each BWAT item for the primary lesion 
• Absolute change in BWAT-CUA, BWAT total, Pain VAS, and Wound-QoL score by visit 
• Proportion of subjects with new CUA lesions between baseline and Week 12 
• Absolute change from baseline to Week 12 in the Wound-QoL scores for the body, 
everyday life, and psyche subscales 


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• Absolute change from baseline to Week 12 in the BWAT-CUA score for the secondary 
and tertiary lesions 
• Proportion of subjects requiring an increase in pain medication related to their CUA 
lesion(s) between baseline and Week 12 
• Proportion of subjects with a decrease in pain medication related to their CUA lesion(s) 
between baseline and Week 12 
• Absolute change from baseline to Week 12 in opioid use as measured in MME 
Additional exploratory endpoints for Part 2 are described in Section 8.1.1. 
Safety Endpoints: 
• Proportion of subjects with AEs, SAEs, and deaths 
• Changes from baseline in the following: 
 Laboratory parameters 
 Holter monitoring results 
 QTc interval and other ECG parameters 
 Vital signs 
• Proportion of subjects with a CUA wound-related infection, sepsis, hospitalization, or 
any CUA wound-related complication 


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Statistical Methods 
Alternate Primary Endpoints 
The comparison of absolute change from baseline to Week 12 in BWAT-CUA score between 
treatment groups will be achieved using a mixed model repeated measures (MMRM) analysis 
to estimate the difference between randomized treatment group least squares means 
(LS means) at 12 weeks. The model will include fixed effect terms for randomized treatment 
group, visit, and visit by randomized treatment group interaction. The model will be stratified 
for STS use at randomization and baseline BWAT-CUA score use will be included as a covariate. 
Subject will be fitted as a random effect and an unstructured variance-covariance matrix will be 
used. 
The comparison of absolute change from baseline to Week 12 in Pain VAS will be analyzed 
using an MMRM analysis similar to that for the change in BWAT-CUA score with covariates of 
baseline Pain VAS and stratified for STS use at randomization. 
Secondary Efficacy Endpoints 
The secondary endpoints will be evaluated hierarchically. The first secondary efficacy endpoint 
of the absolute change from baseline to Week 12 in Wound-QoL score will be analyzed using an 
MMRM analysis similar to that for the alternate primary efficacy endpoints with baseline 
Wound-QoL score as a covariate and stratified for STS use at randomization. The second 
secondary efficacy endpoint of the absolute change from baseline to Week 12 in the BWAT 
total score will be analyzed using an MMRM analysis with baseline BWAT total score as a 
covariate and stratified by STS use at randomization. The third secondary endpoint of 
qualitative wound image evaluation for the primary lesion at Week 12 will be analyzed using 
generalized estimating equations. Results will be displayed in terms of the odds ratio of SNF472 
vs placebo along with the associated 95% CI and 2-sided p-value. The fourth secondary 
endpoint of rate of change in opioid use from baseline to Week 12 will be analyzed via a mixed 
model random coefficients analysis.  
Overall Type I Error Control 
To prevent any overall Type I error inflation, the alternate primary endpoints will be assessed 
using a Hochberg procedure with a 2-sided alpha level of 4%. If both alternate primary 
endpoints are met, the alpha apportioned will be recycled so that the secondary endpoints will 
be assessed hierarchically at the 5% alpha level, 2-sided. If only one alternate primary endpoint 
is met, the secondary endpoints will be assessed hierarchically at the 1% alpha level, 2-sided.  
Sample Size Re-estimation 
A SSRE procedure is planned when primary endpoint data is available from approximately 33 of 
the planned total of 66 subjects randomized and treated for 12 weeks. This procedure will be 
conducted blind to the sponsor by an external independent statistical service provider. Any 
increase in sample size with be capped at 50% of the planned sample size (i.e., the maximum 
total sample size will be capped at 66 + 1/2 x 66 = 99 subjects). Details are provided in Section 
8.2.2. 


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Safety Data 
Safety data will be analyzed descriptively and will include frequencies of AEs, serious AEs 
(SAEs), deaths, and wound-related complications. Summaries of changes from baseline in 
laboratory parameters, Holter monitoring, QTc interval and other ECG parameters, and vital 
signs will be provided.  
 














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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................ 1 
PROTOCOL AGREEMENT PAGE ................................................................................................. 2 
PROTOCOL AMENDMENT 3 - SUMMARY OF CHANGES ........................................................... 3 
PROTOCOL SYNOPSIS ................................................................................................................ 4 
SCHEDULE OF ASSESSMENTS .................................................................................................. 12 
TABLE OF CONTENTS............................................................................................................... 18 
LIST OF IN-TEXT FIGURES ........................................................................................................ 22 
LIST OF IN-TEXT TABLES .......................................................................................................... 22 
LIST OF ABBREVIATIONS ......................................................................................................... 23 
1 INTRODUCTION ................................................................................................................. 25 
1.1 
Indication/Background to the Disease ................................................................. 25 
1.1.1 
Calciphylaxis .............................................................................................. 25 
1.1.2 
Current CUA Care ...................................................................................... 26 
1.2 
SNF472 .................................................................................................................. 26 
1.3 
SNF472 Nonclinical Data ....................................................................................... 28 
1.4 
Clinical Experience ................................................................................................ 28 
1.4.1 
Pharmacokinetic and Pharmacodynamic Results ..................................... 29 
1.4.2 
SNFCT2015-04, a Phase 2 Study in CUA .................................................... 29 
1.4.3 
SNFCT2015-05, A Phase 2 Study Evaluating Safety and Efficacy on 
Progression of CVC .................................................................................... 30 
1.4.4 
Safety and Tolerability Results with SNF472 ............................................ 30 
1.5 
Rationale for the Study ......................................................................................... 32 
1.6 
Risk-benefit assessment ....................................................................................... 32 
2 STUDY OBJECTIVES ............................................................................................................ 33 
3 STUDY DESIGN .................................................................................................................. 33 
3.1 
Study Design Overview ......................................................................................... 33 
3.2 
Discussion of Study Design ................................................................................... 35 
3.3 
Appropriateness of Assessments .......................................................................... 36 
3.4 
Study Population ................................................................................................... 37 
3.4.1 
Inclusion Criteria ....................................................................................... 37 
3.4.2 
Exclusion Criteria....................................................................................... 37 
4 STUDY TREATMENTS ......................................................................................................... 38 
4.1 
Study Drugs ........................................................................................................... 38 


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4.2 
Dose Rationale ...................................................................................................... 39 
4.3 
Treatment Assignment ......................................................................................... 40 
4.4 
Blinding, Packaging, and Labeling ......................................................................... 40 
4.4.1 
Blinding ..................................................................................................... 40 
4.4.2 
Unblinding ................................................................................................. 40 
4.4.3 
Packaging, Labelling, and Storage ............................................................. 41 
4.5 
Administration of Study Drug ............................................................................... 41 
4.6 
Supplies and Accountability .................................................................................. 42 
4.7 
Prior and Concomitant Medications, Background Care for CUA, Wound Care, 
Dialysis Parameters, and Lifestyle Restrictions .................................................... 43 
4.7.1 
Prohibited Concomitant Medications ....................................................... 43 
4.7.2 
All Prior and Concomitant Medications .................................................... 43 
4.7.3 
Background Care for CUA ......................................................................... 43 
4.7.3.1 
Stabilizing Pain Medications ............................................................. 44 
4.7.3.2 
Maintenance of Pain Management During the Trial ........................ 44 
4.7.3.3 
CUA Wound Care .............................................................................. 45 
4.7.3.4 
Dialysis Parameters ........................................................................... 45 
4.7.4 
Lifestyle Restrictions ................................................................................. 46 
4.7.4.1 
Dietary Restrictions ........................................................................... 46 
4.7.4.2 
Contraception Requirements ........................................................... 46 
5 STUDY PROCEDURES AND ASSESSMENTS ........................................................................ 47 
5.1 
Screening Period ................................................................................................... 47 
5.2 
Part 1: Double-Blind, Randomized, Placebo-Controlled Treatment Period ......... 48 
5.3 
Part 2: Open-Label Treatment Period ................................................................... 48 
5.4 
Follow-Up Period/ Early Termination ................................................................... 48 
5.5 
Order of Assessments ........................................................................................... 49 
5.5.1 
Prior to Start of Dialysis ............................................................................ 49 
5.5.2 
During Dialysis ........................................................................................... 49 
5.6 
Efficacy Assessments ............................................................................................ 49 
5.6.1 
Wound Evaluation ..................................................................................... 49 
5.6.1.1 
Quantitative Wound Evaluation with BWAT and BWAT-CUA .......... 50 
5.6.1.2 
Qualitative Wound Evaluation .......................................................... 51 
5.6.1.3 
New CUA Lesions .............................................................................. 51 
5.6.2 
Pain VAS .................................................................................................... 51 


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5.6.3 
Wound-QoL ............................................................................................... 52 
5.6.4 
Pain Medications ....................................................................................... 52 
5.7 
Pharmacodynamics, Pharmacokinetics, and Biomarker Assessments ................. 52 
5.7.1 
Pharmacodynamics ................................................................................... 53 
5.7.2 
Pharmacokinetics ...................................................................................... 53 
5.7.3 
Biomarkers ................................................................................................ 53 
5.8 
Safety Assessments ............................................................................................... 53 
5.8.1 
Adverse Events .......................................................................................... 53 
5.8.2 
Medical History ......................................................................................... 53 
5.8.3 
Physical Examination and Body Weight .................................................... 53 
5.8.4 
Vital Signs .................................................................................................. 54 
5.8.5 
Holter Monitoring and Electrocardiograms .............................................. 54 
5.8.6 
Laboratory Evaluations ............................................................................. 55 
6 ADVERSE EVENTS .............................................................................................................. 56 
6.1 
Definitions ............................................................................................................. 56 
6.1.1 
Adverse Event ........................................................................................... 56 
6.1.2 
Serious Adverse Event .............................................................................. 57 
6.1.3 
Wound-Related Complications ................................................................. 57 
6.1.4 
Adverse Event by Severity or Intensity ..................................................... 57 
6.1.5 
Relationship between Adverse Events and Study Drug............................ 58 
6.1.6 
Adverse Event Outcome ........................................................................... 59 
6.1.7 
Abnormal Laboratory Values .................................................................... 59 
6.1.8 
Pregnancy and In Utero Drug Exposure .................................................... 60 
6.2 
Hemodialysis-Related Events ................................................................................ 60 
6.3 
Documentation and Reporting of Adverse Events ............................................... 61 
6.3.1 
Documentation and Reporting of Adverse Events by Investigator .......... 61 
6.3.1.1 
Recording of Adverse Events ............................................................ 61 
6.3.1.2 
Reporting of Serious Adverse Events ................................................ 61 
6.3.2 
Reporting of Adverse Events to Regulatory Authorities and Independent 
Ethics Committees/Institutional Review Boards ...................................... 62 
6.4 
Data and Safety Monitoring Board ....................................................................... 62 
7 DISCONTINUATION AND WITHDRAWALS ......................................................................... 62 
7.1 
Discontinuation of Study Drug .............................................................................. 62 
7.2 
Withdrawal of Subject from the Study ................................................................. 63 


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7.3 
Storage of Samples ............................................................................................... 64 
8 STATISTICAL METHODS ..................................................................................................... 64 
8.1 
Endpoints .............................................................................................................. 64 
8.1.1 
Efficacy Endpoints ..................................................................................... 64 
8.1.2 
Pharmacodynamic and Biomarker Endpoints .......................................... 66 
8.1.3 
Pharmacokinetic Endpoints ...................................................................... 66 
8.1.4 
Safety Endpoints ....................................................................................... 66 
8.2 
Determination of Sample Size .............................................................................. 66 
8.2.1 
Planned Sample Size ................................................................................. 66 
8.2.2 
Sample Size Re-Estimation ........................................................................ 67 
8.3 
Analysis Populations ............................................................................................. 68 
8.4 
Subgroups, Covariates, and Strata ........................................................................ 68 
8.5 
General Statistical Considerations ........................................................................ 68 
8.6 
Efficacy Analyses ................................................................................................... 69 
8.6.1 
Primary Efficacy Endpoint Analysis ........................................................... 69 
8.6.2 
Secondary Efficacy Endpoint Analyses ...................................................... 69 
8.6.3 
Overall Type I Error Control ...................................................................... 70 
8.6.4 
Exploratory Efficacy Endpoint Analyses .................................................... 70 
8.7 
Pharmacodynamics Analyses ................................................................................ 71 
8.8 
Pharmacokinetics Analyses ................................................................................... 71 
8.9 
Safety Analyses ..................................................................................................... 71 
8.9.1 
Adverse Events .......................................................................................... 71 
8.9.2 
Hemodialysis-Related Events .................................................................... 71 
8.9.3 
Clinical Laboratory Evaluation .................................................................. 71 
8.9.4 
Holter Monitoring and Electrocardiograms .............................................. 72 
8.9.5 
Vital Signs .................................................................................................. 72 
8.9.6 
CUA Wound Care ...................................................................................... 72 
8.9.7 
Physical Examination Findings .................................................................. 72 
9 DATA MANAGEMENT, MONITORING AND AUDITS .......................................................... 72 
9.1 
Study Monitoring .................................................................................................. 72 
9.2 
Data Capture and Verification .............................................................................. 72 
9.3 
On-Site Audits ....................................................................................................... 73 
10 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ........................................................... 74 
10.1 
Good Clinical Practice ........................................................................................... 74 


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10.2 
Informed Consent ................................................................................................. 74 
10.3 
Subject Confidentiality and Disclosure ................................................................. 74 
10.4 
Independent Ethics Committee/ Institutional Review Board Approvals and 
Notifications .......................................................................................................... 75 
10.5 
Study Closure ........................................................................................................ 76 
10.6 
Record Retention .................................................................................................. 76 
11 STEERING COMMITTEE ..................................................................................................... 76 
12 STUDY REPORT AND PUBLICATION POLICY ...................................................................... 77 
13 REFERENCES ...................................................................................................................... 78 
APPENDIX 1. BATES-JENSEN WOUND ASSESSMENT TOOL (BWAT) ....................................... 82 
APPENDIX 2. WOUND-QOL QUESTIONNAIRE ......................................................................... 85 
APPENDIX 3. PROTOCOL AMENDMENT 1 - SUMMARY OF CHANGES .................................... 86 
APPENDIX 4. PROTOCOL AMENDMENT 2 - SUMMARY OF CHANGES .................................... 88 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Design Flowchart ........................................................................................... 35 
Figure 2. Method of Study Drug Administration .................................................................... 42 
Figure 3. Pain Visual Analog Scale ........................................................................................... 52 
 
LIST OF IN-TEXT TABLES 
Table 1. Schedule of Events for Part 1 .................................................................................... 12 
Table 2. Schedule of Events for Part 2 and Follow-Up ........................................................... 15 
Table 3. Identity of the Study Drugs ....................................................................................... 38 
Table 4. Holter Instructions and Timing .................................................................................. 54 
Table 5. Local ECG Tracing Collection Timepoints .................................................................. 55 
Table 6. Laboratory Parameters ............................................................................................. 56 
Table 7. Definitions of Adverse Events Severity Based on CTCAE .......................................... 58 
Table 8. Guidelines for Assessing the Potential Relationship Between Adverse Event and the 
Study Drug ................................................................................................... 59 
Table 9. Adverse Event Outcome ............................................................................................ 59 
Table 10. Decision Rules for Sample Size Increase ................................................................. 67 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the time-concentration curve 
BLQ 
below the limit of quantitation 
BWAT 
Bates Jensen Wound Assessment Tool 
Cmax 
observed maximum concentration 
CRO 
contract research organization 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CUA 
calciphylaxis (calcific uremic arteriolopathy) 
CVC 
cardiovascular calcification 
CYP 
cytochrome p450 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOI 
end of infusion 
ESRD 
end-stage renal disease 
ET 
early termination 
FDA 
Food and Drug Administration 
FGF23 
fibroblast growth factor 23 
GCP 
Good Clinical Practice 
GDF15 
growth differentiation factor 15 
GLP 
Good Laboratory Practice 
HAP 
hydroxyapatite 
HD 
hemodialysis 
IC50, IC65, IC80 
50%, 65%, and 80% maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification 
IEC 
Independent Ethics Committee 
IP6 
myo-inositol hexaphosphate (phytate) 


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IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
IV 
Intravenous 
Kt/V 
urea clearance x dialysis time / total body water volume 
LS mean 
least squares mean 
MGP 
matrix gla protein 
mITT 
modified Intent-to-treat 
MME 
morphine milligram equivalents 
MMRM 
mixed model repeated measures 
N 
count 
PD 
pharmacodynamics 
PIL 
patient information leaflet 
PK 
pharmacokinetics 
PP 
per protocol 
PTH 
parathyroid hormone 
Q1, Q3 
first quartile, third quartile 
QoL 
quality of life 
QTc, QTcF 
corrected QT interval, QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
Sanifit 
Sanifit Therapeutics S.A. (Sponsor) 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SSRE 
sample size re-estimation 
STS 
sodium thiosulfate 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TIW 
3 times weekly 
URR 
Urea reduction ratio 
US 
United States 
VAS 
Visual Analog Scale 
VSMC 
vascular smooth muscle cells 


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1 INTRODUCTION 
1.1 
INDICATION/BACKGROUND TO THE DISEASE 
1.1.1 
Calciphylaxis 
Calciphylaxis is a rare disease seen predominantly in patients receiving dialysis. As of 31 
December 2015, the number of patients on dialysis was approximately 430,519 in Europe and 
492,227 in the United States (US) (European Renal Association – European Dialysis and 
Transplant Association Registry, 2017; United States Renal Data System, 2017). Calciphylaxis in 
the end-stage renal disease (ESRD) population is also known as calcific uremic arteriolopathy 
[CUA]. The estimated prevalence of CUA is between 1% and 4% of the ESRD population (Goel et 
al, 2011; Nunley, 2017; Schlieper et al, 2009), suggesting a prevalence of 4,305 to 17,221 in 
Europe and 4,923 to 19,691 in the US. In addition, recent estimates of incidence of CUA have 
been reported as <1500 patients on dialysis in the US based on sodium thiosulfate (STS) use, 
0.12% of dialysis patients per year in the United Kingdom (UK Registry, personal communication 
with Smeeta Sinha), and 0.04% of dialysis patients per year in Germany (Brandenburg et al, 
2017).  
Calciphylaxis in patients with ESRD is a life-threatening condition with 1-year mortality rates of 
45-55% (McCarthy et al, 2016; Nigwekar et al, 2016; Weenig et al, 2007). In addition, a high rate 
of mortality was observed within the first few months after diagnosis of CUA (Mazhar et al, 
2001). Major surgical interventions are common in these patients with one study reporting that 
69% of patients required extensive debridement, revascularization, or amputation (Obialo and 
Quarshi 2017).  
The disease is characterized by accelerated soft tissue calcification, including calcification and 
thrombosis of smaller arteriolar vessels, leading to progressive and painful necrotic skin 
ulcerations (Nigwekar et al, 2018). The pathophysiology of CUA involves the deposition of 
calcium in the tunica media of smaller arteriolar vessels. The deposition of calcium is 
accompanied by local inflammation and arteriolar thrombosis, leading to regional ischemia and 
subsequent necrosis of subcutaneous fat and the overlying skin. The skin and subcutaneous 
lesions of CUA are the primary manifestation of the disease. Lesions most commonly appear in 
the lower extremities and in the trunk, particularly in the abdomen. Less commonly reported 
locations include the arms, hands and fingers, buttock/hip, chest, and genitals (Chinnadurai et 
al 2021; Weenig et al, 2007) On palpation, skin and soft tissue surrounding necrotic areas often 
show a characteristic plaque-like hardening. The progressive, ischemic ulcers are extremely 
painful, and patients often require opioids for pain control. In addition to the pain, these 
patients have an increased susceptibility to wound infection, which is ultimately responsible for 
over 50% of the mortality (Weenig et al, 2007). 
In these patients, calcification of arterial walls and heart valves leads to coronary heart disease, 
heart failure, myocardial infarction and cardiovascular events, which are often fatal. While 
much remains unclear about the triggers for the pathogenic process of CUA, the vascular 
deposition of calcium appears to be a necessary, but possibly not a sufficient, factor in 
development of the full clinical profile. A diagnosis can be made based on clinical characteristics 


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and can be confirmed by a skin biopsy which shows arterial calcification and occlusion in the 
absence of vasculitis. 
1.1.2 
Current CUA Care 
There are currently no approved medicinal products or devices for the treatment of CUA, and 
no specific guidelines. Current care relies on 1) reducing clinical factors that may exacerbate the 
deposition of calcium in vascular tissue, 2) wound care, and 3) control of pain (Goel et al, 2011; 
Seethapathy et al, 2019). Clinical interventions aimed at reducing the impact of CUA are listed 
below.  
• Topical wound care with measures to prevent infection 
• Pain management 
• Elimination of potential precipitating factors such as Vitamin K antagonist-based 
anticoagulation (e.g., warfarin, as a reduction in vitamin K appears to promote calcium 
deposition) 
• Avoidance of calcium-based phosphate binder therapy 
• Reduction in vitamin D administration (as vitamin D appears to promote calcium 
deposition) 
• Use of low calcium concentration in the dialysis bath 
• Patients on peritoneal dialysis might benefit from switching to HD (Fine and Fontaine, 
2008) with a low calcium dialysate. 
• Intensification of dialysis prescription 
• Treatment with calcimimetics such as cinacalcet or etelcalcetide (Robinson et al, 2007) 
• Parathyroidectomy  
• Hyperbaric oxygen might relieve ischemic features (Podymow et al, 2001). 
• Bisphosphonates 
• Use of STS for pain control and potentially a reduction in calcium deposition 
None of the therapeutic interventions listed above have been subjected to adequate evaluation 
in controlled clinical trials. STS is widely used off-label for treatment of CUA although evidence 
supporting its efficacy is largely limited to retrospective chart reviews (Nigwekar et al, 2013) 
and case reports (Peng et al, 2018; Smith et al, 2012). Calcium-chelation, direct vascular 
calcification inhibitory effects, antioxidant effects, and vasodilatory properties have all been 
proposed as mechanisms through which STS may improve CUA (as reviewed, O’Neill 2013). 
1.2 
SNF472 
SNF472 is a selective calcification inhibitor that works by binding to the growth sites of the 
hydroxyapatite (HAP) crystals. Chemically, SNF472 is the hexasodium salt of myo-inositol 
hexaphosphate (IP6, phytate). 


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SNF472 is being developed by Sanifit Therapeutics S.A. (Sanifit) for the treatment of CUA and 
cardiovascular calcification (CVC) in patients with ESRD undergoing HD. 
Multiple mechanisms lead to the formation and growth of calcified deposits in arterioles and 
other small vessels, which appear to be fundamental to the development of CUA. SNF472 is a 
novel entity with a new mechanism of action selectively directed to inhibit the final and 
common step in the pathway of vascular calcification by chemically blocking calcium crystal 
formation and growth. Regardless of the triggering mechanism for ectopic calcification (e.g., 
loss of calcification inhibitors, accumulated protein aggregates, inflammation, phenotypic 
osteogenic cellular transformation, or disordered mineral metabolism), the final common 
pathway of HAP aggregation creates the growing calcium crystal structure. 
The active ingredient of SNF472 is IP6, a natural substance found in beans, brown rice, corn, 
sesame seeds, wheat bran, and other high-fiber content foods. In mammalian tissues 
intracellular concentrations of IP6 are much higher than extracellular concentrations. 
Intracellular IP6 is naturally present at the 10 to 100 µM level and is formed de novo from IP3 
and the subsequent inositol polyphosphates family (IP4, IP5) (Grases et al, 2004; Perelló et al, 
2004). Extracellular IP6 originates from dietary sources and reaches physiological levels in the 
0.2 to 0.3 µM range (Grases et al, 2000). The calcium salt of IP6 is listed by the US Food and 
Drug Administration (FDA) as Generally Recognized as Safe. It is highly polar and poorly 
absorbed when given orally.  
Based on current information, it is hypothesized that SNF472 is able to slow the process of 
vascular calcification by: 
• Blocking the formation and growth of HAP crystals in the blood vessels. SNF472 is a 
polyphosphate with a high affinity for solid calcium salts. It quickly binds the surface of a 
forming nucleus or on the faces of a growing crystal and acts as an inhibitor of 
crystallization since it specifically binds to the growth sites (not the entire crystal surface), 
blocking the calcification process. An effect on the circulating colloidal calciprotein particles 
in the blood stream is also likely. SNF472 might be adsorbed on the surface of these 
nanoparticles, giving them negative charge and avoiding their aggregation to form the solid 
HAP crystal. 
• Preventing the transformation of vascular smooth muscle cells (VSMC) to an osteogenic 
phenotype. Osteogenic mechanisms play a role in the development of CVC and cells derived 
from the vascular media undergo bone and cartilage-like phenotypic change and 
calcification in vitro under various conditions, including elevated calcium and phosphorous 
(Jono et al, 2000; Yang et al, 2004). SNF472 has been demonstrated to interfere in the 
molecular mechanisms that lead to the de-differentiation of VSMC to osteoblast-like cells 
(unpublished data on file, Sanifit). 
• Reducing bone mass loss, which is a source of circulating calcium, especially relevant in 
patients receiving HD in whom there is an imbalance in the equilibrium of calcium between 
bone, blood, and soft tissues (Grases et al, 2010). 


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By stopping the progressive deposition of calcium within small arteriolar vessels, the principal 
pathological process underlying the development of the obliterative vasculopathy is halted. This 
is hypothesized to result in a reduction in pain and an improved ability for natural healing 
through neovascularization, white blood cell recruitment to fight infection, and a reduction in 
local inflammatory mediators. 
1.3 
SNF472 NONCLINICAL DATA 
SNF472 has been extensively studied in nonclinical models for efficacy, safety, 
pharmacokinetics (PK), and toxicity, and showed a promising profile that supported progression 
to studies in humans. The results of nonclinical studies are summarized in the Investigator’s 
Brochure. 
In vitro and in vivo studies show that SNF472 inhibits calcification. In vivo studies show that 
SNF472 blocks the deposition of calcium (in the form of HAP crystallization) in heart and aorta 
tissue. A pharmacodynamic (PD) assay developed for use as a biomarker of SNF472 activity 
demonstrates that SNF472 reduces HAP crystallization in plasma, thus likely preventing further 
growth and progression of calcification in soft tissue and the vasculature. The initial validation 
of the PD assay was conducted in human and rat plasma (Ferrer et al, 2017), in which the 
addition of SNF472 to plasma samples in vitro or in vivo reduced the HAP crystallization rate. 
Subcutaneous administration of SNF472 in rats reduced the HAP crystallization potential of 
plasma up to 70%. Importantly, a correlation was shown between the PD assay results and 
vascular tissue calcification using the in vivo vitamin D model.  
Nonclinical safety, reprotoxicology, and toxicology work has been completed, including studies 
of up to 6 months in rats and 9 months repeated-dose toxicology in dogs. No observed adverse 
effect levels obtained in these studies establish a wide safety margin that provides appropriate 
toxicology support to proceed to clinical studies.  
Importantly, SNF472 did not significantly inhibit or bind to ion channels and transporters 
responsible for cardiac function, such as the human ether-a-go-go (hERG) channel. Therefore, 
SNF472 is not expected to have any direct effect on cardiac function in humans.  
In vitro, SNF472 did not inhibit relevant human efflux transporters; uptake transporters; human 
cytochrome p450 (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; and did 
not induce human CYP1A2, CYP2B6, and CYP3A4. Therefore, clinically relevant drug-drug 
interactions are not anticipated with SNF472 in humans. 
1.4 
CLINICAL EXPERIENCE 
Two Phase 1 studies of SNF472 have been completed: SNFCT2012-03 in healthy volunteers and 
subjects receiving HD and SNFCT2014-03 in subjects with ESRD receiving HD. Two Phase 2 
studies have been completed: SNFCT2015-04 in subjects with CUA and SNFCT2015-05, to assess 
the effect of SNF472 on progression of CVC in addition to standard of care in approximately 270 
subjects with ESRD receiving HD. 


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1.4.1 
Pharmacokinetic and Pharmacodynamic Results 
In the two Phase 1 studies (SNFCT2012-03 and SNFCT2014-03), PK parameters were similar 
between healthy volunteers and subjects receiving HD, indicating that HD therapy has little 
influence on the PK of SNF472. In both studies, the maximum observed concentration (Cmax) of 
SNF472 occurred immediately following the end of the infusion, after which concentrations 
declined rapidly to below the limit of quantification (BLQ) within approximately 6 to 8 hours. 
The mean half-life (t1/2) in these studies was between approximately 30 and 60 minutes. 
No accumulation of SNF472 over time was observed in either Phase 2 study. In SNFCT2015-04 
(SNF472 doses of 5.6 - 8.6 mg/kg TIW) the Cmax of SNF472 was similar at Weeks 1 and 12. In 
SNFCT2015-05 (SNF472 doses of 300 mg or 600 mg TIW) the Cmax of SNF472 was similar within 
dose groups at Weeks 1 and 52. 
Mean inhibitions of ex vivo HAP crystallization (PD assay) up to approximately 80% were 
observed in the Phase 1 studies and up to 65-75% in the Phase 2 studies. Dose-PD relationship 
analysis using the human HD patient plasma samples showed that SNF472 inhibited systemic 
blood calcification with an IC50 of 2.2 mg/kg and IC80 of >5.6 mg/kg.  
1.4.2 
SNFCT2015-04, a Phase 2 Study in CUA 
SNFCT2015-04 was a Phase 2 open-label, single-arm, repeat-dose study which examined the 
effect of SNF472 in addition to background care on wound healing and other parameters of 
therapeutic response in 14 subjects with CUA (Brandenburg et al 2019). SNF472 was 
administered at 3 HD sessions per week for 12 consecutive weeks. SNF472 (400 to 900 mg) was 
dosed according to body weight category, resulting in doses ranging from 5.6 to 8.6 mg/kg, 
administered by a constant infusion during the dialysis session of approximately 2.5 to 3 hours 
in duration.  
Wound healing, pain, and quality of life (QoL) were assessed using the Bates-Jensen Wound 
Assessment Tool (BWAT), independent qualitative review of wound images, the Pain Visual 
Analog Scale (VAS), and the Wound-QoL questionnaire. BWAT total is a standardized tool for 
quantitative assessment of wound healing which rates wounds according to these 13 items: 
size, depth, edges, undermining, necrotic tissue type, necrotic tissue amount, exudate type, 
exudate amount, surrounding skin color, peripheral tissue edema, peripheral tissue induration, 
granulation tissue, and epithelialization.  
Consistent improvement was observed across all of these measures. A statistically significant 
improvement from baseline in wound healing of the primary lesion was observed at Weeks 10 
and 12 as measured by the BWAT total. The mean decrease from baseline in BWAT total score 
at Week 12 was 8.1 (p<0.001). Independent review of wound images closely followed the BWAT 
scores with the same trend in improvement observed in most subjects. In addition, reductions 
in Pain VAS were observed starting from Week 6. The mean decrease from baseline in Pain VAS 
at Week 12 was 23.6 mm (p=0.015). Improvements in the Wound-QoL questionnaire global 
score were observed with a mean decrease from baseline at Week 12 of 0.9 units (p=0.003).  
In a post-hoc analysis, a targeted modification of the BWAT, the “BWAT-CUA” was developed 
with input from an interdisciplinary group of experts in calciphylaxis and wound care. The 


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BWAT-CUA items focus on the most clinically relevant features of CUA lesions: necrotic tissue 
type, necrotic tissue amount, exudate type, exudate amount, skin color surrounding wound, 
peripheral tissue edema, peripheral tissue induration, and granulation tissue. Each item was 
scored on a scale of 1 to 5 with a range of possible scores from 8 to 40. Mean (SE) BWAT-CUA 
improved from 21.2 ±2.0 at baseline to 14.9 ±1.4 at Week 12 (p<0.002; Sinha et al, 2018).  
1.4.3 
SNFCT2015-05, A Phase 2 Study Evaluating Safety and Efficacy on Progression of 
CVC 
SNFCT2015-05 (CaLIPSO) is a completed Phase 2b, randomized, double-blind, placebo-
controlled study that assessed the effect of 2 dose levels of SNF472 (300 mg and 600 mg) on 
progression of CVC when added to standard care in subjects with ESKD on HD (Raggi 2020). A 
total of 273 subjects received at least 1 dose of study drug: SNF472 300 mg (n=92), SNF472 
600 mg (n=91), or placebo (n=90) administered by intravenous (IV) infusion TIW during dialysis 
for 52 weeks. The primary endpoint was change in coronary artery calcium (CAC) volume score 
from baseline to Week 52 as measured by CT scan. In the modified Intent to Treat (ITT) 
population, SNF472 significantly reduced the progression of CAC compared with placebo: the 
mean change in CAC volume score was 11% (95% confidence interval [CI], 7% to 15%) in the 
SNF472 combined dosing group compared with 20% (95% CI, 14% to 26%) in the placebo group 
(p=0.016 vs SNF472). Additionally, SNF472 significantly reduced the progression of calcium 
volume score relative to placebo in the aortic valve (14% [95% CI: 5% to 24%] versus 98% [95% 
CI: 77% to 123%]; p<0.001) but not in the thoracic aorta (23% [95% CI: 16% to 30%] versus 28% 
[95% CI, 19–38]; p=0.40).  
1.4.4 
Safety and Tolerability Results with SNF472 
SNF472 has been well tolerated in clinical studies to date.  
In Study SNFCT2012-03 (N=28), the majority of non-serious adverse events (AEs) observed in 
healthy volunteers were infusion site-related events that were considered to be related to 
SNF472 by the Investigator. In HD subjects, similar infusion site-related adverse events were 
not observed as SNF472 was infused through the dialysis circuit with dilution in blood before 
reaching the subject’s blood vessels. There were mild to moderate AEs reported in the multiple 
ascending dose Study SNFCT2014-03 but none were considered related to SNF472.  
In the open-label Phase 2 CUA Study SNFCT2015-04 (N=14), AEs reported in more than one 
subject were cellulitis, diarrhea, prolonged QT interval, fluid overload, hypertension, 
hypoesthesia, nausea, and skin lesion (n=2 each); all other AEs were reported in 1 subject. Most 
of the AEs were mild to moderate in intensity.  
In Study SNFCT2015-05 (CaLIPSO), the most common treatment-emergent AEs for which 
subject incidences were higher in the combined SNF472 treatment group than in the placebo 
group by a difference of at least 2% were abdominal pain upper (7.1% vs 2.2%), atrial fibrillation 
(6.6% vs 2.2%), hypoglycemia (6.6% vs 1.1%), hyperkalemia (6.0% vs 3.3%), and 
hyperphosphatemia (3.8% vs 0%). All subjects in this study with AEs of hypoglycemia had a 
history of diabetes, most AEs of hypoglycemia were mild to moderate, all but one were 


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considered not related to study drug, and all resolved. The AEs of hyperkalemia and 
hyperphosphatemia were expected in subjects on HD.  
Serious AEs (SAEs) were reported by 1 subject (polycystic kidney infection) in the Phase 1 Study 
SNFCT2014-03 (N=18) and by 7 subjects in the Phase 2 Study SNFCT2015-04. The SAEs reported 
in Study SNFCT2015-04 were abdominal wound dehiscence, cardiogenic shock, cellulitis, dry 
gangrene, fluid overload, gangrene, hematemesis, hypertensive emergency, nausea, pulmonary 
edema, renal failure, sepsis, and urinary tract infection, n=1 for each. Most of the SAEs are 
commonly seen in this patient population. None of the SAEs reported in either study were 
considered related to SNF472 by the Investigator. In Study SNFCT2015-05, the most commonly 
reported SAE was renal transplant which was similar between combined SNF472 dose group 
and placebo (10.9% vs. 10.0%). Renal transplants are expected in this population and meet SAE 
criteria (hospitalization) but are not considered a negative outcome in this population. The 
other SAE that was reported for more than 5% of subjects overall was pneumonia (3.8% in the 
combined dose groups and 7.8% in the placebo group). The following SAEs were reported for 
no subjects in the placebo group and >3% of subjects in the SNF472 600 mg group: cardiac 
arrest (4 subjects), gastrointestinal hemorrhage (3 subjects), atrial flutter (3 subjects), and 
pyrexia (3 subjects). 
Two deaths were reported during the Phase 2 Study SNFCT2015-04; neither death (1 due to 
cardiogenic shock and 1 due to cardiopulmonary arrest subsequent to withdrawal from 
hemodialysis) was considered related to SNF472 by the Investigator. In Study SNFCT2015-05, 
death occurred in 7 subjects (4%) who received SNF472 and 5 subjects (6%) who received 
placebo; 2 of the deaths were cardiovascular (cardiac arrest in the 600 mg group and cardiac 
failure congestive in the placebo group); none were considered by the Investigator to be 
related to study drug. 
Overall, in clinical studies no clinically significant effects were reported in vital signs or 
laboratory values, including hypocalcemia. In the open-label study (SNFCT2015-04), there were 
2 TEAEs of QT prolongation and 1 of tachycardia. One TEAE of QT prolongation was considered 
not related. The other event of QT prolongation occurred 7 days after SNF472 infusion but was 
considered possibly related by the Investigator, and the event of tachycardia was considered 
possibly related by the Investigator. In the placebo-controlled study (SNFCT2015-05) incidence 
of tachycardia was similar between SNF472 600 mg (4.4%) and placebo (3.3%); none of the 
tachycardia TEAEs were considered related by the Investigator. There was 1 TEAE of QT 
prolongation reported in the SNF472 300 mg group (1.1%) in SNFCT2015-05 and considered 
possibly related by the Investigator. 
Based on the totality of nonclinical and clinical data generated to date, no clinically relevant 
safety risks have been identified that preclude continued human investigation with SNF472.  
Refer to the Investigator’s Brochure for additional details. 


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1.5 
RATIONALE FOR THE STUDY 
Calciphylaxis is a life-threatening disease with a high mortality rate that mainly occurs in 
patients with ESRD receiving dialysis (Section 1.1.1). As there are no approved therapies for 
CUA (Section 1.1.2), there is an unmet need to improve the course of wounds and, ultimately, 
to improve CUA-related outcomes for patients. Thus, this Phase 3, double-blind, randomized, 
placebo-controlled study is designed to assess the efficacy and safety of SNF472 when added to 
background care for the treatment of CUA in subjects with ESRD receiving HD. The study 
hypothesis is that administration of SNF472 in addition to background care over 12 weeks will 
improve wound healing, pain, and wound-related QoL compared to placebo. 
1.6 
RISK-BENEFIT ASSESSMENT 
Potential Benefits of Study Participation 
Benefits to individual subjects may include: 
• Receipt of a potentially efficacious treatment for calciphylaxis 
• Intensive monitoring of calciphylaxis wounds that may be more thorough and frequent 
than usually received through standard care outside of a clinical trial 
• Contribution to the development of a treatment for patients suffering from calciphylaxis 
Subjects treated with placebo during Part 1 of the study will receive SNF472 during Part 2. 
During Part 1, placebo-treated subjects may benefit from the closer follow-up and will continue 
to receive calciphylaxis background care. 
 
Risks from Study Participation 
In nonclinical studies, transient hypocalcemia associated with some degree of QT prolongation 
was induced with rapid infusion of high concentration SNF472 but was not induced when the 
same concentration was administered via a slow infusion over 2 hours. Hypocalcemia and 
associated QT prolongation are not expected in dialysis patients since a dilute solution of 
SNF472 is infused slowly into the dialysis circuit with constant exposure to a standard calcium 
concentration gradient across the dialysis membrane. Indeed, no clinically significant trends in 
hypocalcemia or QT prolongation have been observed in either of the Phase 2 studies 
(SNFCT2015-04 and SNFCT2015-05). Those studies used comparable doses of SNF472 as in this 
study. Monitoring for changes in calcium and heart rhythm in the current study include pre- 
and post-dose collection of blood samples for measuring ionized calcium levels, pre- and post-
dose 12-lead ECGs, and continuous Holter monitoring over a 4-4.5 hour window including the 
time of study drug infusion. 
Safety monitoring procedures described in the protocol are considered to be adequate to 
protect subject safety. In addition, an independent Data and Safety Monitoring Board (DSMB) 
will perform regular, periodic assessments of blinded and unblinded data to detect any 
potential safety signals that may arise during the study and will advise the sponsor accordingly. 


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COVID-19 Management  
During the global SARS-CoV-2 pandemic and without appropriate social distancing and personal 
protective equipment, there is a potential for increased exposure to SARS-CoV-2. Subjects are 
required to attend healthcare facilities for their hemodialysis sessions three times in a week 
during which they will receive study drug and undergo all study procedures. No separate or 
additional visits outside of the subjects’ hemodialysis sessions are expected. Clinical sites are to 
follow their SARS-CoV-2 procedures and local guidelines to ensure an appropriate COVID-19 
prevention and protection strategy. 
Overall Benefit/Risk Conclusion 
Calciphylaxis is a life-threatening disease with a high mortality rate that mainly occurs in 
patients with ESRD receiving dialysis. As there are no approved therapies for calciphylaxis, there 
is an unmet need to improve the course of wounds and, ultimately, to improve calciphylaxis-
related outcomes for patients. The totality of nonclinical and clinical data generated to date, 
including data from a 52-week placebo-controlled Phase 2 study (SNFCT2015-05), support a 
favorable benefit/risk profile for the study of SNF472 in this calciphylaxis population. Potential 
for additional risks will be monitored over the course of the trial and in the SNF472 clinical 
development program more broadly.  
More detailed information about the efficacy and safety profile of SNF472 is provided in the 
Investigator’s Brochure. 
 
2 STUDY OBJECTIVES 
The objectives of this study are: 
• To evaluate the efficacy of SNF472 compared with placebo when added to background care 
for the treatment of CUA 
• To evaluate the safety and tolerability of SNF472 compared with placebo when added to 
background care for the treatment of CUA 
 
3 STUDY DESIGN 
3.1 
STUDY DESIGN OVERVIEW 
This Phase 3, global, multicenter study will include a screening period of up to 5 weeks 
(35 days), a 12-week double-blind, randomized, placebo-controlled period (Part 1) followed by 
a 12-week open-label treatment period (Part 2), and a 4-week follow-up period.  
A study flow chart is provided in Figure 1. 


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Screening Period: 
Informed consent will be obtained prior to performing any study procedures. Subject eligibility 
will be evaluated during the screening period, which will be conducted as a two-step process. In 
addition, the subject’s pain medications should be stabilized between Screening Visit 1 and 
Screening Visit 2 to determine the baseline maintenance pain medication dose. Details of the 
screening process are provided in Section 5.1 
In addition to pain medications, other aspects of the background care regimen (including 
wound care, dialysis parameters, other concomitant medications relevant to the management 
of CUA; Section 4.7.3) should be stabilized (or maintained if already stable) during the screening 
period.  
Completion of screening within 4 weeks or less is preferred but up to 5 weeks is allowed.  
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to receive either 7 mg/kg 
of SNF472 or matching placebo in a double-blind manner. Randomization will be stratified 
based on intravenous STS use at the time of randomization (yes/no). 
Double-Blind, Randomized, Placebo-Controlled Treatment Period (Part 1): Subjects will 
receive SNF472 or placebo for 12 weeks in addition to background care (in accordance with the 
clinical practices of each site). No changes to the background care regimen, including pain 
medications, should be made after randomization unless medically indicated in the opinion of 
the Investigator.  
The Schedule of Events for Screening Period and Part 1 is provided in Table 1. 
Open-Label Treatment Period (Part 2): Subjects who complete Part 1 will be eligible to 
participate in Part 2, in which all subjects will receive open-label SNF472 for 12 weeks and 
continue stable background care (in accordance with the clinical practices of each site), 
including pain medication, with no changes unless medically indicated in the opinion of the 
Investigator.  
The Schedule of Events for Part 2 and the follow-up visit is provided in Table 2.  
Follow-Up Period/ Early Termination: Subjects completing the study will return for a follow-up 
visit 4 weeks after the last dose of study drug. Subjects should continue on stable background 
care during the 4-week follow-up period, including pain medication, with no changes unless 
medically indicated in the opinion of the Investigator. Subjects who discontinue study drug 
during Part 1 or Part 2 will be asked to complete study assessments throughout the respective 
part of the study (Part 1 or Part 2) and complete the follow-up visit. Subjects who discontinue 
study drug and are unwilling to complete the remaining study assessments will be encouraged 
to return for an early termination visit 4 weeks after the last dose of study drug. 
A subject is considered to have completed the study if the subject has completed all study 
visits, including the final follow-up visit. 
The end of the study is defined as the date of the last study visit of the last subject in the study. 
 


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Figure 1. Study Design Flowchart 
 
TIW = 3 times weekly 
  
3.2 
DISCUSSION OF STUDY DESIGN 
This Phase 3 study has been designed to assess the efficacy and safety of SNF472 for the 
treatment of CUA. Part 1 of the study will be conducted in a randomized, double-blind, placebo-
controlled manner. All subjects will receive SNF472 in Part 2, giving subjects who received 
placebo in Part 1 the opportunity to receive the active treatment, and generating a total of up 
to 24 weeks of safety and efficacy data in those subjects who received SNF472 in Part 1. 
The control therapy will be a matching placebo, rather than an active comparator, because 
there are currently no approved medicinal products or devices for the treatment of this 
disease. Subjects in both treatment groups should receive background care for CUA in 
accordance with the clinical practices at each site, and this treatment should continue for the 
duration of the study, including during the follow-up period. Current background care usually 
includes 1) reducing clinical factors that may exacerbate the deposition of calcium in vascular 
tissue, 2) wound care, and 3) control of pain (Goel et al, 2011; Seethapathy et al, 2019), and is 
described further in Section 1.1.2.  
The efficacy of SNF472 will be assessed using clinically meaningful quantitative endpoints of 
wound healing assessed by BWAT, pain assessed by VAS, and quality of life assessed with the 
wound-related QoL questionnaire. These endpoint assessments are described further in 
Section 5.6 and Section 3.3. Safety will be evaluated including assessment of AEs, laboratory 
parameters, 12-lead ECGs, Holter monitoring, and vital signs. 
The 12-week duration of Part 1 was selected as appropriate for assessment of the primary and 
secondary efficacy endpoints based upon data from the Phase 2 CUA Study SNFCT2015-04. As 
summarized in Section 1.4.2, clinically and statistically significant improvements in wound 
healing, pain, and quality of life were observed following 12 weeks of SNF472 treatment in that 
study. 


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The second part of the study (Part 2) will be a 12-week open-label treatment period in which all 
subjects will receive SNF472. Thus, maximum exposure to SNF472 will be up to 24 weeks.  
Diagnosis of CUA will be made by the Investigator. A central wound rating group will review 
wound images to confirm the primary lesion is due to CUA. No consensus has been established 
as to whether confirmation by biopsy is necessary for diagnosis of CUA and some experts 
believe it has a risk of inducing new lesions and infectious complications (Brandenburg et al 
2016). Therefore, confirmation of CUA diagnosis by skin biopsy is not required for inclusion in 
this trial. While evidence of arteriolar calcification from biopsy is supportive of a CUA diagnosis 
its absence does not rule out CUA as findings are highly dependent upon sample quality and the 
location from which it is obtained. However, biopsies may be performed based on Investigator 
decision. 
3.3 
APPROPRIATENESS OF ASSESSMENTS 
The primary and secondary efficacy assessments in this study (BWAT-CUA, Pain VAS, 
Wound-QoL, and BWAT total) are well-characterized, as described below. BWAT total, Pain 
VAS, and Wound-QoL were pre-specified endpoint measures in the Phase 2 study of SNF472 for 
the treatment of CUA (SNFCT2015-04).  
BWAT total and subsets of the BWAT have been widely used for measuring and predicting 
wound healing in clinical settings and have been used successfully in clinical studies of chronic 
wounds, including pressure ulcers, diabetic ulcers, and venous leg ulcers (e.g., Bellingeri et al, 
2016; Chan and Lai, 2014; Gupta et al, 2009). Content validity, concurrent validity, predictive 
validity, intra-rater reliability, and inter-rater reliability of the BWAT total have been well 
documented (Cauble, 2010; Bates-Jensen and Sussman 2011). The BWAT-CUA is a modification 
of BWAT which focuses on the prototypical features of CUA lesions and was developed with 
reference to the Phase 2 results. The BWAT-CUA was selected as a primary efficacy measure for 
Phase 3 to provide an objective, quantitative CUA-focused tool that can be applied 
systematically across study sites to assess changes in CUA lesions over time. 
Both BWAT-CUA and BWAT total showed statistically significant improvements in wound 
healing from baseline to Week 12 with SNF472 (Section 1.4.2) in the Phase 2 study, 
demonstrating their suitability for evaluating improvement in wound healing over time in 
subjects with CUA. A correlation between improvement in BWAT total and Pain VAS was also 
demonstrated in that study. 
The Pain VAS, a well-characterized self-assessment tool, has been shown to be a reliable 
method for measurement of pain intensity and responses to pain treatment (Hawker et al, 
2011; Katz and Melzack, 1999; Swanson, 2014).  
The Wound-QoL questionnaire is a validated self-assessment tool that has been shown to be 
feasible for assessing health-related QoL in patients with chronic wounds (Augustin et al, 2014; 
Blome et al, 2014). 


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3.4 
STUDY POPULATION 
Planned enrollment is approximately 66 subjects from approximately 60 sites in multiple 
countries. Number of subjects may be adjusted up to a maximum of 99 based on results of a 
sample size re-estimation (SSRE). 
3.4.1 
Inclusion Criteria 
Subjects meeting all of the following criteria will be considered for enrollment in the study: 
1. ≥18 years of age 
2. Receiving maintenance HD in a clinical setting for at least 2 weeks prior to screening 
3. Clinical diagnosis of CUA by the Investigator including ≥1 CUA lesion with ulceration of the 
epithelial surface. A central wound rating group will review wound images to confirm the 
primary lesion is due to CUA.  
4. CUA wound-related pain shown by a Pain VAS score ≥50 out of 100 
5. Primary lesion that can be clearly photographed for the purpose of protocol-specified 
wound healing assessments 
6. Willing and able to understand and sign the informed consent form (ICF) and willing to 
comply with all aspects of the protocol 
3.4.2 
Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. Subjects whose primary lesion is due to causes other than CUA 
2. History of treatment with bisphosphonates within 3 months of baseline (Week 1 Day 1) 
3. Severely ill subjects without a reasonable expectation of survival for at least 6 months based 
on the assessment of the Investigator  
4. Subjects with a scheduled parathyroidectomy during the study period 
5. Expectation for kidney transplant within the next 6 months based on Investigator 
assessment or identification of a known living donor 
6. Pregnant or trying to become pregnant, currently breastfeeding, or of childbearing potential 
(including perimenopausal women who have had a menstrual period within one year) and 
not willing to either completely avoid sexual intercourse with a person of the opposite sex 
or use a highly effective method of birth control (specified in Section 4.7.4.2) from screening 
through at least 30 days after last dose of study drug 
7. Significant noncompliance with dialysis treatment evidenced by repeated missed dialysis 
sessions (including if due to hospitalizations where dialysis treatment is unavailable) or 
significant noncompliance with medication regimen, in the judgment of the Investigator 
8. Any history of active malignancy within the last year (history of localized basal cell or 
squamous cell carcinoma that has been excised/appropriately treated or a fully excised 
malignant lesion with a low probability of recurrence will not be considered exclusionary) 


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9. Clinically significant illness other than CUA within 30 days prior to screening that in the 
judgment of the Investigator could interfere with interpretation of study results, impair 
compliance with study procedures, or impact the safety of the subject (e.g., unstable 
angina, unstable heart failure, stroke, uncontrolled hypertension, or other illness requiring 
hospitalization) 
10. Participation in an investigational study and receipt of an investigational drug or 
investigational use of a licensed drug (with the exception of intravenous STS) within 30 days 
prior to screening. If participating in an investigational study of intravenous STS, all visits of 
that study must be completed prior to screening for this study. Note: Off-label use of 
intravenous STS outside of an investigational study is not restricted. 
11. Past or current participation in another clinical study with SNF472 
12. History or presence of active alcoholism or drug abuse as determined by the Investigator 
within 6 months before screening or concurrent social conditions that, in the opinion of the 
Investigator, would potentially interfere with the subject's study compliance 
13. Mental impairment or history of or current significant psychiatric disease that, in the 
opinion of the Investigator, may impair ability to provide informed consent or impact 
compliance with study procedures 
14. Any other condition or circumstance that, in the opinion of the Investigator, may make the 
subject unlikely to complete the study or comply with study procedures and requirements, 
or may pose a risk to the subject's safety and well-being 
15. Subjects whose CUA lesions exhibit significant improvement, in the opinion of the 
Investigator, between the first and second screening visit 
 
4 STUDY TREATMENTS 
4.1 
STUDY DRUGS 
Description of the study drugs are provided in Table 3. 
Table 3. Identity of the Study Drugs 
Active Treatment 
Matching Placebo (Part 1 only) 
Code name 
SNF472 
Not applicable 
Description 
Clear, colorless solution free from visible 
particles 
Clear, colorless solution free from visible 
particles 
Composition 
SNF472, 30 mg per 1 mL of physiological 
saline (0.9% sodium chloride) 
Physiological saline (0.9% sodium 
chloride) 
Dosage form 
Solution for IV infusion 
Solution for IV infusion 
Strength 
30 mL sterile vials containing 30 mg/mL 
(900 mg/vial)  
Identical 30 mL sterile vials containing 
physiological saline  
Dose (based on body 
weight) 
7 mg/kg 
none 
IV=intravenous 


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Each kit will be given a unique code number, traceable to the batch number of the study drugs.  
4.2 
DOSE RATIONALE 
The dose of SNF472 for this study is 7 mg/kg, to be administered 3 times weekly (TIW) over 
approximately 2.5 – 3 hours at dialysis sessions during the 2 treatment periods. This dose was 
selected based on the results from the Phase 2 study in CUA (Brandenburg et al, 2018) and 
supported by nonclinical toxicology and PK studies along with PK and PD results from the Phase 
1 and 2 clinical studies (SNFCT2012-03, SNFCT2014-03, and SNFCT2015-04). 
Nonclinical data have shown that SNF472 is a potent and selective calcification inhibitor in vitro, 
in vivo, and in a biomarker assay that estimates PD activity by measuring inhibition of HAP 
crystallization (Ferrer et al, 2017; Section 1.3). Efficacy of SNF472 was demonstrated between 2 
and 10 µM in animal models, with a very steep dose-response relationship and a narrow range 
between initial evidence of efficacy and asymptotic maximal efficacy. 
The two Phase 1 clinical Studies SNFCT2012-03 and SNFCT2014-03 evaluated single-dose and 
multiple-dose administration in subjects receiving HD (Section 1.4). The single dose studied was 
9 mg/kg (720 mg/day for an 80-kg subject) and the multiple doses ranged from 1 to 20 mg/kg 
TIW for 1 week (up to 1600 mg/day for an 80-kg subject) and 10 mg/kg (800 mg/day for an 
80-kg subject) TIW for 1 month. The Cmax of SNF472 for the 20 mg/kg dose was 101 µM at Day 1 
and 85 µM at Day 5, and showed no accumulation after repeat TIW dosing, consistent with the 
short SNF472 t1/2 of approximately 30 to 60 minutes (Section 1.4.1).  
The dose used in the Phase 2 CUA Study SNFCT2015-04 was based on PK/PD and dose-PD 
relationships using a single direct-effect model based on the Hill approach (Goutelle et al, 2008) 
or a sigmoid Emax model, using the systemic exposure (Cmax and AUC) and doses, respectively, 
from the Phase 1 Study SNFCT2014-03. The dose of SNF472 administered at each session was 
400-900 mg, based on body weight categories designed to have all subjects with an 
administered dose close to 7 mg/kg. The actual range of doses administered was 5.6-8.6 mg/kg.  
The mean (± standard deviation [SD]) Cmax in Study SNFCT2015-04 was 29.1 ± 19.1 µM and 
28.1 ± 21.0 µM at Weeks 1 and 12, respectively. The mean (± SD) PD effect was 65% ± 14 % and 
60% ± 29% inhibition at Weeks 1 and 12, respectively. No dose-PD correlation was apparent 
because the lowest dose of 5.6 mg/kg provided a maximal PD response, and higher doses were 
within the plateau of the PD response observed in the previous clinical studies. 
The dose of 7 mg/kg (e.g., 560 mg/day in an 80-kg subject) was selected for this Phase 3 study 
based on the following considerations: 
• This dose is expected to provide maximal inhibition of calcification based on dose-PD 
analyses from the Phase 1 and Phase 2 studies. 
• The pharmacological response shows a very narrow window between no activity and 
maximal activity. 
• There is no accumulation of the compound after repeat TIW dosing; therefore, estimations 
of plasma concentrations expected for certain doses performed from 1- and 3-month 
clinical studies should also apply for a treatment duration of 6 months. 


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• SNF472 will be administered via IV infusion directly into the dialysis tubing, the same method 
used in the Phase 2 CUA Study SNFCT2015-04. 
• This dose provides adequate safety margins of systemic exposure in toxicology studies 
conducted in nonclinical species. 
4.3 
TREATMENT ASSIGNMENT 
Eligible subjects will be randomized in a 1:1 manner to either 7 mg/kg SNF472 or placebo. 
Randomization will be stratified based on intravenous STS use (yes/no) at the time of 
randomization.  
Randomization will occur at Screening Visit 2 which may occur up to one week prior to the start 
of dosing on Week 1 Day 1 and will be performed using a centralized electronic randomization 
system that is part of the Interactive Response Technology (IRT). 
In Part 2, all subjects will receive open-label 7 mg/kg SNF472. 
4.4 
BLINDING, PACKAGING, AND LABELING 
4.4.1 
Blinding 
Part 1 will be performed in a double-blind manner. Part 2 will be open label. The Investigator, 
site staff, subjects, and Sponsor staff (including designees) involved in the conduct of the study 
and data management will remain blinded to the treatment assignment for Part 1 for the 
duration of the study including Part 2 and follow-up until the study database is locked, except 
as described in Section 4.4.2.  
To maintain the blinded nature of Part 1 of the study, the SNF472 and matching placebo 
treatments will be identical in appearance, and the volume of solution administered to subjects 
in both treatment groups will be based on body weight. 
4.4.2 
Unblinding 
The study blind for Part 1 should not be broken except in a medical emergency (where 
knowledge of the study drug administered would affect the treatment of the emergency) or 
regulatory requirement (e.g., for SAEs).  
The decision to break the blind can only be made by the Investigator, or other persons duly 
registered in the clinical trial file as sub-Investigators. If possible, the Investigator should consult 
with the Medical Monitor prior to breaking the blind. Unblinded staff members will not convey 
information regarding treatment assignments in the study, whether informally or formally, to 
any other person, unless required for medical reasons. If the blind is broken, the date, time, and 
reason must be recorded and included in any associated AE report. 
If an emergency unblinding becomes necessary, the Investigator should request the unblinding 
information through the centralized electronic randomization system and notify the 
Sponsor/Medical Monitor of the unblinding.  


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The ethics committee should be informed if a subject’s treatment is unblinded at the site level. 
After the unblinding the Investigator shall determine if the subject is to continue or discontinue 
study drug. The Investigator’s decision should be based on the risk to benefit determination for 
the subject and should be discussed with the medical monitor prior to implementing the 
decision when possible. The Sponsor should be informed of the decision. 
4.4.3 
Packaging, Labelling, and Storage 
The study drugs will be labelled according to the applicable local health authority and/or 
regulatory requirements. Study drugs will be sent to the central or local depots and the depots 
will then send the study drugs to the study site. Study drug shipments will be under refrigerated 
conditions. 
All supplies of study drug must be stored under refrigeration at the sites. The Sponsor should be 
notified of any significant study drug temperature excursions. 
4.5 
ADMINISTRATION OF STUDY DRUG 
Preparation of study drug for administration will be done by trained and qualified technicians 
or pharmacists. Detailed instructions on preparation of the study drug for administration will be 
provided in the Pharmacy Manual.  
The study drug should be administered TIW in conjunction with the subject’s dialysis sessions. If 
subjects have dialysis sessions more than 3 times per week, the study drug will only be 
administered TIW according to the schedule of events outlined in Table 1 and Table 2.  
In Part 1, the dose of blinded study drug will be based on the subject’s body weight recorded 
after hemodialysis during screening. In Part 2, the dose of SNF472 will be based on the subject’s 
body weight recorded after hemodialysis at Week 12, Day 5 of Part 1. 
The appropriate volume of the study drug will be removed from the vial and then diluted in 
physiological saline and administered as a constant rate IV infusion with an infusion pump 
connected directly to the dialysis machine before the dialyzer via an IV infusion set, as shown in 
Figure 2. The preparation of study drug and the infusion procedure will be described in the 
Pharmacy Manual. The study drug should NOT be administered by bolus or directly into the 
vein. The study drug should ALWAYS be administered via the dialysis tubing before the dialyzer. 
The infusion should begin just after the start of the HD procedure and should be administered 
over a period of approximately 2.5 – 3 hours. The total dose should be delivered at each dosing 
session, even in the event of infusion interruptions that may extend the dosing duration. 
No direct interactions are expected between SNF472 and STS, however no studies have been 
conducted to evaluate administration of the two drugs together, thus SNF472 should NOT be 
administered concomitantly with STS. In the event that both drugs need to be administered to 
the subject, the administration of STS should occur after administration of SNF472 during the 
last 30 minutes of the HD session. 
Investigators should consider whether any changes to the dialysis prescription will be needed to 
account for the volume of saline used for delivery of the study drug and track the weight of 


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subjects after hemodialysis (as per usual practice), adjusting dialysis settings if needed for 
maintaining volume balance. 
 
For each study drug infusion, the site will document the actual start and stop times of the 
infusion, the total volume infused, and any interruption and resumption of the infusion along 
with the reason for the interruption.  
Figure 2. Method of Study Drug Administration 
 
 
 
Note: SNF472 is not removed by dialysis and the diluted study drug should be added to the 
dialysis line before the dialyzer. 
4.6 
SUPPLIES AND ACCOUNTABILITY 
The Investigator or designee is responsible for maintaining accurate accountability records of 
the study drug vials throughout the clinical study.  
Cumulative inventory and dispensing of study drug will be recorded throughout the study using 
the centralized electronic system and electronic data capture (EDC).  


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All sites will return unused study drug vials to the depot. Broken or damaged vials will be 
destroyed on-site following the site’s Drug Destruction Policy and accounted for within the drug 
accountability records. The unused study drug return for destruction will only occur after drug 
accountability has been performed, after any discrepancies have been resolved, and after 
receiving approval of destruction by the Sponsor or designee. 
4.7 
PRIOR AND CONCOMITANT MEDICATIONS, BACKGROUND CARE FOR CUA, 
WOUND CARE, DIALYSIS PARAMETERS, AND LIFESTYLE RESTRICTIONS 
4.7.1 
Prohibited Concomitant Medications 
• Bisphosphonates should not be used within 3 months prior to baseline (Week 1 Day 1) 
or at any time throughout the study.  
• Intralesional STS treatment of the wound should not be used from the time of 
randomization or at any time throughout the study. 
4.7.2 
All Prior and Concomitant Medications 
The use of any other treatments or medications considered necessary by the Investigator for 
management of the subject’s health and medical condition are allowed during this study. 
At screening, medications taken during the past 30 days will be recorded as prior medications in 
the eCRF (including dose, duration, and reason for administration).  
New medications and/or changes in ongoing prior medications relative to screening will be 
documented before the first dose of study drug on Week 1 Day 1. 
After the first dose of study drug, new medications and/or changes to ongoing medications, 
including pain medications, will be recorded as concomitant medications in the eCRF with 
details including but not limited to dose, duration, and reason for administration according to 
the schedule in Table 1 and Table 2. 
4.7.3 
Background Care for CUA 
All subjects should receive background care for CUA in accordance with the clinical practices at 
each site. Background care includes wound care, dialysis parameters (calcium concentration in 
the dialysate, dialysis frequency and duration), pain medications, and other concomitant 
medications relevant to the management of CUA. A stable background care regimen should be 
established (or maintained if already in place) during the screening period and should continue 
throughout Parts 1 and 2 and the follow-up period. Additional information on stabilizing pain 
medications is provided in Section 4.7.3.1. After the screening period, no changes to the 
background care regimen, including the maintenance pain medication dose, should be made 
during the study unless medically indicated in the opinion of the Investigator.  
Consideration should be given to potential triggers for CUA and Investigators should consider 
whether these measures are appropriate for their subjects: replacement of warfarin with 
another anticoagulant, withdrawal of calcium-based phosphate binders unless being used for 


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hypocalcemia, reduction in vitamin D administration, and a hemodialysis regimen of 4 hours, 
three times per week. Wounds should be monitored regularly for infection. 
4.7.3.1 
Stabilizing Pain Medications 
The site staff should establish (or maintain if already in place) a stable pain medication regimen 
between Screening Visit 1 and Screening Visit 2.  
At Screening Visit 1, the site staff will assess and record the details of all pain medications the 
subject is currently using to control pain for CUA and other reasons. Pain medications used for 
the prior 30 days will be included in the eCRF. The subject should be provided with a diary at 
Screening Visit 1 and instructed to record all use of pain medications (opioids and non-opioids) 
on a daily basis, indicating if the pain medication was for CUA lesion pain or pain from other 
causes. Subjects will be asked to record all pain medications they are currently taking and any 
newly prescribed pain medications taken during the screening period. Subjects should be 
instructed to bring the diary with them to the site at each visit. The site staff should review the 
diary with subjects at least weekly during the screening period and clarify, as needed, 
medications used, frequency, and dosage. Actual use from the diaries will be recorded by site 
staff in the eCRF. The Investigator or designee will evaluate pain medication stabilization 
beginning at Screening Visit 1 and on a weekly basis until Screening Visit 2.  
The stable dose of pain medication used for CUA will be based on the subject’s usage during a 
7-day period prior to Screening Visit 2. A 2-week period of evaluation is suggested, but this 
duration may require less time or more time, up to three to four weeks, based on the needs of 
the subject. The week used for determining the stable dose should not be a week during which 
additional but short-term use of opioids was required during or due to medical procedures 
(e.g., surgical debridement, fistula procedures). If such additional opioid use occurred, the 
7 days prior to the procedure or the 7 days after the procedure should be used to determine 
the stable dose. Note: Up to 5 weeks for screening is permitted, but the screening period may 
be shorter for some subjects.  
When a stable dose has been determined, it be will be defined as the subject’s maintenance 
dose for the remainder of the trial. The maintenance opioid dose will be calculated centrally as 
the average daily morphine milligram equivalents (MME) based on the information entered in 
the eCRF.  
4.7.3.2 
Maintenance of Pain Management During the Trial 
Subjects will continue to record all pain medications taken in the diary on a daily basis 
throughout the trial and the site staff will continue to review the diary with subjects weekly and 
record actual pain medications used in the eCRFs. 
Investigators should continue the prescriptions for pain medications established during the 
screening period as the baseline maintenance dose. If applicable, Investigators should 
coordinate with other providers involved in pain management for the subject and encourage 
them not to change pain medication unless medically indicated for worsening of pain control. 


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Also, Investigators should request the provider to inform them of any change in dose or 
addition of new pain medications. 
The following general guidance for pain management during the study, based on pain severity, 
should be followed: 
• Mild pain should be treated with acetaminophen and adjuvants such as pregabalin or 
gabapentin.  
• If this combination is inadequate for pain control, addition of a low dose opiate such as 
oxycodone should be considered.  
• Only if further pain control is required, use of higher doses and/or stronger opiates (e.g., 
fentanyl patch) should be considered, up to a maximally tolerated dose.  
• If pain is not controlled despite this guidance, Investigators may follow regional or 
institution guidelines for management of pain. 
4.7.3.3 
CUA Wound Care 
CUA wound care will be at the discretion of the treating physician but should avoid agents 
known to inhibit healing such as liquid povidone iodine and hydrogen peroxide. Surgical 
debridement may be considered, if necessary, to prevent systemic infection. Wound care 
received for CUA lesions will be recorded periodically according to the schedule in Table 1 and 
Table 2. CUA wound care recorded can include:  
• Absorptive dressing (gauze, alginate) 
• Impregnated, non-adherent gauze 
• Gel dressing 
• Cream/ointment therapy 
• Enzymatic debridement 
• Surgical debridement 
• Negative pressure therapy 
• Hyperbaric oxygen 
• Other (specify) 
4.7.3.4 
Dialysis Parameters 
Sites will be requested to record calcium concentration in the dialysate, the frequency and 
duration of dialysis, and record dialysis adequacy (Kt/V or URR) at each of the visits indicated in 
Table 1 and Table 2. Estimated values from the dialysis machine or calculated values using local 
lab measurements may be used. For each subject, the same measure of dialysis adequacy (Kt/V 
or URR) should be recorded at the visits indicated and it should be based on the same data 
source (dialysis machine or calculation using local labs) throughout the study. 
 


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4.7.4 
Lifestyle Restrictions 
4.7.4.1 
Dietary Restrictions 
No dietary restrictions are required for participation in this study. In addition, no restrictions on 
the timing of food or fluid intake with respect to dosing are required because the study drug 
administration will be IV. 
4.7.4.2 
Contraception Requirements 
To prevent pregnancy, female subjects and female partners of male subjects, must not be of 
childbearing potential (i.e., menopausal for >1 year, surgically sterilized), must practice true 
abstinence, or must practice one of the highly effective contraceptive methods (i.e., results in 
<1% failure rate when used consistently and correctly) listed below from screening through 
30 days after the last dose of study drug. True abstinence is defined as abstinence that is part of 
the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and declaration of abstinence for the duration of 
exposure to study drug are not acceptable. Withdrawal is also not an acceptable method of 
contraception. 
• Female subjects of childbearing potential who are sexually active should use one of the 
following contraceptive methods: 
o Intrauterine device or intrauterine system in place for at least 3 months prior to first 
dose of study drug 
o Partner has had a vasectomy 
 Note: Vasectomy in the partner is only considered to be highly effective provided 
the partner is the sole sexual partner of the female subject of childbearing 
potential and the vasectomized partner has had a medical assessment of the 
surgical success. 
o Stable hormonal contraception associated with inhibition of ovulation (such as oral, 
transdermal, or depot regimen) for at least 3 months prior to first dose of study drug 
o Bilateral tubal ligation 
• Male subjects who are sexually active and have a partner who is of childbearing potential 
should use a condom in addition to having their female partner use another acceptable 
method (see bullet point above) from screening through 30 days after the last dose of study 
drug. 
o Note: Male subjects must not have unprotected sexual intercourse with a female who 
is pregnant or breastfeeding during the study. 
 


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5 STUDY PROCEDURES AND ASSESSMENTS 
5.1 
SCREENING PERIOD 
The schedule of assessments during the Screening Period is provided in Table 1. 
Informed consent will be obtained prior to performing any study procedures. Screening will be 
conducted in two steps (Screening Visit 1 and Screening Visit 2).  
Screening Visit 1: 
At Screening Visit 1, the study staff should initiate the screening process by evaluating the 
inclusion/exclusion criteria, collecting the CUA lesion images (photographs and videos), 
demographic information (sex, age, race, ethnicity), prior/concomitant medications, including 
pain medication use, dialysis parameters, medical history, physical exam (including weight and 
height), and vital signs.  
As the initial step during the screening process, the site personnel will complete and enter 
demographic information into the IRT system, acquire images of the subject’s suspected CUA 
lesion(s) and will rate undermining, peripheral tissue edema, and peripheral tissue induration 
for these lesion(s). In addition, the site personnel will administer the Pain VAS pain and Wound 
QoL. The central wound rating group will confirm whether lesion(s) are due to CUA (according 
to details provided in the Central Wound Rating Charter). The subject should be provided with a 
pain medication diary and instructed to record on a daily basis all pain medications (opioids and 
non-opioids) taken and the reason the pain medications were taken (i.e., for CUA lesion pain or 
other non-CUA lesion pain).  
Site personnel will be notified through the IRT system that the subject’s lesion(s) and Pain VAS 
score have met eligibility requirements. Site staff can then continue to complete the remaining 
eligibility requirements (laboratory specimen collection, completion of medical history, and 
other evaluations).  
During the subsequent week(s) prior to Screening Visit 2, the Investigator or designee should 
review the subject diary with the subject at least weekly, record actual pain medication use in 
the eCRF, and titrate the pain medications as needed (see Section 4.7.3.1 for additional details) 
until a stable pain medication regimen is achieved. When a stable dose is achieved, it be will be 
defined as the subject’s pain maintenance dose for the remainder of the trial. 
In addition to pain medications, other aspects of the background care regimen (including 
wound care, dialysis parameters, other concomitant medications relevant to the management 
of CUA; Section 4.7.3) should be stabilized (or maintained if already stable) and recorded.  
Screening Visit 2 
At Screening Visit 2, the CUA lesions identified at Screening Visit 1 and confirmed as CUA lesions 
by the central wound rating group, will be evaluated for significant improvement, based on the 
opinion of the Investigator, since the initial assessment. If the CUA lesion has not significantly 
improved, in the opinion of the investigator, any incomplete eligibility criteria should be 


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completed, including Holter monitoring and local ECGs. Subjects meeting all eligibility criteria 
will be randomized in a 1:1 ratio to receive either 7 mg/kg of SNF472 or matching placebo. 
A subject who does not meet all of the eligibility criteria will be screen failed. Subjects who 
have failed screening may be rescreened on a case-by-case basis after discussion with the 
Medical Monitor. 
Due to visit scheduling, a subject’s Week 1 Day 1 visit may occur up to 7 days after 
randomization. If during this period and prior to the administration of the first dose of study 
drug the Investigator observes changes to the primary lesion (e.g., significant improvement 
from screening) or changes to the subject’s clinical condition which may make the subject 
ineligible, the Medical Monitor should be consulted.  
5.2 
PART 1: DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TREATMENT 
PERIOD 
The schedule of assessments during Part 1 is provided in Table 1. 
Subjects will receive SNF472 or placebo for 12 weeks in addition to background care (in 
accordance with the clinical practices of each site). No changes to the background care 
regimen, including pain maintenance dose, should be made after randomization unless 
medically indicated in the opinion of the Investigator. Medically indicated changes to 
background care will be recorded on the eCRF. 
In Part 1, subjects should continue to record all pain medications taken in the pain medication 
diary and bring their diary with them to each visit. Diaries should be reviewed with the subject 
at least weekly and pain medications will be recorded in the eCRF. 
5.3 
PART 2: OPEN-LABEL TREATMENT PERIOD 
The schedule of assessments during Part 2 is provided in Table 2. 
Subjects who complete Part 1 will be eligible to participate in Part 2, in which all subjects will 
receive open-label SNF472 for 12 weeks and continue stable background care (in accordance 
with the clinical practices of each site), including pain maintenance dose, with no changes 
unless medically indicated in the opinion of the Investigator. Medically indicated changes to 
background care will be recorded on the eCRF. 
In Part 2, subjects should continue to record all pain medications taken in the pain medication 
diary and bring their diary with them to each visit. Diaries should be reviewed with the subject 
at least weekly and pain medications will be recorded in the eCRF. 
If a visit is missed in Part 1 or Part 2, subjects should return to the normal schedule after the 
missed visit. Missed assessments should be conducted at the next visit.  
5.4 
FOLLOW-UP PERIOD/ EARLY TERMINATION 
The schedule of assessments for the Follow-Up/ Early Termination is provided in Table 2. 


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Subjects completing the study will return for a follow-up visit 4 weeks after the last dose of 
study drug. Subjects should continue on stable background care during the 4-week follow-up 
period with no changes unless medically indicated in the opinion of the Investigator. Subjects 
who discontinue study drug during Part 1 or Part 2 will be asked to complete study assessments 
throughout the respective part of the study (Part 1 or Part 2) and complete a follow-up visit. 
Subjects who discontinue study drug and are unwilling to complete the remaining study 
assessments should be encouraged to return for an early termination visit 4 weeks after the last 
dose of study drug. Additional information on early discontinuation of study drug and 
withdrawal from the study is provided in Section 7.  
In the follow-up period, subjects should continue to record all pain medications taken in the 
pain medication diary and bring their diary with them to each visit. Diaries should be reviewed 
with the subject at least weekly and pain medications will be recorded in the eCRF. 
5.5 
ORDER OF ASSESSMENTS 
5.5.1 
Prior to Start of Dialysis 
The following should be performed prior to the start of dialysis and the following order is 
recommended:  
1. Pain VAS 
2. Wound QoL questionnaire 
3. BWAT and image (photos and video) collection 
4. Placement of the Holter monitor and initiation of recording with Holter monitor prior to 
dialysis  
5.5.2 
During Dialysis 
When more than one of the following assessments is conducted at the same time point, they 
should be performed in the following order: 
1. Perform local ECGs (see Section 5.8.5 for time points) 
2. Blood sampling for ionized calcium and safety labs 
3. Blood sampling for biomarkers, PD, and PK  
Data will be recorded in an eCRF implemented in an appropriate EDC system, as described in 
Section 9.2. 
5.6 
EFFICACY ASSESSMENTS 
5.6.1 
Wound Evaluation 
Using a standardized device and imaging software, images (photos and videos) of CUA lesions 
will be acquired and stored, according to details provided in the Site Imaging and BWAT Manual 
at the visits specified in Table 1 and Table 2. The course of the lesion(s) will be assessed 


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quantitatively with BWAT (Section 5.6.1.1) and with qualitative image review (Section 5.6.1.2). 
If a subject has more than one CUA lesion, the course of up to 3 lesions (primary, secondary, 
tertiary) will be assessed. Which lesions are primary, secondary, and tertiary will be defined 
based on the total area as measured by the wound imaging software at screening. In addition, 
occurrence of new CUA lesions will be monitored (Section 5.6.1.3). 
The central wound rating group will review image quality and notify the site if wound imaging 
needs to be repeated at a following visit for a technical reason. 
5.6.1.1 
Quantitative Wound Evaluation with BWAT and BWAT-CUA 
The BWAT (APPENDIX 1; Bates-Jensen and Sussman, 2011) is a standardized tool for 
quantitative assessment of wound healing that includes evaluation of these 13 items:  
• Size 
• Depth 
• Edges 
• Undermining 
• Necrotic tissue type 
• Necrotic tissue amount 
• Exudate type 
• Exudate amount 
• Skin color surrounding wound  
• Peripheral tissue edema 
• Peripheral tissue induration 
• Granulation tissue 
• Epithelialization 
Each item is rated on a scale of 0 or 1 (best) to 5 (worst). Two scores will be calculated as 
endpoints for this study, BWAT total and BWAT-CUA. BWAT total is the sum of all 13 items with 
a possible range of scores from 9 to 65. In addition, a targeted modification of BWAT, the 
BWAT-CUA, will be calculated which focuses on the following prototypical features of CUA 
lesions: necrotic tissue type, necrotic tissue amount, exudate type, exudate amount, skin color 
surrounding wound, peripheral tissue edema, peripheral tissue induration, and granulation 
tissue. The possible range of scores for BWAT-CUA is 8 to 40. 
Two additional items are collected in BWAT, location and shape, but do not contribute to the 
scoring. 
Site personnel will be trained and responsible for obtaining quality wound photographs and 
videos with the provided device and imaging software, along with scoring undermining, 
peripheral tissue edema, and peripheral tissue induration, according to the procedures 


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described in the Site Imaging and BWAT Manual. Every effort should be made for the same 
person at the site to perform evaluation of these items at all visits for each subject. As with all 
other study personnel, the central wound rating group will be blinded to treatment assignment. 
The central raters will review the site’s ratings and will rate the remaining BWAT items based 
upon review of the photographs and videos. Rating of the size item will be aided by automated 
measurements from the imaging software. The scoring procedure will be described in detail in 
the Central Wound Rating Charter. 
 
5.6.1.2 
Qualitative Wound Evaluation 
The central wound rating group will perform a qualitative review of the baseline (Week 1 Day 1) 
and Week 12 images of the primary lesion after the completion of the Week 12 visit. The Week 
12 wound will be assigned to one of the following categories:  
o Worsened from baseline 
o Equal to baseline 
o Improved from baseline 
A similar qualitative comparison will be made between Week 12 and Week 24 images of the 
primary lesion after the completion of the Week 24 visit. 
Qualitative reviewers will not be involved in confirmation of CUA lesions or BWAT rating during 
the trial. In addition to being blinded to treatment assignment in Part 1, the qualitative 
reviewers will be blinded to the order of study visits in both Part 1 and 2. The review procedure 
is described in detail in the Central Wound Rating Charter. 
5.6.1.3 
New CUA Lesions 
Occurrence of new CUA lesions since baseline (Week 1 Day 1) will be monitored periodically as 
specified in Table 1 and Table 2 to assess overall lesion burden. The site will collect images of 
the suspected CUA lesion(s) that were not present at baseline and the central wound rating 
group will review the images (according to the procedure described in Central Wound Rating 
Charter) to determine whether the new lesion is a CUA lesion. BWAT-CUA and BWAT total will 
not be scored for the new CUA lesions. 
5.6.2 
Pain VAS 
The Pain VAS will be used to assess the level of CUA wound-related pain experienced by the 
subject in reference to all of the subject’s lesions. A VAS is an instrument that aims to measure 
a characteristic or attitude that is believed to range across a continuum of values and cannot 
easily be directly measured.  
Pain VAS will be electronically administered, requiring the subject to mark a position anywhere 
on a 10-cm (100-mm) long horizontal line to indicate the worst wound-related pain experienced 
during the previous 24 hours. From this mark, the VAS score will be electronically recorded in 
mm based on measurement along the line. The VAS line will be anchored by the word 


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descriptors at each end of “no pain” and “worst possible pain”. An example of a Pain VAS is 
illustrated in Figure 3. 
Figure 3. Pain Visual Analog Scale 
 
5.6.3 
Wound-QoL 
The Wound-QoL questionnaire, provided in APPENDIX 2, measures the disease-specific, 
health-related QoL of patients with chronic wounds. It consists of 17 items on impairments that 
are assessed in reference to the preceding 7 days. Each rated on a 5-point Likert scale with 
responses ranging from “not at all” (0) to “very much” (4). 
The Wound-QoL will be electronically administered. The global score and subscale scores will 
be calculated programmatically in accordance with the scoring rules. 
5.6.4 
Pain Medications 
Subjects will record all pain medications used in a daily pain medication diary. Site staff will 
review the diary with subjects at least weekly and record actual pain medications used in the 
eCRFs. 
 
5.7 
PHARMACODYNAMICS, PHARMACOKINETICS, AND BIOMARKER ASSESSMENTS 
Blood samples for PD, PK, and biomarker analyses must be collected on a dialysis day when 
study drug dosing occurs. Samples will be obtained from the dialysis port and should be either 
stored in a -80°C (±10°C) freezer prior to shipment or be shipped on dry ice on the same day as 
collection. Samples for PK, PD, and biomarker analyses will be collected pre-dose and within 
20 minutes prior to the end of infusion (EOI)at Weeks 1, 12, 13, and 24. For the follow-up/early 
termination visit, the biomarker sample should be collected prior to the start of dialysis.  
Collection (including sample volumes), storage, and handling of blood samples for PD, PK, and 
biomarker analyses will be detailed in the Laboratory Manual.  
The PD, PK, and biomarker analyses summarized in Sections 5.7.1, 5.7.2, and 5.7.3, respectively, 
will be performed at central laboratories. 


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5.7.1 
Pharmacodynamics 
The PD of SNF472 will be assessed in pre-dose and EOI samples by an in vitro method to 
determine the propensity for HAP crystal formation in plasma.  
5.7.2 
Pharmacokinetics 
The plasma concentration of SNF472 will be determined in pre-dose and EOI samples. The EOI 
sample corresponds to Cmax. 
5.7.3 
Biomarkers 
The following biomarkers will be assessed in pre-dose and EOI samples: fetuin A, intact 
fibroblast growth factor 23 (iFGF23), c-terminal fibroblast growth factor 23 (c-FGF23), matrix gla 
protein (MGP), sclerostin, growth differentiation factor 15 (GDF15), tartrate-resistant acid 
phosphatase 5b (TRAP5b), bone alkaline phosphatase (BALP), Dickkopf WNT signaling pathway 
inhibitor 1 (DKK1), osteocalcin, osteoprogeterin, osteopontin, bone morphogenetic protein-9 
(BMP-9), iron, ferritin, and transferrin, and lipids (LDL, HDL, total cholesterol, triglycerides). 
Biomarker testing may include RNA measurements. No DNA testing will be performed.  
5.8 
SAFETY ASSESSMENTS 
The safety assessments described in this section will be performed at the visits specified in 
Table 1 and Table 2. 
5.8.1 
Adverse Events 
The assessment and reporting of AEs are discussed in detail in Section 6. 
5.8.2 
Medical History 
The subject’s relevant medical history will be recorded at screening. Previous illnesses and 
history of drug and alcohol abuse will be recorded. Medical history will be updated prior to the 
first day of dosing in Part 1.  
5.8.3 
Physical Examination and Body Weight 
The physical examination will include an examination of general appearance, skin, head and 
neck, chest, lungs, heart, abdomen, extremities and basic nervous system evaluation. If any 
physical findings are abnormal, the Investigator must document the abnormality as 
nonclinically significant (NCS) or clinically significant (CS). Subsequent to the screening 
examination, any abnormality assessed as ‘CS’ must be recorded as an AE if not explained by a 
coexisting condition (documented in the medical history).  
Physical examinations will include body weight which will be recorded post-dialysis, without 
shoes. If body weight cannot be assessed without shoes, then it should be assessed under the 
same conditions throughout the study. Height will be included in the physical examination at 
screening only. 


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5.8.4 
Vital Signs 
Vital signs (heart rate, systolic and diastolic blood pressures, respiratory rate, and body 
temperature) will be assessed post-dialysis after the subject has been sitting for 5 minutes. The 
results of these protocol-specified assessments will be recorded in the eCRF; however, 
additional vital signs assessments taken as part of background care do not need to be recorded. 
5.8.5 
Holter Monitoring and Electrocardiograms 
Holter monitoring and local ECGs must be completed on dialysis days and, with the exception of 
screening visits, only on a day when the study drug is administered. Holter monitoring during 
dialysis will be performed as part of Screening Visit 2 (may be conducted at any dialysis session 
during the last week of screening prior to Week 1 Day 1), and at Weeks 1, 6, 12, 13, and 24. The 
Holter monitor will be placed on the subject and the recording started prior to the beginning of 
dialysis (at least 30 minutes) and continue to the end of dialysis.  
Holter instruction and timing are summarized in Table 4. Refer to the Holter and ECG Manual 
for additional details and procedures.  
Table 4. Holter Instructions and Timing 
Visit 
Holter Instructions and Time Point Collection 
Screening Visit 2 
Start Holter recording prior to the start of dialysis (at least 30 
minutes). Record the start time of dialysis. Record the stop 
time of dialysis and manually end the Holter recording. 
Week 1 Day 1 
Start Holter recording prior to the start of dialysis (at least 30 
minutes). Record the start time of dialysis. Collect times of 
start and end of study drug infusion. Record the stop time of 
dialysis and manually end the Holter recording.  
Week 6 Day 3 (± 2 days) 
Week 12 Day 5 
Week 13 Day 1 
Week 24 Day 5 
 
Local ECGs will be obtained using the ECG instrument that will be supplied with the Holter 
monitor and will be assessed for abnormalities by the Investigator. The Screening Visit 2 ECGs 
should be recorded at the start of dialysis and 2.5 hours after the start of dialysis and may be 
conducted at any dialysis session during the last week of screening prior to Week 1 Day 1. Local 
ECGs should be obtained pre-dose and within 20 minutes prior to EOI at Weeks 1, 12, 13, and 
24. Abnormalities the Investigator judges to be clinically significant should be recorded as 
adverse events. These ECGs should be considered source documentation and be included as 
part of the subject’s chart. 
Local ECG collection timepoints are summarized in Table 5. For additional details on local ECG 
procedures refer to the Holter and ECG Manual.  


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Table 5. Local ECG Tracing Collection Timepoints 
Visit  
ECG Tracing Collection Timepoints  
Screening Visit 2 
Start of Dialysis 
Screening Visit 2 
2.5 hours after the start of dialysis 
Week 1 Day 1 
Pre-dose 
Week 1 Day 1 
Within 20 minutes before the End of Infusion 
Week 12 Day 5 
Pre-dose 
Week 12 Day 5 
Within 20 minutes before the End of Infusion 
Week 13 Day 1 
Pre-dose 
Week 13 Day 1 
Within 20 minutes before the End of Infusion 
Week 24 Day 5 
Pre-dose 
Week 24 Day 5 
Within 20 minutes before the End of Infusion  
 
5.8.6 
Laboratory Evaluations 
Laboratory parameters to be evaluated during this study are provided in Table 6. Blood samples 
will be collected via the dialysis port pre-dose for these laboratory evaluations. Blood samples 
for the assessment of ionized calcium will also be collected at EOI at specified visits (within 
20 minutes prior to the end of the study drug infusion) and must be shipped on day of 
collection under ambient conditions to the central laboratory.  
Collection (including sample volumes), storage, and handling of the blood samples will be 
detailed in the Laboratory Manual. Safety laboratory sample analyses will be performed at the 
central laboratory in accordance with standard laboratory procedures, as specified in the 
Laboratory Manual. 


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Table 6. Laboratory Parameters 
Hematology 
Hematocrit 
Hemoglobin (including MCV, MCH, MCHC) 
Platelet count 
White blood cell (WBC) count (total and differential) 
Chemistry 
Alanine transaminase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate transaminase (AST) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium, total 
Calcium, ionized 
Chloride 
Creatine kinase (CK) 
Creatinine  
Gamma-glutamyl transpeptidase 
(GGT) 
Glucose (non-fasting) 
hs-CRP 
Lactic acid dehydrogenase (LDH) 
Magnesium 
Parathyroid hormone (PTH, intact) 
Phosphate/phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
Vitamin K 
 
Other 
Serum pregnancy test (females of 
childbearing potential only) 
 
 
6 ADVERSE EVENTS 
6.1 
DEFINITIONS 
6.1.1 
Adverse Event 
An AE is defined by the ICH Guideline for Good Clinical Practice (ICH GCP) as any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment. 
A treatment-emergent AE is defined as an AE that begins or that worsens in severity after at 
least one dose of the study drug has been administered. 
Surgical procedures or laboratory values themselves are not AEs. Surgical procedures are 
therapeutic measures for conditions that require surgery. Abnormal laboratory values may lead 
to diagnosis of a condition. The condition for which the surgery or laboratory value is indicative 
of is an AE if it occurs or is detected during the study period. Planned surgical measures and the 
condition(s) leading to these measures are not AEs if the condition(s) was (were) known before 
the period of observation. In the latter case the condition should be reported as medical 
history. 


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6.1.2 
Serious Adverse Event 
An SAE is an AE that at any dose (including overdose) that meets at least one of the following 
criteria: 
• Results in death 
• Is life-threatening (i.e., the subject was at immediate risk of death at the time of the SAE; it 
does not refer to a SAE that hypothetically might have caused death if it were more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization (i.e., a hospital 
inpatient admission or prolongation of hospital stay was required for the treatment of the 
AE, or that one or the other occurred as a consequence of the event) 
• Results in persistent or significant disability or incapacity (i.e., a permanent or significant and 
substantial disruption of a person’s ability to carry out normal life functions) 
• Is a congenital anomaly or birth defect 
• Is an important medical event (If an AE doesn’t meet one of the criteria above, but the 
Investigator considers the event to be clinically important, then the event could be classified 
as an SAE under the criterion of ‘important medical event’. Examples of such medical events 
may include bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias, or convulsions that don’t result in inpatient hospitalization.) 
6.1.3 
Wound-Related Complications 
Each adverse event will be assessed as CUA wound-related or not CUA wound-related by the 
Investigator or designee. 
6.1.4 
Adverse Event by Severity or Intensity 
Assessment of severity of an AE will be rated by the Investigator or designee according to the 
criteria in Table 7. 


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Table 7. Definitions of Adverse Events Severity Based on CTCAE  
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL1. 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL2 
Grade 4 (Life-
Threatening) 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 (Fatal) 
Death related to AE 
ADL = activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events.  
1 Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
It is important to note that severity and seriousness are separate characteristics of an AE: 
severity denotes the intensity of the AE (Table 7), whereas seriousness is an AE categorization 
based on the criteria listed in Section 6.1.2 that denotes whether expedited reporting is 
required for an AE (see Section 6.3.1.2 and Section 6.3.2). 
Any AE with a severity of Grade 4 or 5 would meet the criteria for seriousness. A Grade 3 AE 
may or may not meet the criteria for seriousness depending upon whether any of the other 
criteria for seriousness in Section 6.1.2 are met.  
6.1.5 
Relationship between Adverse Events and Study Drug 
The relationship between all AEs and the study drug must be assessed the Investigator or 
clinician designee based on the temporal relationship and his/her clinical judgement using the 
guidelines in Table 8. In addition to a temporal relationship, the Investigator should consider 
the following when determining the relationship between an AE and study drug: whether an 
alternative etiology has been identified, mechanism of action of the study drug, and/or the 
biological plausibility of a relationship. 


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Table 8. Guidelines for Assessing the Potential Relationship Between Adverse Event and the 
Study Drug 
Related 
This causal relationship is assigned if the AE is known to occur with the 
study drug, there is a reasonable possibility that the study drug caused 
the AE, or there is a temporal relationship between study drug 
administration and the event. Reasonable possibility means that there 
is evidence to suggest a causal relationship between the study drug 
and the AE. 
Not Related 
This causal relationship is assigned when there is not a reasonable 
possibility that the administration of the study drug caused the event, 
there is no temporal relationship between the study drug 
administration and event onset, or an alternate etiology has been 
established. 
 
6.1.6 
Adverse Event Outcome 
If the same AE occurs more than one time in the same subject, then the AE in question must be 
documented and assessed as a new event each time, unless the AE is considered to be a 
continuation of the previously reported event rather than a reoccurrence of the event.  
The AE outcome will be recorded as defined in Table 9. 
Table 9. Adverse Event Outcome 
Not recovered/not resolved - One of the possible results of an AE outcome that indicates 
that the event has not improved or recuperated. 
Recovered/resolved - One of the possible results of an AE outcome that indicates that the 
event has improved or recuperated. The subject recovered from the AE.  
Recovering/resolving - One of the possible results of an AE outcome that indicates that the 
event is improving.  
Recovered/resolved with sequelae - One of the possible results of an AE outcome where the 
subject recuperated but retained pathological conditions resulting from the prior disease or 
injury. 
Unknown - There is an inability to access the subject or the subject’s records to determine 
the outcome (i.e., subject withdraws consent or is lost to follow-up).  
Fatal - The AE directly caused death.  
6.1.7 
Abnormal Laboratory Values 
The Investigator is responsible for reviewing laboratory test results and determining whether 
an abnormal value in a subject represents a clinically significant change from subject’s baseline 
value (Week 1, Day 1). In general, abnormal laboratory findings without clinical significance 


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(based on the Investigator's judgment) or not requiring treatment should not be recorded as 
AEs. 
6.1.8 
Pregnancy and In Utero Drug Exposure 
Since SNF472 has not been evaluated in pregnant or nursing women, the treatment of pregnant 
women or women of childbearing potential who are not using effective contraception is 
contraindicated (see Section 4.7.4.2 for instructions on birth control). 
Pregnancies occurring in female subjects, or female partners of male subjects are considered 
immediately reportable events if the pregnancy occurs during the study treatment through 30 
days after the subject’s last dose of study drug. If a pregnancy occurs in a subject, study drug 
must be discontinued immediately. 
The pregnancy must be reported to the Sponsor or designee within 24 hours of the 
Investigator’s knowledge of the pregnancy using the Pregnancy Notification Form.  
The Investigator will follow the pregnant subject until completion of the pregnancy and must 
notify the Sponsor of the pregnancy outcome within 24 hours of the Investigator’s knowledge 
of the outcome. The Investigator will provide this information on the Pregnancy Outcome 
Report Form. This notification includes pregnancies resulting in live, “normal” births. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the pregnancy 
meets any of the serious criteria (i.e., spontaneous abortion [any congenital anomaly detected 
in an aborted fetus is to be documented], stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures for reporting SAEs specified in Section 6.3.1.2. 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
causality) should be reported as SAEs to the Sponsor or designee. In addition, any infant death 
or congenital anomaly occurring after 30 days that the Investigator suspects is related to the in 
utero exposure to the study drug should also be reported to the Sponsor or designee. 
6.2 
HEMODIALYSIS-RELATED EVENTS 
The following events are known to occur during HD treatments and should be recorded in the 
eCRF as HD-related events rather than AEs. However, they should be recorded as AEs if they are 
considered to be unrelated to the HD treatment procedure or if they worsen in severity or 
increase in frequency during HD compared to baseline (Week 1 Day 1). 
• Hypotension 
• Muscle cramps 
• Disequilibrium syndrome 
• Nausea  
• Vomiting 
• Headache 
• Fatigue 


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• Chest pain 
• Itching 
• Fever 
• Chills 
• Pyrogen reaction 
• Hypertension 
6.3 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS 
6.3.1 
Documentation and Reporting of Adverse Events by Investigator 
6.3.1.1 
Recording of Adverse Events 
AEs will be collected from the first time a subject receives study drug until completion of either 
the follow-up visit or an early termination visit. For subjects who discontinue study drug early 
and agree to complete all study assessments, all AEs should be collected until the follow-up 
visit. Subjects who discontinue study drug early and withdraw consent for completing further 
study assessments should complete an early termination visit 4 weeks after last dose of study 
drug and all AEs should be collected up to that time. 
All AEs after informed consent signature but before the first dose of study drug should be 
captured as medical history. 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the event has resolved or stabilized, until there is a satisfactory explanation for the changes 
observed, until the subject is lost to follow-up, or until study follow-up is complete. 
All AEs, regardless of the relationship to study drug, will be recorded. All AE reports should 
contain a brief description of the event, date, and time of onset, date and time of resolution, 
severity, seriousness, treatment required, causal relationship to study drug, action taken with 
the study drug, and outcome. 
In general, an AE that is the primary cause of subsequent events should be identified by the 
primary cause (e.g., for dehydration due to diarrhea, the AE would be diarrhea). However, AEs 
occurring secondary to an initiating event that are separated in time should be recorded as 
independent events (e.g., sepsis secondary to pneumonia, both events should be recorded). 
6.3.1.2 
Reporting of Serious Adverse Events 
All SAEs that occur during the period of observation (see Section 6.3.1.1) whether considered to 
be associated with the study drug or not, must be entered in the eCRF for reporting within 
24 hours of the Investigator’s first knowledge of the event. An alternative method of reporting 
will be provided to sites if eCRF access is not available. 


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The Investigator should not delay initial SAE report entry due to missing data. As soon as the 
minimum information is available, and no later than 24 hours after becoming aware of the SAE, 
the initial SAE report will be entered into eCRF. 
If necessary, the Investigator will provide follow-up reports in a timely manner after knowledge 
of further relevant information. 
Detailed SAE reporting instructions and training will be provided to study site personnel. 
6.3.2 
Reporting of Adverse Events to Regulatory Authorities and Independent Ethics 
Committees/Institutional Review Boards 
The Sponsor or designee will be responsible for informing the regulatory authority of SAEs 
according to local requirements. 
The Sponsor or their designee will provide annual safety reports to the regulatory authorities, 
as applicable. These updates will include information on suspected unexpected serious adverse 
reactions (SUSARs) and other relevant safety findings. 
The Sponsor or designee will notify regulatory authorities of any AE that is serious, unexpected, 
and related to study drug (i.e., a SUSAR) according to applicable local safety reporting 
requirements. 
The Sponsor or designee will notify the Investigators of SUSARs that are submitted to 
regulatory authorities according to local country requirements. 
The Investigator will be responsible for informing the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) of SAEs and SUSARs according to local requirements. 
6.4 
DATA AND SAFETY MONITORING BOARD 
To minimize the possibility of exposing subjects to unusual risk, an external independent DSMB 
has been established. The DSMB will review safety data on a regular basis and will make 
recommendations to the Sponsor as to whether or not to continue the study. The roles and 
responsibilities of the DSMB are defined in the DSMB Charter. 
 
7 DISCONTINUATION AND WITHDRAWALS 
7.1 
DISCONTINUATION OF STUDY DRUG 
Subjects may discontinue study drug at any time. The reasons for which a subject may 
discontinue from study drug include, but are not limited to, the following: 
• AE 
• Subject request 
• Protocol violation 


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• Investigator’s determination that discontinuation from treatment is appropriate (with 
documentation of the reason)  
• Discontinuation of study drug due to a CTCAE Grade 4 AE that is considered by the 
Investigator to be related to the study drug and not due to comorbidities or the disease.  
Subjects may request to stop study drug at any time without penalty and for any reason 
without prejudice to his/her future medical care.  
If a subject requests to discontinue study drug, the Investigator should discuss the subject’s 
reasons for this request with the subject, including asking about the possible contribution of 
adverse events to the request. Based upon the subject’s responses, the Investigator should 
encourage the subject to continue receiving study drug if the subject’s concerns can be 
addressed. If the subject still requests to discontinue study drug, the reason for the request will 
be recorded in the eCRFs.  
Subjects who discontinue study drug during Part 1 should be asked to continue to complete all 
study assessments through the end of Part 1 and the follow-up visit as if they had remained on 
study drug. These subjects are not eligible to participate in Part 2 of the study.  
Subjects completing Part 1 who subsequently discontinue SNF472 during Part 2 should be asked 
to continue to complete all study assessments through the end of Part 2 and the follow-up visit 
as if they had remained on SNF472.  
Adverse events will continue to be collected from subjects who request early discontinuation 
from the study drug during Part 1 or Part 2 but continue to participate in the trial assessments 
for remaining visits.  
All subjects requesting early discontinuation and withdrawal of consent for follow-up visits 
should be informed of the potential greater public health value of the study if they complete 
the follow-up assessments and visits. 
7.2 
WITHDRAWAL OF SUBJECT FROM THE STUDY 
Subjects may be withdrawn from the study for any of the following reasons including but not 
limited to: 
• Pregnancy 
• AE (including CTCAE Grade 4 AE considered related by Investigator as defined above) 
• Subject request/ withdrawal of consent 
• Investigator’s determination that discontinuation from treatment is appropriate (with 
documentation of the reason)  
• Death 
• Discontinuation of the study or the study center by Sponsor’s decision 
Subjects who discontinue study drug and are unwilling to complete the remaining study 
assessments will be encouraged to return for an early termination visit 4 weeks after the last 


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dose of study drug to complete the procedures outlined in the Schedule of Assessments 
(Table 2). Subjects who withdraw consent for continuing assessments and follow-up visits and 
for non-patient contact (e.g., medical records check) will be asked to sign the withdrawal of 
consent form, indicating withdrawal of consent for the remaining follow-up visits, assessments, 
and/or disallowing further access to their medical records. 
If a subject is withdrawn from the study due to an AE, the subject should continue to be 
provided medical care. This may include, if needed, referral to another physician. The AE that 
led to study withdrawal should be followed until an outcome can be defined.  
If a subject withdraws consent from the study and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should 
be collected. The sponsor may retain and continue to use any data collected before such refusal 
for further follow-up. 
7.3 
STORAGE OF SAMPLES 
Blood samples collected for PK, PD, and biomarker analyses will be stored under the control of 
the Sponsor for a maximum of 1.5 years after study end and then destroyed.  
 
8 STATISTICAL METHODS 
The methods for the planned statistical analyses of efficacy, PK, PD, and safety endpoints are 
summarized in the following sections. Statistical analyses for additional parameters (e.g., 
subject characteristics, disposition, exposure, compliance); and more detailed descriptions of 
the methods presented in this section will be provided in the statistical analysis plan (SAP). Any 
major deviations from the planned analyses specified in the protocol and SAP will be 
documented in the clinical study report. 
8.1 
ENDPOINTS 
Unless otherwise indicated “baseline” refers to the assessment on Week 1, Day 1. 
8.1.1 
Efficacy Endpoints 
In Part 1, the primary, secondary, and exploratory efficacy endpoints will compare the placebo 
and SNF472 groups as follows: 
 
Alternate Primary Efficacy Endpoints: 
• Absolute change from baseline to Week 12 in the BWAT-CUA score for the primary 
lesion 
• Absolute change from baseline to Week 12 in Pain VAS score 
Secondary Efficacy Endpoints (assessed hierarchically):  
• Absolute change from baseline to Week 12 in the Wound-QoL score 


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• Absolute change from baseline to Week 12 in the BWAT total score for the primary 
lesion 
• Qualitative wound image evaluation for the primary lesion (worsened, equal to, or 
improved relative to baseline) at Week 12 
• Rate of change in opioid use as measured in morphine milligram equivalents (MME) 
from baseline to Week 12 
 
Exploratory Efficacy Endpoints: 
• Absolute change from baseline to Week 12 in wound size for the primary lesion 
• Absolute change from baseline to Week 12 in each BWAT item for the primary lesion 
• Absolute change in BWAT-CUA, BWAT total, Pain VAS, and Wound-QoL score by visit 
• Proportion of subjects with new CUA lesions between baseline and Week 12 
• Absolute change from baseline to Week 12 in the Wound-QoL scores for the body, 
everyday life, and psyche subscales 
• Absolute change from baseline to Week 12 in the BWAT-CUA score for the secondary 
and tertiary lesions 
• Proportion of subjects requiring an increase in pain medication related to their CUA 
lesion(s) between baseline and Week 12 
• Proportion of subjects with a decrease in pain medication related to their CUA lesion(s) 
between baseline and Week 12 
• Absolute change from baseline to Week 12 in opioid use as measured in MME 
In Part 2, the exploratory efficacy endpoints will be within-group comparisons for the following: 
• Absolute change from baseline to Week 24 vs Week 12 in the BWAT-CUA score for the 
primary lesion 
• Absolute change from baseline to Week 24 vs Week 12 in the Pain VAS score 
• Absolute change from baseline to Week 24 vs Week 12 in the Wound-QoL score 
• Absolute change from baseline to Week 24 vs Week 12 in the BWAT total score for the 
primary lesion 
• Qualitative wound image evaluation for the primary lesion at Week 24 vs Week 12 
(worsened, equal to, or improved relative to baseline)  
• Absolute change from baseline to Week 24 vs Week 12 in wound size for the primary 
lesion 
• Absolute change from baseline to Week 24 vs Week 12 in each BWAT item for the 
primary lesion 


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• Absolute change from Week 24 to the follow-up visit in the BWAT-CUA score for primary 
lesion 
• Absolute change from Week 24 to the follow-up visit in the Pain VAS score 
8.1.2 
Pharmacodynamic and Biomarker Endpoints 
• Percent inhibition of HAP crystallization between pre-dose and EOI at Weeks 1, 12, 13, 
and 24 
• Changes in biomarker concentrations from baseline to Week 12 and from Week 13 to 
Week 24 
• Changes in biomarker concentrations between pre-dose and EOI at Weeks 1, 12, 13, and 
24 
8.1.3 
Pharmacokinetic Endpoints 
• Concentration of SNF472 in pre-dose and EOI at Weeks 1, 12, 13, and 24 
8.1.4 
Safety Endpoints 
• 
Proportion of subjects with AEs, SAEs, and deaths  
• 
Changes from baseline in the following: 
o Laboratory parameters  
o Holter monitoring results 
o QTc interval and other ECG parameters 
o Vital signs 
• Proportion of subjects with a CUA wound-related infection, sepsis, hospitalization, or 
any CUA wound-related complication 
8.2 
DETERMINATION OF SAMPLE SIZE 
8.2.1 
Planned Sample Size 
The sample size calculation is based on the effect sizes and standard deviations (SD) observed 
for changes in BWAT-CUA and Pain VAS from baseline to Week 12 in the Phase 2 study 
(SNFCT2015-04). The effect sizes for BWAT-CUA and Pain VAS were 6.3 and 24 units, 
respectively, with SDs of 6.5 and 31.4 units. Assuming similar results and based on 1,000,000 
trial simulations, a sample size of 66 subjects (33 per group) will provide an overall power of 
between 95.1% and 99.0% (corresponding to correlations between test statistics of ρ = 0.90 to 
0) when the alternate primary endpoints are tested using a Hochberg closed test procedure 
with a 4% alpha level, 2-sided. 


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8.2.2 
Sample Size Re-Estimation 
A SSRE procedure is planned when primary endpoint data is available from approximately 33 of 
the planned total of 66 subjects randomized and treated for 12 weeks. This procedure will be 
conducted blind to the Sponsor by a fully independent statistical service provider. The 
conditional power (CP) will be computed for both alternate primary endpoints, BWAT CUA and 
Pain VAS, using the methods described by Mehta and Pocock (2011). Table 10 gives the 
decision rule with regards to continuation of the study with or without a sample size increase. 
Any increase in sample size will be capped at 50% of the planned sample size (i.e., the 
maximum total sample size will be capped at 66 + 1/2 x 66 = 99 subjects). With 100,000 trial 
simulations, this procedure was shown not to inflate the overall type I error and, hence, no 
alpha adjustment is required in the final analysis.  
 
 Table 10. Decision Rules for Sample Size Increase  
 
 
The CP computed as per Mehta and Pocock (2011) will give rise to two CP values, CP1 and CP2, 
for each of the two primary endpoints respectively; based on these CP values, Equation 9 in 
Mehta and Pocock (2011) will be used to compute the corresponding post-interim sample sizes, 
𝑛𝑛෤1 and 𝑛𝑛෤2, required to deliver the cross tabulated power as displayed in Table 10. This, in turn, 
will give two new sample size totals for the study, 𝑁𝑁1 and 𝑁𝑁2, relating to the two primary 
endpoints. The larger of 𝑁𝑁1 and 𝑁𝑁2 will be taken as the revised sample size for the study subject 
to a maximal increase of 99 subjects (i.e., at most a 50% increase over the planned sample size 
of N=66 subjects). The final analysis will then combine the pre- and post-interim z-values for 
each of the two primary endpoints using NOT the approach suggested by Mehta and Pocock 
2011 but rather the approach defined by Cui et al (1999) which guarantees no alpha inflation 
regardless of how the post-interim sample sizes (i.e., 𝑛𝑛෤1 and 𝑛𝑛෤2) are determined.  
 
The independent statistical service provider will provide the conditional power and sample size 
computations to the independent DSMB only. The DSMB will review these results and the 


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associated decision rule from Table 10 and provide only the sample size recommendation to 
the Sponsor. The Sponsor will not receive the conditional power assessments. 
 
Finally, the Sponsor retains full discretion with regards to the outcome of the sample size re-
estimation procedure and may decide to continue the trial with the sample size increased as 
described above or unchanged. 
8.3 
ANALYSIS POPULATIONS 
The following analysis populations will be defined: Safety, modified Intent-to-Treat (mITT), Per 
Protocol (PP), PK, and PD. 
The Safety population will consist of all randomized subjects who receive at least one dose of 
study drug. Subjects will be analyzed according to the treatment they received. The Safety 
analysis population will be used for analyses of safety endpoints. 
The mITT population will consist of all enrolled subjects who are randomized, receive at least 
one dose of study drug, and have at least one post-randomization efficacy evaluation. Subjects 
will be analyzed according to the treatment to which they were randomized. Consistent with 
ICH E9, the mITT population will be the primary analysis population for efficacy endpoints.  
The PP population will be the subset of subjects in the mITT population who do not have major 
protocol violations, have evaluable primary efficacy data, and have received a pre-specified 
minimum study drug exposure. The PP population will be used for supportive analyses of 
efficacy endpoints. Additional details will be outlined in the Statistical Analysis Plan. 
The PK population will consist of all subjects who are randomized and receive at least one dose 
of study drug and for whom the primary PK parameter (Cmax) can be calculated. 
The PD population will consist of all subjects who are randomized and receive at least one dose 
of study drug and for whom both pre-dose and EOI HAP crystallization inhibition can be 
calculated for at least one timepoint. 
8.4 
SUBGROUPS, COVARIATES, AND STRATA 
The primary and secondary efficacy endpoint analyses will be stratified by STS use at 
randomization. For endpoints measuring change from baseline, baseline values of the efficacy 
variable will be included in statistical models as covariates. The following subgroups may be 
explored for the primary and secondary endpoints: age, sex, race, region, and major comorbid 
conditions (e.g., diabetes mellitus, peripheral vascular disease). 
8.5 
GENERAL STATISTICAL CONSIDERATIONS 
Efficacy, PK, PD, biomarker, and safety data will be summarized descriptively using mean, 
median, SD, standard error (SE), first quartile (Q1), third quartile (Q3), minimum, and maximum 
values for continuous variables and using counts (n) and percentages for categorical variables. 
Unless specified otherwise, all baseline assessments will be based upon the Week 1, Day 1 pre-
dose assessment. 


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8.6 
EFFICACY ANALYSES 
The mITT population will be the primary analysis population for all primary, secondary and 
exploratory efficacy endpoint analyses. Unless otherwise indicated “baseline” refers to the 
assessment on Week 1, Day 1. 
8.6.1 
Primary Efficacy Endpoint Analysis 
The comparison of absolute change from baseline to Week 12 in BWAT-CUA score between 
treatment groups will be achieved using a mixed model repeated measures (MMRM) analysis 
to estimate the difference between randomized treatment group least squares means 
(LS means) at 12 weeks. The model will include fixed effect terms for randomized treatment, 
visit, and visit by randomized treatment interaction; the model will also be stratified for STS use 
at randomization and baseline BWAT-CUA score and will be included as covariates. Subject will 
be fitted as a random effect and an unstructured variance-covariance matrix will be used. 
The comparison of absolute change from baseline to Week 12 in the Pain VAS score will be 
analyzed using an MMRM analysis similar to that for the change in BWAT-CUA score with 
covariates for baseline Pain VAS score and stratified for STS use at randomization. 
The MMRM analysis assumes any missing data are missing at random; therefore, sensitivity 
analyses under the assumption of missing not at random will be used to assess the robustness 
of the primary MMRM analysis. These sensitivity analyses will include (i) jump to reference 
multiple imputation (MI) which assumes that subjects with monotone missingness in the 
experimental treatment arm follow the same distribution as observations from subjects in the 
control arm and (ii) a tipping point analysis to identify whether the penalty, if applied to 
subjects with missing data in the experimental treatment arm, would result in the loss of 
statistical significance of the primary analysis (Ouyang et al, 2017). 
8.6.2 
Secondary Efficacy Endpoint Analyses 
The secondary endpoints will be evaluated hierarchically in the following order: 
1. Absolute change from baseline to Week 12 in the Wound-QoL score 
2. Absolute change from baseline to Week 12 wound healing assessed by the BWAT total 
score 
3. Qualitative wound image evaluation for the primary lesion (worsened, equal to, or 
improved relative to baseline) at Week 12 
4. Rate of change in opioid use as measured in MME from baseline to Week 12 
The first secondary efficacy endpoint of the absolute change from baseline to Week 12 in 
Wound-QoL score will be analyzed using an MMRM analysis similar to that for the alternate 
primary efficacy endpoints with covariates for baseline Wound-QoL score and stratified for STS 
use at randomization. 
The second secondary efficacy endpoint of the absolute change from baseline to Week 12 
wound healing assessed by the BWAT total score will be analyzed with MMRM in the same 
fashion with baseline BWAT total score as a covariate and stratified by STS use at 
randomization.  


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The third secondary efficacy endpoint will be analyzed using generalized estimating equations 
with the primary result displayed in terms of the Week 12 odds ratio for SNF472 vs placebo 
along with the associated 95% CI and 2-sided p-value.  
For the fourth secondary endpoint, the daily average opioid dose in MME will be calculated for 
all subjects prior to randomization and post-randomization on a weekly basis. The maintenance 
opioid dose will be defined as the average daily opioid dose in MME during the week prior to 
Screening Visit 2. To assess the extent to which opioid use may have differed between 
randomized treatment arms over time, the change from baseline in daily average MME value 
will be analyzed via a mixed model random coefficients analysis. MME data collected between 
Week 1 and Week 12 will be the dependent variable with random subject effects for intercepts 
and slopes. Fixed effects for randomized treatment, baseline MME value, week, and 
randomized treatment-by-week interaction will be included and an unstructured covariance 
matrix assumed to estimate the rate of change of opioid use over time for both SNF472 and 
placebo and assess whether the rate of use differs between randomized treatments. The 
treatment effect will therefore be the contrast between SNF472 and placebo slope estimates 
over 1 to 12 weeks. The associated slope estimates, difference in slopes, CI, and two-sided p-
value will be extracted from the model and presented. 
For each of the secondary endpoints, sensitivity analyses to explore the influence of missing 
data will be performed using multiple imputation and tipping point analyses. 
8.6.3 
Overall Type I Error Control 
With two alternate primary endpoints assessed using a closed test procedure followed by 
secondary endpoints tested hierarchically (if at least one of the alternate primary endpoints is 
statistically positive), there is no scope for Type I error inflation if SNF472 is fully in the null, i.e., 
is identical to placebo treatment. However, if it is assumed that SNF472 is simultaneously a 
placebo for one alternate endpoint yet is a highly effective treatment for the second, the 
overall Type I error rate can be inflated when testing is extended to the secondary endpoints. 
To prevent any overall Type I error inflation the alternate primary endpoints will be assessed 
using a Hochberg procedure with a 2-sided alpha level of 4%. If both alternate primary 
endpoints are met, the alpha apportioned will be recycled so that the secondary endpoints will 
be assessed at the 5% alpha level, 2-sided. If only one of the alternate primary endpoints is met, 
the secondary endpoints will be assessed at the 1% alpha level, 2-sided.  
8.6.4 
Exploratory Efficacy Endpoint Analyses 
Briefly, mean changes over time will be assessed using MMRM modelling, binary response 
endpoints will be assessed using generalized linear mixed effect modelling, and time-to-event 
endpoints will be assessed using Kaplan-Meier analysis. Given these analyses are exploratory, 
they will not be subject to Type I error control, nominal p-values will be presented and 
interpreted accordingly. 


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8.7 
PHARMACODYNAMICS ANALYSES 
At Weeks 1, 12, 13, and 24 the level of HAP crystal formation in EOI samples will be compared 
to the level of HAP crystal formation in the pre-dose sample and will be reported as a percent 
(%) inhibition of crystallization. 
Percent inhibition of HAP crystallization between pre-dose and EOI at Weeks 1, 12, 13, and 24, 
will be analyzed using descriptive statistics. 
8.8 
PHARMACOKINETICS ANALYSES 
The PK endpoint, SNF472 plasma concentrations pre-dose and EOI at Weeks 1, 12, 13, and 24, 
will be analyzed using descriptive statistics. Accumulation effects will be assessed by comparing 
the individual and mean EOI plasma concentrations between Weeks 1, 12, 13, and 24. 
8.9 
SAFETY ANALYSES 
Safety endpoints will be analyzed descriptively using the Safety population. The primary 
analysis of safety endpoints will use the period from the first dose of study drug until 30 days 
after the last dose of study drug. 
8.9.1 
Adverse Events 
All reported terms (Investigator descriptions) for AEs will be coded using the most recent 
version of the Medical Dictionary for Regulatory Activities (MedDRA). All treatment-emergent 
AEs will be summarized using counts and percentages by treatment group, study period (Part 1, 
Part 2, and follow-up), system organ class (SOC) classification, and preferred term. Additionally, 
treatment-emergent AEs in the following categories will be summarized: AEs leading to death, 
SAEs, AEs leading to discontinuation from the study, treatment-related AEs, AEs by Common 
Terminology Criteria for Adverse Events (CTCAE) severity grade, and CUA wound-related AEs. 
For all AE summaries, events will be counted only once for each subject by primary SOC and 
preferred term. When an AE occurs more than once for a subject, the maximum severity and 
causality will be used. 
8.9.2 
Hemodialysis-Related Events 
HD-related events will be summarized using counts and percentages by treatment group, study 
period (Part 1, Part 2, and follow-up). 
8.9.3 
Clinical Laboratory Evaluation 
Laboratory assessments and change from baseline will be summarized using descriptive 
statistics by panel, test, treatment group, and time point. Additionally, abnormal results will be 
summarized using counts and percentages by laboratory grade, panel, test, treatment group, 
and time point. 


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8.9.4 
Holter Monitoring and Electrocardiograms 
Holter data will be analyzed centrally by extracting triplicate ECGs from the recordings at each 
of the following 3 timepoints: pre-dose, EOI, and end of dialysis. The central reader will be 
blinded to the treatment assignment for Part 1 for the duration of the study, including Part 2 
and follow-up until the study database is locked. 
The results from the central reader assessment of ECGs extracted from the Holter as well as the 
results of the Holter will be used in the analyses. The following intervals will be summarized 
using counts and percentages by treatment group and time point: PR, QRS, RR, HR, uncorrected 
QT, QTcB, and QTcF. Details of additional analyses will be provided in the SAP. 
8.9.5 
Vital Signs 
The change from baseline of vital signs (heart rate, systolic and diastolic blood pressures, 
respiratory rate, and body temperature) and body weight will be summarized with descriptive 
statistics by treatment group and time point. 
8.9.6 
CUA Wound Care  
Wound care received for CUA lesions will be listed by subject. 
8.9.7 
Physical Examination Findings 
Physical examination findings will be listed by subject. 
 
9 
DATA MANAGEMENT, MONITORING AND AUDITS 
9.1 
STUDY MONITORING 
The Sponsor will be responsible for monitoring the study according to ICH GCP, although the 
actual monitoring visits may be conducted by a CRO in accordance with Sponsor requirements, 
as specified in the Monitoring Plan. Both central and on-site monitoring will be conducted. 
Central monitoring will include data review by the monitor via the EDC off-site, with a focus on 
incomplete fields and fields in which potential errors could exist, based on the monitor’s 
understanding of the data specification. 
On site, the monitor will review the eCRF data entry against the source documents. Handling of 
queries and clarification/reconciliation of queries between the monitor and the site will be 
described in the Data Management Plan (DMP). 
9.2 
DATA CAPTURE AND VERIFICATION 
Data capture and management will be conducted using multiple electronic systems (e.g., RTSM, 
ePRO, imaging software, and EDC). All systems will be compliant with the Health Insurance 
Portability and Accountability Act (HIPAA), meet all requirements for 21 Code of Federal 
Regulations Part 11 and Annex 11 of EUDRALEX Rules Governing Medicinal Product in the 


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European Union, Volume 4, Good Manufacturing Practice. The processes and responsibilities of 
data collection, management, and quality assurance will be specified in the DMP. 
All applicable study data collected for each subject will be entered into the designated 
system(s) by trained study personnel according to the completion expectations. This training 
will be available on demand for refresher training. Study visit assessment data (e.g., vital signs, 
physical exam, ECG, Pain VAS, Wound-QoL, and BWAT) are expected to be entered directly into 
the designated system(s) at the time of the subject visit or when the assessment is performed 
(e.g., central wound rating group qualitative image review). Data already located in the 
subject’s medical chart (medical history, medications, laboratory results) or data collected by 
study personnel untrained on the use of the EDC may be transcribed into the eCRF. Source 
documents, such as the clinic chart, are to be maintained separately from the eCRF to allow 
data verification. Because of the potential for errors, inaccuracies, and illegibility in transcribing 
data into eCRFs, original documentation of transcribed study data must be maintained at the 
site. 
Authorized personnel will verify data entered into eCRFs for completeness and accuracy with 
reference to the source documents and records and will issue data queries to correct missing 
data or discrepancies found against the source within the EDC system. Data validation will 
consist of automated and manual edit checks that are created directly in the EDC system. Edit 
checks will be executed on all data points defined and documented by the study team and data 
management will be able to issue manual queries as needed to the eCRF. Study metrics will be 
reported from the EDC system. 
Only authorized site personnel will be able to enter/modify/correct data in the eCRF. Once all 
data have been verified by the Sponsor or designee, the Investigator must electronically sign 
the eCRF; this responsibility may not be delegated to other study personnel. 
Non-transcribed data entered into an applicable system will be validated with automated edit 
checks at the time of entry. Data entered into systems other than EDC require an authorized 
electronic signature at the time of record save and do not require verification. 
9.3 
ON-SITE AUDITS 
During the course of the study and/or after study completion, one or more study sites may be 
audited by authorized representatives of the Sponsor. The purpose of the audit is to determine 
whether or not the study is being conducted and monitored in compliance with ICH GCP and 
relevant local regulations. 
Additionally, the study may be inspected by the IRB/IEC or regulatory authorities. These 
inspections may take place at any time during or after completion of the study and are based 
on local regulations. 
 


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10 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
10.1 GOOD CLINICAL PRACTICE 
The procedures set out in this protocol are designed to ensure that the Sponsor and the 
Investigator abide by the principles of ICH GCP and the Declaration of Helsinki and applicable 
amendments. The study will also be conducted in accordance with applicable regional, national, 
and local regulatory and legal requirements. 
10.2 INFORMED CONSENT 
All subjects will be required to participate in the consent process. During the consent process, 
Investigator or designee obtaining consent will inform the subject of all elements of informed 
consent. No protocol-specific procedures, including screening procedures, will be performed 
until the subject has signed and dated an IRB/IEC-approved ICF. Study participation will start 
with the signing and dating of the ICF. A copy of the ICF will be provided to the subject for their 
records, and the original signed and dated ICF will be maintained in the source documentation 
files at the study site. 
The Investigator must ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, and possible risks and benefits of the study. Subjects 
must also be notified that participation in the study is voluntary and that they are free to 
withdraw from the study at any time without prejudice to future care. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.  
In case of protocol amendment, the patient information leaflet (PIL)/subject information sheet 
and ICF may need to be revised to reflect the changes. If the PIL/subject information sheet and 
ICF are revised, they must be reviewed and approved by the responsible IRB/IEC and signed by 
all subjects subsequently enrolled in the study as well as those currently enrolled in the study. 
10.3 SUBJECT CONFIDENTIALITY AND DISCLOSURE 
All study findings and documents will be regarded as confidential. The Investigator and 
members of his research team must not disclose such information without prior written 
approval from the Sponsor. 
The Investigator must anonymize the data of the participating subjects. In this regard, the Sites 
and the Investigators shall be the unique parties with access to the personal data of the 
participating subjects. As a consequence, from a data protection approach, the Investigator 
and/or the Site acts as Data Controller of the personal data of the participating subjects and 
shall comply with all of its obligations under the General Data Protection Regulation, including 
obtaining the informed consent of the data subjects. The Investigator shall ensure that the data 
has been anonymized in accordance with the General Data Protection Regulation. The Sites and 
the Investigator shall also be responsible to comply with “HIPAA Privacy Rule” (which means 
the privacy rule issued under Health Insurance Portability and Accountability Act of 1996 and 
codified at 45 C.F.R. Parts 160 and 164). 


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The anonymity of participating subjects must be maintained. All subject data will be identified 
only by a subject ID number. Subject names and addresses must be maintained in a separate 
log. Documents that identify the subject (e.g., ICF) must be maintained in confidence by the 
Investigator.  
However, in compliance with regulatory guidelines regarding the monitoring of clinical studies 
and in fulfilment of his/her obligations to the Sponsor, the Investigator must allow the study 
monitor, Sponsor representative or auditor, and/or IRB/IEC and relevant regulatory authority 
representatives access to the portion of the subject’s medical record that is directly related to 
the study. The data to which the Sponsor representative or auditor would have access in this 
case will be anonymized at all times. Such information shall include all study-relevant 
documentation, including medical history to verify eligibility, admission/discharge summaries 
for hospital stays occurring while the subject is enrolled in the study, and autopsy reports if a 
death occurs during the study. 
The anonymized data received by Sponsor may be subject to international transfers. 
 
10.4 INDEPENDENT ETHICS COMMITTEE/ INSTITUTIONAL REVIEW BOARD 
APPROVALS AND NOTIFICATIONS 
Before the start of the study, the protocol and other relevant documents will be approved by 
the IRB/IEC and relevant regulatory authorities in accordance with local regulatory 
requirements. The Sponsor must ensure that all ethical and legal requirements have been met 
before the first subject is enrolled in the study. The Investigator must conduct the study in 
compliance with the protocol. 
Alterations to the protocol by the Sponsor will be documented in the form of a protocol 
amendment. Administrative changes may be made by the Sponsor without the need for a 
formal protocol amendment. All protocol amendments and administrative changes will be 
distributed by the Sponsor to all protocol recipients, with appropriate instructions. 
The protocol amendments must be approved by the IRB/IEC and relevant regulatory authority 
prior to implementation (as appropriate) unless immediate implementation of the amendment 
is needed to eliminate a hazard to a subject or subjects.  
During the course of the study, the Investigator should promptly inform the IRB/IEC of the 
following: 
• Deviations from, or changes of, the protocol to eliminate immediate hazards to the study 
subjects 
• Changes increasing the risk to subjects and/or affecting significantly the conduct of the study 
• All adverse drug reactions that are both serious and unexpected 
• New information that may affect adversely the safety of the subjects or the conduct of the 
study 


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• Study suspension or closure (Section 10.5) 
If a safety issue of clinical relevance is identified, from review of any data, then the Sponsor will 
promptly notify the Investigator and relevant regulatory authorities, and the Investigator must 
inform the IRB/IEC of the safety issue as soon as possible after notification. 
A safety issue of clinical relevance is one that has a relevant impact on the course of the study 
or program (including the potential for suspension of the study, program, or amendments to 
the protocol) or warrants immediate update of the PIL and ICF. 
10.5 STUDY CLOSURE 
The study may be temporarily suspended or prematurely terminated by the Sponsor at any 
time for any reason. Reasons for suspension or termination of the study may include, but are 
not limited to, determination of unacceptable risk to subject safety, noncompliance or 
insufficient data, or early determination of efficacy or futility. Written notification, documenting 
the reason for suspension/termination, will be provided to the Investigators and relevant 
regulatory authorities. 
The Investigator must promptly notify the subjects and IRB/IEC of study completion or 
suspension/ET. In the event of suspension/ET, the notification should include the reason for the 
change in study status, and subjects must be contacted regarding any applicable changes to the 
study visit schedule. 
The Investigator must submit eCRFs and all other relevant data and records to the Sponsor as 
soon as possible after the completion or ET of the study. 
10.6 RECORD RETENTION 
According to ICH GCP, essential documents should be retained for a minimum of 2 years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study drug. However, these documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. The Sponsor will inform the Investigator when these 
documents no longer need to be retained. 
 
11 STEERING COMMITTEE 
A trial steering committee composed of academic nephrology, wound care and surgical experts, 
and dialysis care experts participated in the development of the protocol and will provide 
advice and guidance in the conduct and interpretation of the study and the 
presentation/publication of its results. 
 


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12 STUDY REPORT AND PUBLICATION POLICY 
The aggregate results of the study will be documented by the Sponsor in the clinical study 
report for the purposes of regulatory submission. 
By signing the protocol, the Investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical 
and pharmaceutical professionals. As appropriate, the regulatory authorities will be notified of 
the Investigator’s name, address, qualifications, and extent of involvement. 
An Investigator shall not publish, or present for publication any articles or papers, or make any 
presentations, nor assist any other person in publishing any articles or papers, or making any 
presentations, or making any public declaration relating or referring to the study, the results of 
the study, in whole or in part, without the prior written consent of the Sponsor. 


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Grases F, Sanchis P, Prieto RM, Perelló J, López-González ÁA. Effect of tetracalcium 
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Grases F, March JG, Prieto RM, Simonet BM, Costa-Bauzá A, García-Raja A, et al. Urinary 
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Gupta A, Taly AB, Srivastava A, Kumar S, Thyloth M. Efficacy of pulsed electromagnetic field 
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Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for 
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Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, et al. Phosphate regulation of 
vascular smooth muscle cell calcification. Circ Res. 2000;87:e10-e17. 
Katz J, Melzack R. Measurement of pain. Surg Clin North Am. 1999;79(2):231-252. 
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Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan MJ, Davis CL, et al. Risk factors and 
mortality associated with calciphylaxis in end-stage renal disease. Kidney Int. 2001;60:324-332. 
McCarthy JT et al. Survival, risk factors, and effect of treatment in 101 patients with 
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Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med. 2011 Dec 10;30(28):3267-84. 
Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E. Sodium thiosulfate therapy 
for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8(7):1162-70. 
Nigwekar SU, Zhao S, Wenger J, Hymes JL, Maddux FW, et al A nationally representative study 
of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol 27: 3421–3429, 2016. 
Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378:1704-1714. 
Nunley JR. Calciphylaxis. 2017. Available from: 
https://emedicine.medscape.com/article/1095481-overview [Accessed 12 November 2017]. 
Obialo CI and Quarshi A. Calcific uremic arteriolopathy: mortality outcomes with and without 
sodium thiosulfate therapy. J Nephrol Renal Disease 2017; 1:1. 
O'Neill WC, Sodium thiosulfate: mythical treatment for a mysterious disease? Clin J Am Soc 
Nephrol. 2013;8(7):1068-9.  
Ouyang J, Carroll KJ, Koch G, Li J. Coping with missing data in pivotal phase III registration trials: 
Tolvaptan in subjects with kidney disease, a case study. Pharma Stats. 2017;16:250-266. 
Peng T, Zhuo L, Wang Y, Jun M, Li G, Wang L, Hong D. Systematic review of sodium thiosulfate 
in treating calciphylaxis in chronic kidney disease patients. Nephrology (Carlton). 
2018;23(7):669-675.  
Perelló J, Isern B, Muñoz JA, Valiente M, Grases F. Determination of phytate in urine by high 
performance liquid chromatography – mass spectrometry. Chromat. 2004;60:265-268. 
Podymow T, Wherrett C, Burns KD. Hyperbaric oxygen in the treatment of calciphylaxis: a case 
series. Nephrol Dial Transplant. 2001;16(11):2176-2180. 
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Robinson MR, Augustine JJ, Korman NJ. Cinacalcet for the treatment of calciphylaxis. Arch 
Dermatol. 2007;143(2):152-154. 
Schlieper G, Brandenburg V, Ketteler M, Floege J. Sodium thiosulfate in the treatment of calcific 
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Management of Calciphylaxis. QJM. 2019; 112(1):29-34. 
Sinha S, Gould L, Brandenburg V, Chertow GM, Miller S, Garg R, Gold A, and Perelló J. 
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Swanson T. Assessment – Pain in Wound Management for the Advanced Practitioner. Swanson 
T, Asimus M, McGuiness B, eds. 2014;IP communications, Melbourne Australia: p.76-81. 
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Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk 
factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569-579. 
Windhorst S, Lin H, Blechner C, Fanick W, Brandt L, Brehm MA, et al. Tumour cells can employ 
extracellular Ins(1,2,3,4,5,6)P(6) and multiple inositol-polyphosphate phosphatase 1 (MINPP1) 
dephosphorylation to improve their proliferation. Biochem J. 2013;450(1):115-125. 
Yang H, Curinga G, Giachelli CM. Elevated extracellular calcium levels induce smooth muscle cell 
matrix mineralization in vitro. Kidney Int. 2004;66:2293–2299. 


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APPENDIX 1. BATES-JENSEN WOUND ASSESSMENT TOOL (BWAT) 
Sample paper collection form showing BWAT scoring. In this study, sites will be trained to score 
undermining, peripheral tissue edema, and peripheral tissue induration. A central wound rating 
group will rate the remaining BWAT items based upon review of the images (photos and videos) 
obtained by the site. Rating of the size item will be aided by automated measurements from 
the imaging software.  
 




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APPENDIX 2. Wound-QoL Questionnaire 
 


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APPENDIX 3. PROTOCOL AMENDMENT 1 - SUMMARY OF CHANGES 
 
1) Revision of screening to a 2-step process (Screening Visit 1 and Screening Visit 2). CUA 
lesions will be evaluated at Screening Visit 2 to determine if there was significant healing 
since Screening Visit 1. Pain medications will be stabilized during the screening period. 
Holter monitoring and ECG will be conducted during Screening Visit 2. Subjects will be 
randomized at Screening Visit 2. SYNOPSIS, Table 1, Sections 3.1, 4.3, 5.1  
2) Addition of Exclusion Criterion 15 specifying that subjects with significant improvement in 
their lesions between the first and second screening visit will be excluded. SYNOPSIS, 
Section 3.4.2 
3) Addition of a pain medication diary in which subjects should record on a daily basis all 
pain medications taken. Site staff will review the diary with subjects at least weekly and 
record actual pain medications used in the eCRF. Average daily morphine milligram 
equivalents (MME) will be calculated centrally based on the information entered in the 
eCRF. SYNOPSIS, Table 1, Table 2, Sections 4.7.3.1, 4.7.3.2, 5.6.4 
4) Revision of Inclusion Criterion 4 to increase the minimum score to 50 out of 100. 
SYNOPSIS, Section 3.4.1 
5) Specification that the sites will be responsible for rating 3 BWAT components: 
undermining, peripheral tissue induration, and peripheral tissue edema. An expert central 
wound rating group will review the site’s ratings and rate the remaining BWAT items 
based on review of the wound images (photos and video), aided by automated 
measurements from the imaging software for the wound size assessment. SYNOPSIS, 
Section 5.6.1.1 
6) Addition of an external independent Data and Safety Monitoring Board. SYNOPSIS, 
Section 6.4 
7) Addition of a secondary endpoint to assess the rate of change in opioid use from baseline 
to Week 12 as measured in MME. SYNOPSIS, Sections 8.1.1, 8.6.2 
8) Addition of an exploratory endpoint to assess absolute change from baseline to Week 12 
in opioid use as measured in MME. SYNOPSIS, Sections 8.1.1, 8.6.4 
9) Processes for discontinuation from study drug and withdrawal from further follow-up are 
more clearly differentiated. Subjects who discontinue study drug early during Part 1 or 
Part 2 will be asked to complete study assessments throughout the respective part of the 
study (Part 1 or Part 2) and complete a follow-up visit. Subjects who discontinue study 
drug and are unwilling to complete the remaining study assessments will be encouraged 
to return for an early termination visit 4 weeks after the last dose of study drug. 
SYNOPSIS, Table 1, Table 2, Sections 3.1, 5.4, 7 


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10) Specification that the Pain VAS will be in reference to the subject’s worst wound-related 
pain during the previous 24 hours. SYNOPSIS, Section 5.6.2 
11) Specification that local ECGs will be obtained using the ECG instrument that will be 
supplied with the Holter monitor. Clarification of the recording window and timepoints for 
screening and dosing days. Table 1, Table 2, Section 5.8.5 
12) Specification that ionized calcium samples must be shipped on day of collection under 
ambient conditions. Table 1, Table 2, Section 5.8.6 
13) Specification that dialysis parameters to be collected include calcium concentration in the 
dialysate, dialysis frequency and duration, and Kt/V or URR. Estimated Kt/V or URR from 
the dialysis machine or calculated values using local lab measurements may be collected 
but the same measure and same data source must be used throughout the study. Table 1, 
Table 2, Section 4.7.3.4 
14) Clarification of the distinction between hemodialysis-related events and adverse events. 
Table 1, Table 2, Section 8.9.2 
15) Specification that blinding to the treatment assignment for Part 1 will be maintained for 
the duration of the study including Part 2 and follow-up until the study database is locked. 
This applies to the Investigator, site staff, subjects, central wound rating group, central 
Holter/ECG readers, and Sponsor staff (including designees) involved in the conduct of the 
study and data management. Sections 4.4.1, 5.6.1.2, 8.9.4 
16) Clarification that background care for CUA includes wound care, dialysis parameters 
(calcium concentration in the dialysate, dialysis frequency and duration), pain 
medications, and other concomitant medications relevant to the management of CUA. 
Section 4.7.3 
17) The processes for stabilizing pain medications during screening and maintenance of pain 
management during the trial are provided. Sections 4.7.3.1, 4.7.3.2 
18) The types of wound care to be collected are provided. Section 4.7.3.3 
19) The order of assessments is clarified. Section 5.5 
20) Additional details on the sample size re-estimation are provided. Section 8.2.2 
21) Details on how missing data will be handled under the assumption of missing not at 
random. Section 8.6.1 
22) Additional minor formatting and clarifications throughout. 
 
 


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APPENDIX 4. PROTOCOL AMENDMENT 2 - SUMMARY OF CHANGES  
1) Protocol Agreement Page: Administrative update to the Sponsor signatory. 
2) SYNOPSIS and Section 3.4 Study Population: Increased the number of study sites to 
“approximately 60”. 
3) SYNOPSIS and Section 5.6.1 Wound Evaluation: 
a. Added the specification that the central reviewers will be unaware of the order 
of the visits when completing BWAT ratings and qualitative review.  
b. Central BWAT raters will perform a quality review of the site’s ratings. 
c. Qualitative review of wound healing will be conducted only for the primary 
lesion. 
4) SYNOPSIS and Section 8.1.1 Efficacy Endpoints: Added the Wound-QoL subscales to the 
exploratory endpoints. 
5) Table 1. Schedule of Events for Part 1. Footnote 14: Added the specification that the 
sample for the serum pregnancy test must be drawn within 7 days prior to the first dose 
of study drug. 
6) Table 1. Schedule of Events for Part 1 and Section 5.1 Screening Period: Clarified that 
randomization may occur up to one week prior to Week 1 Day 1 rather than on Week 1 
Day 1. 
7) Table 1. Schedule of Events for Part 1: Removed “pre-dose and EOI” from the ECG row 
because there is no study drug dose during screening. Timing of the local ECGs is 
specified in footnote 10. Removed ECG assessment at Week 6. 
8) Table 1. Schedule of Events for Part 1 Footnote 10 and Table 2. Schedule of Events for 
Part 2 and Follow-Up Footnote 8, and Section 5.8.5 Holter Monitoring and 
Electrocardiograms: Adjusted the collection window for the EOI local ECG to within 20 
minutes prior to EOI. 
9) Table 1. Schedule of Events for Part 1 and Table 2. Schedule of Events for Part 2 and 
Follow-Up and Section 5.5 Order of Assessments and Section 5.8.5 Holter Monitoring 
and Electrocardiograms: Specified that the Holter monitor will be placed on the subject 
30 min prior to the beginning of dialysis and that the recording window will be from that 
time until the end of dialysis.  
10) Table 1. Schedule of Events for Part 1: Removed indicator in the table for New CUA 
Lesion Assessment at Week 1 Day 1 because a new lesion is defined as one that has 
occurred since Week 1 Day 1 (as defined in Section 5.6.1.3). 


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11) Table 1. Schedule of Events for Part 1 Footnotes 11 and 19 and Table 2. Schedule of 
Events for Part 2 and Follow-Up Footnotes 9, 17, and 18 and Section 5.7 PK, PD, and 
Biomarkers and Section 5.8.6 Laboratory Evaluations: Adjusted the collection window 
for the EOI samples to within 20 minutes prior to EOI. 
12) Section 1.1.1 Calciphylaxis: Updated description of typical lesion locations to “Lesions 
most commonly appear in the lower extremities and in the trunk, particularly in the 
abdomen. Less commonly reported locations include the arms, hands and fingers, 
buttock/hip, chest, and genitals.” 
13) Section 1.4 Clinical Experience: Added relevant results from completed Study 
SNFCT2015-05. 
14) Section 1.6 Risk-Benefit Assessment: New section summarizing risk-benefit assessment. 
15) Section 3.1 Study Design Overview: Added definitions of subject study completion and 
end of study. 
16) Section 3.2 Discussion of Study Design: Clarified the CUA diagnosis will be made by the 
Investigator with confirmation from the central wound rating group based on review of 
images of the primary lesion. Biopsy results will not be collected. 
17) Section 4.4.2 Unblinding: Removed the requirement that the Investigator consult with 
the Medical Monitor prior to unblinding and removed the requirement for a subject to 
be discontinued from study drug if the subject’s treatment is unblinded.  
18) Figure 2. Method of Study Drug Administration: Replaced figure with an improved 
schematic. Note, there are no changes in the method of study drug administration. 
19) Section 4.7.3.1 Stabilizing Pain Medications: Added that subjects should be instructed to 
bring the pain medication diary with them to the site at each visit. 
20) Section 4.7.4.2 Contraception Requirements: 
a. Added the specification that abstinence is acceptable only as defined as true 
abstinence in line with the preferred and usual lifestyle of the subject.  
b. Further clarified what methods of contraception are not acceptable.  
c. Specified that male subjects should adhere to the contraception requirements 
from screening through 30 days after the last dose of study drug. 
21) Section 5.1. Screening Period: Due to visit scheduling, a subject’s Week 1 Day 1 visit may 
occur up to 7 days after randomization. Added the specification that the Medical 
Monitor should be consulted if the Investigator observes changes to the primary lesion 
(e.g., significant improvement from screening) or changes to the subject’s clinical 


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condition which may make the subject ineligible during the time between 
randomization and Week 1 Day 1. 
22) Table 4. Holter Instructions and Timing: New table with additional instructions added for 
clarity. 
23) Table 5. Local ECG Tracing Collection Timepoints: New table with additional instructions 
added for clarity. 
24) Section 7.1 Discontinuation of Study Drug and Section 7.2 Withdrawal of Subject from 
the Study: Added the specification that a subject should be discontinued from study 
drug if they experience a CTCAE Grade 4 adverse event that is considered by the 
Investigator to be related to the study drug and not due to comorbidities or the disease.  
 
25) Section 13 References: Section updated. 
26) Appendix 3: The summary of changes from the previous version of the protocol 
(Amendment 1) has been moved to an appendix. 
27) Minor changes for clarity and revisions of amendment number and date throughout. 
 

SAP_001.pdf: 


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SAP Version 1.3  Summary of Changes from Version 1.2 
Section 6.3 Retests, Unscheduled Visits and Early Termination Data 
Description of handling of unscheduled measurements had been inadvertently omitted and has 
been added. Unscheduled measurements will be assigned to the nearest scheduled visit. If a 
measurement does not fall into a specified visit window, then that measure will be listed only 
and will be excluded from data summaries and analyses. 
 
Section 6.6 Multiple Wound Images 
This new section describes determination of BWAT score, wound area, and qualitative review 
when greater than one photo was required to image a wound. 
 
Section 9 Disposition and Withdrawals 
An incomplete sentence has been corrected. 
 
Section 15.1.2. Primary Analysis of Primary Efficacy Variables 
 An error has been corrected in the description of the MMRM model for the Pain VAS 
alternate primary endpoint. The inclusion of pain medication use at each time point was 
stated in error and has been deleted. 
 An error has been corrected for the confidence level for Pain VAS difference in LS 
means. 
 
 


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SAP Version 1.2  Summary of Changes from Version 1.1 
1) Section 7.4 Multiple Comparisons/ Multiplicity. The formulas to compute the final 
analysis z values were corrected to properly reflect that the square root of the weights 
should be used. 


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 SAP Version 1.1  Summary of Changes from Version 1.0  
1) Section 6.2 Baseline. Additional details are provided on handling of missing baseline 
values. Unless otherwise specified, if the assessment is missing, the last pre-dose 
assessment will be assigned as baseline. For Pain VAS, missing baseline data will be 
imputed with the lowe
last pre-dose Pain VAS value 
OR the mean baseline Pain VAS value among subjects in the same treatment arm. 
2) Section 15.1.2 Primary Analysis of Primary Efficacy Variables. An error has been 
corrected in 
deleted from the list of fixed effect terms.  
 
3) Section 15.1.3.3 Sensitivity Analyses with Regard to Pain Medication Use Over Time. An 
error has been corrected in the description of the random coefficient MMRM model. 
 
 
4) Section 15.2.1.3 Qualitative Wound Image Evaluation for the Primary Lesion. An error 
has been corrected in the longitudinal logistic regression 
Week 1 
 
 
5) Section 15.1.3.2 Sensitivity Analyses with Regard to Missing Baseline Primary Endpoint 
Data. A sensitivity analysis has been added in which the primary analyses of BWAT and 
Pain VAS are repeated without imputation of missing baseline values. 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
1. 
INTRODUCTION ......................................................................................................12 
2. 
STUDY DESIGN .......................................................................................................12 
2.1. 
General Description ....................................................................................................12 
2.2. 
Schedule of Events .....................................................................................................12 
2.3. 
Sample Size ................................................................................................................13 
3. 
STUDY OBJECTIVES ..............................................................................................13 
3.1. 
Primary Endpoints ......................................................................................................13 
3.2. 
Secondary Endpoints ..................................................................................................13 
3.3. 
Exploratory Endpoints ................................................................................................13 
3.4. 
Safety Endpoints .........................................................................................................14 
4. 
PLANNED ANALYSES ............................................................................................16 
4.1. 
Interim Analysis for Sample Size Re-estimation (SSRE) ..........................................16 
4.2. 
Final Analysis .............................................................................................................17 
5. 
ANALYSIS POPULATIONS ....................................................................................17 
5.1. 
Enrolled Population ....................................................................................................17 
5.2. 
Randomized Population ..............................................................................................17 
5.3. 
Safety Analysis Population .........................................................................................18 
5.4. 
Modified Intent-to-Treat Population (mITT) ..............................................................18 
5.5. 
Intent-to-Treat Population (ITT) .................................................................................18 
5.6. 
Per Protocol Population (PP) ......................................................................................18 
6. 
GENERAL CONSIDERATIONS ..............................................................................18 
6.1. 
Reference Start Date and Study Day ..........................................................................18 
6.2. 
Baseline .......................................................................................................................19 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ..........................................19 
6.4. 
Statistical Tests ...........................................................................................................21 
6.5. 
Common Calculations ................................................................................................22 
6.6. 
Multiple Wound Images .............................................................................................22 
6.7. 
Software Version ........................................................................................................22 
7. 
STATISTICAL CONSIDERATIONS .......................................................................22 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .........................22 


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7.2. 
Multicenter Studies .....................................................................................................22 
7.3. 
Missing data ................................................................................................................23 
7.4. 
Multiple Comparisons/ Multiplicity ...........................................................................23 
7.5. 
Examination of Subgroups .........................................................................................23 
8. 
OUTPUT PRESENTATIONS....................................................................................24 
9. 
DISPOSITION AND WITHDRAWALS ...................................................................24 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................25 
10.1. 
Derivations ..................................................................................................................27 
11. 
PROCEDURE AND MEDICAL HISTORY .............................................................27 
12. 
MEDICATIONS .........................................................................................................27 
13. 
STUDY DRUG EXPOSURE .....................................................................................27 
13.1. 
Derivations ..................................................................................................................28 
13.2. 
Exposure .....................................................................................................................28 
14. 
STUDY DRUG COMPLIANCE ................................................................................28 
15. 
EFFICACY OUTCOMES ..........................................................................................28 
15.1. 
Primary Efficacy .........................................................................................................28 
15.1.1. 
Primary Efficacy Variables & Derivations .................................................................28 
15.1.2. 
Primary Analysis of Primary Efficacy Variables .......................................................29 
15.1.3. 
Sensitivity Analysis of Primary Efficacy Variables ...................................................30 
15.1.3.1. 
Sensitivity Analyses with Regard to Missing Primary Endpoint Data .......................30 
15.1.3.2. 
Sensitivity Analyses with Regard to Missing Baseline Primary Endpoint 
Data .............................................................................................................................32 
15.1.3.3. 
Sensitivity Analyses with Regard to Pain Medication Use Over Time ......................32 
15.2. 
Secondary Efficacy .....................................................................................................33 
15.2.1. 
Secondary Efficacy Variables, Derivations and Analysis ..........................................33 
15.2.1.1. 
Absolute Change from Baseline to Week 12 in the Wound-QoL Score ....................33 
15.2.1.2. 
Absolute Change from Baseline to Week 12 in the BWAT Total Score for 
Primary Lesion ............................................................................................................33 
15.2.1.3. 
Qualitative Wound Image Evaluation for the Primary Lesion (Worsened, 
Equal to, or Improved Relative to Baseline) at Week 12 ...........................................34 
15.2.1.4. 
Rate of Change in Opioid Use as Measured in MME from Baseline to Week 
12 ................................................................................................................................34 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variables .........................................34 


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15.3. 
Exploratory Efficacy ...................................................................................................35 
15.3.1. 
Exploratory Efficacy Variables, Derivations and Analysis ........................................35 
15.3.1.1. 
Absolute Change from Baseline to Week 12 in Wound Size for the Primary 
Lesion .........................................................................................................................35 
15.3.1.2. 
Absolute Change from Baseline to Week 12 in Each BWAT Item for the 
Primary Lesion ............................................................................................................35 
15.3.1.3. 
Absolute Change from Baseline in BWAT-CUA, BWAT Total, Pain VAS 
and Wound-QoL Score by Visit .................................................................................36 
15.3.1.4. 
Proportion of Subjects with the New CUA Lesions Between Baseline and 
Week 12 ......................................................................................................................36 
15.3.1.5. 
Absolute change from baseline to Week 12 in the Wound-QoL scores for the 
body, everyday life, and psyche .................................................................................36 
15.3.1.6. 
Absolute Change from Baseline to Week 12 in the BWAT-CUA Score for 
the Secondary and Tertiary Lesions ...........................................................................37 
15.3.1.7. 
Proportion of Subjects Requiring an Increase in Pain Medication Related to 
their CUA lesion(s) Between Baseline and Week 12 .................................................37 
15.3.1.8. 
Proportion of Subjects with a Decrease in Pain Medication Related to their 
CUA Lesion(s) Between Baseline and Week 12 ........................................................37 
15.3.1.9. 
Absolute Change from Baseline to Week 12 in Opioid Use as Measured in 
MME ...........................................................................................................................37 
15.3.1.10. Absolute Change from Baseline to Week 24 vs Week 12 in the BWAT-CUA 
Score for the Primary Lesion ......................................................................................37 
15.3.1.11. Absolute Change from Baseline to Week 24 vs Week 12 in the Pain VAS 
Score ...........................................................................................................................38 
15.3.1.12. Absolute Change from Baseline to Week 24 vs Week 12 in the Wound-QoL 
Score ...........................................................................................................................38 
15.3.1.13. Absolute Change from Baseline to Week 24 vs Week 12 in the BWAT Total 
Score for the Primary Lesion ......................................................................................38 
15.3.1.14. Qualitative Wound Image Evaluation for the Primary Lesion at Week 24 vs 
Week 12 (Worsened, Equal to, or Improved Relative to Baseline) for the 
Primary Lesion ............................................................................................................38 
15.3.1.15. Absolute Change from Baseline to Week 24 vs Week 12 in Wound Size for 
the Primary Lesion ......................................................................................................38 
15.3.1.16. Absolute Change from Baseline to Week 24 vs Week 12 of each BWAT 
Item for the Primary Lesion ........................................................................................39 
15.3.1.17. Absolute Change from Week 24 to the Follow-up Visit in the BWAT-CUA 
Score for Primary Lesion ............................................................................................39 


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15.3.1.18. Absolute Change from Week 24 to the Follow-up Visit in the Pain VAS 
Score ...........................................................................................................................39 
15.3.2. 
Missing Data Methods for Exploratory Efficacy Variables .......................................39 
16. 
SAFETY OUTCOMES ..............................................................................................39 
16.1. 
Adverse Events ...........................................................................................................39 
16.1.1. 
All TEAEs ..................................................................................................................40 
16.1.1.1. 
Severity and Intensity .................................................................................................40 
16.1.1.2. 
Relationship to Study Drug ........................................................................................40 
16.1.2. 
TEAEs Leading to Discontinuation of Study drug .....................................................40 
16.1.3. 
Serious Adverse Events ..............................................................................................41 
16.1.4. 
Adverse Events Leading to Death ..............................................................................41 
16.1.5. 
CUA Wound-Related Adverse Events .......................................................................41 
16.1.6. 
Treatment-Related Adverse Events ............................................................................41 
16.2. 
Deaths .........................................................................................................................41 
16.3. 
Hemodialysis-Related Events .....................................................................................41 
16.4. 
Laboratory Evaluations ...............................................................................................41 
16.4.1. 
Laboratory Reference Ranges and Abnormal Criteria ...............................................42 
16.5. 
Holter Monitoring and Electrocardiograms ................................................................42 
16.5.1. 
ECG Specific Derivations ...........................................................................................43 
16.5.2. 
ECG Markedly Abnormal Criteria .............................................................................43 
16.5.3. 
Holter Arrhythmia Analysis .......................................................................................44 
16.6. 
Vital Signs ..................................................................................................................44 
16.7. 
CUA Wound Care .......................................................................................................44 
16.8. 
Physical Examination .................................................................................................44 
17. 
DIALYSIS PARAMETERS .......................................................................................45 
18. 
REFERENCES ...........................................................................................................46 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ....................................47 
IDDI OUTPUT CONVENTIONS .................................................................................................47 
1. 
ABBREVIATIONS ....................................................................................................47 
2. 
INTRODUCTION ......................................................................................................47 
3. 
OUTPUT FILE NAMING CONVENTIONS ............................................................47 
4. 
PAPER SIZE, ORIENTATION AND MARGINS ....................................................47 
5. 
TABLE AND LISTING OUTPUT CONVENTIONS ...............................................47 


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6. 
EXAMPLE .................................................................................................................49 
7. 
DATES & TIMES ......................................................................................................49 
8. 
SPELLING FORMAT ................................................................................................49 
9. 
PRESENTATION OF TREATMENT GROUPS ......................................................49 
10. 
PRESENTATION OF VISITS ...................................................................................49 
APPENDIX 2. PARTIAL DATE CONVENTIONS ..................................................................54 
APPENDIX 3. A CONTROL-BASED PATTERN-MIXTURE MODEL 
SENSITIVITY ANALYSIS .......................................................................................57 
APPENDIX 4. TIPPING POINT SENSITIVITY ANALYSIS ..................................................60 
APPENDIX 5. PATTERN MIXTURE NEIGHBORING-CASE SENSITIVITY 
ANALYSIS.................................................................................................................61 
APPENDIX 6. SENSITIVITY ANALYSES REGARDING PAIN MEDICATION 
USE 62 
 
LIST OF TABLES 
Table 1: 
Decision Rules for Sample Size Increase ...................................................................17 
Table 2: 
Visit Windows Part 1 ..................................................................................................20 
Table 3: 
Visit Windows Part 2 ..................................................................................................21 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flowchart ............................................................................................. 12 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
BWAT 
Bates-Jensen Wound Assessment Tool 
BWAT-CUA 
Bates-Jensen Wound Assessment Tool  Calcific Uremic Arteriolopathy 
CI 
confidence interval 
CP 
conditional power 
CRF 
case report form 
CRO 
contract research organization 
CUA 
calcific uremic arteriolopathy 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
EOI 
end of infusion 
GEE 
generalized estimating equation 
HD 
hemodialysis 
hs-CRP 
high-sensitivity C-reactive protein 
IDDI 
International Drug Development Institute 
Kt/V 
clearance time / volume 
LS 
least squares 
MAR 
missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
mITT 
modified intent-to-treat 
MME 
morphine milligram equivalent 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
NSAID 
nonsteroidal anti-inflammatory drug 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PMM 
Pattern-Mixture Model 
PP 
per protocol 
PT 
preferred term 
PTH 
parathyroid hormone 
QoL 
quality of life 
SAE 
serious adverse event 


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SAP 
statistical analysis plan 
SI 
International System of Units 
SOC 
system organ class 
SSRE 
sample size re-estimation 
STS 
sodium thiosulfate 
TEAE 
treatment emergent adverse event 
TIW 
three times in a week 
ULQ 
upper limit of quantification 
URR 
urea reduction ratio 
VAS 
visual analog score 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the rules and conventions to be used in the 
presentation and analysis of efficacy and safety data for Study SNFCT2017-06. It describes the 
data to be summarized and analyzed, including specifics of the statistical analyses to be 
performed and is based on protocol Amendment 2 version, dated 21 MAY 2021. 
2. 
STUDY DESIGN 
2.1. 
General Description 
This Phase 3, global multicenter study will examine the efficacy and safety of SNF472 in adult 
subjects on maintenance hemodialysis (HD) who have at least one ulcerated calcific uremic 
arteriolopathy (CUA) lesion. CUA is also referred to 
.  
The sample size is 66 subjects across approximately 60 worldwide sites, with a potential 
adjustment to 99 subjects with the sample size re-estimation (SSRE) procedure planned when 
primary endpoint data are available from approximately 33 of the planned total of 66 subjects 
randomized and treated for 12 weeks.  
The study will include a screening period of up to 5 weeks, a 12-week double-blind, 
randomized, placebo-controlled treatment period (Part 1) followed by a 12-week open-label 
treatment period (Part 2) and a 4-week follow-up period.  
A study flow chart is provided in Figure 1.  
Figure 1: 
Study Design Flowchart 
 
2.2. 
Schedule of Events 
Schedule of events can be found in Table 1 and Table 2 of the protocol. 


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2.3. 
Sample Size 
The sample size calculation is based on the effect sizes and standard deviations (SD) observed 
for changes in the Bates-Jensen Wound Assessment Tool  Calcific Uremic Arteriolopathy 
(BWAT-CUA) and Pain Visual Analog Score (Pain VAS) from baseline to Week 12 in the Phase 2 
study (SNFCT2015-04). The effect sizes for BWAT-CUA and Pain VAS were 6.3 and 24 units, 
respectively, with SDs of 6.5 and 31.4 units. Assuming similar results and based on 1,000,000 
trial simulations, a sample size of 66 subjects (33 per group) will provide an overall power of 
between 95.1% and 99.0% (corresponding to correlations between test statistics of  = 0.90 to 
0) when the alternate primary endpoints are tested using a Hochberg closed test procedure 
with a 4% alpha level, 2 sided. 
3. 
STUDY OBJECTIVES 
The study objectives are: 
 To evaluate the efficacy of SNF472 compared with placebo when added to 
background care for the treatment of CUA.  
 To evaluate the safety and tolerability of SNF472 compared with placebo when 
added to background care for the treatment of CUA.  
3.1. 
Primary Endpoints  
The primary alternate efficacy endpoints are: 
 Absolute change from baseline to Week 12 in the BWAT-CUA score for the primary 
lesion 
 Absolute change from baseline to Week 12 in Pain VAS score 
3.2. 
Secondary Endpoints  
The secondary efficacy endpoints evaluated hierarchically are: 
 Absolute change from baseline to Week 12 in Wound-Quality of Life (Wound-QoL) 
score 
 Absolute change from baseline to Week 12 in the BWAT total score for primary 
lesion 
 Qualitative wound image evaluation for the primary lesion (worsened, equal to, or 
improved relative to baseline) at Week 12 
 Rate of change in opioid use as measured in morphine milligram equivalents (MME) 
from baseline to Week 12 
3.3. 
Exploratory Endpoints  
The exploratory efficacy endpoints are: 


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 Absolute change from baseline to Week 12 in wound size for the primary lesion 
 Absolute change from baseline to Week 12 in each BWAT item for the primary lesion 
 Absolute change in BWAT-CUA, BWAT total, Pain VAS, and Wound-QoL score by visit 
 Proportion of subjects with new CUA lesions between baseline and Week 12 
 Absolute change from baseline to Week 12 in the Wound-QoL scores for the body, 
everyday life, and psyche subscales 
 Absolute change from baseline to Week 12 in the BWAT-CUA score for the 
secondary and tertiary lesions 
 Proportion of subjects requiring an increase in pain medication related to their CUA 
lesion(s) between baseline and Week 12 
 Proportion of subjects with a decrease in pain medication related to their CUA 
lesion(s) between baseline and Week 12 
 Absolute change from baseline to Week 12 in opioid use as measured in MME 
In Part 2, the exploratory efficacy endpoints will be within-group comparisons for the following: 
 Absolute change from baseline to Week 24 vs Week 12 in the BWAT-CUA score for 
the primary lesion 
 Absolute change from baseline to Week 24 vs Week 12 in the Pain VAS score  
 Absolute change from baseline to Week 24 vs Week 12 in the Wound-QoL score 
 Absolute change from baseline to Week 24 vs Week 12 in the BWAT total score for 
the primary lesion 
 Qualitative wound image evaluation for the primary lesion at Week 24 vs Week 12 
(worsened, equal to, or improved relative to baseline) 
 Absolute change from baseline to Week 24 vs Week 12 in wound size for the primary 
lesion 
 Absolute change from baseline to Week 24 vs Week 12 in each BWAT item for the 
primary lesion 
 Absolute change from baseline to Week 24 to the follow-up visit in the BWAT-CUA 
score for primary lesion 
 Absolute change from Week 24 to the follow-up visit in the Pain VAS score 
3.4. 
Safety Endpoints 
The safety endpoints are: 
 Proportion of subjects with Treatment-Emergent and Treatment-Related adverse 
events (AEs), serious AEs (SAEs) and deaths 


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 Change from baseline in the following: 
 Laboratory parameters 
 Holter monitoring results 
 QTc interval and other electrocardiogram (ECG) parameters 
 Vital signs 
 Proportion of subjects with a CUA wound-related infections, sepsis, hospitalization 
or any CUA wound-related complication. 


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4. 
PLANNED ANALYSES 
The following analyses will be performed for this study: 
 Interim analysis for sample size re-estimation (SSRE) will be prepared by an 
independent International Drug Development Institute (IDDI) Biostatistics team 
 Final Analysis  
4.1. 
Interim Analysis for Sample Size Re-estimation (SSRE)  
The SSRE is planned when primary endpoint data are available from approximately 33 of the 
planned total of 66 subjects randomized and treated for 12 weeks. Any increase in sample size 
will be capped at 50% of the planned sample size (i.e., the maximum total sample size will be 
capped at 66 + ½ × 66=99 subjects).  
The IDDI study team, including those responsible for creating the programs to produce the 
outputs for the SSRE, will remain blinded. Once the programs have been produced by the IDDI 
study team, these programs will be sent to an independent statistician, who will confirm the 
process and programming. Upon approval, IDDI will have an unblinded statistician not 
associated with the trial conduct the randomization schedule and provide the conditional 
power and sample size computations to the Data and Safety Monitoring Board (DSMB). 
The conditional power (CP) will be computed for both alternate primary endpoints, BWAT-CUA 
and Pain VAS, using the methods described by Mehta and Pocock (2011). Table 1 gives the 
decision rule with regards to continuation of the study with or without a sample size increase.  
The CP computed as above will give rise to two CP values, CP1 and CP2, for each of the two 
primary endpoints, respectively; based on these CP values, Equation 9 in Mehta and Pocock 
(2011) will be used to compute the corresponding post-interim sample sizes, 1 and 2, 
required to deliver the cross tabulated power as displayed in Table 1. This, in turn, will give two 
new sample size totals for the study, 
1 and 
2, relating to the two primary endpoints. The 
larger of 
1and 
2will be taken as the revised sample size for the study subject to a maximal 
increase of 99 subjects (i.e., at most a 50% increase over the planned sample size of N=66 
subjects). The final analysis will then combine the pre- and post-interim z-values for each of the 
two primary endpoints (
 and 
, say, for the first primary endpoint and 
 and 
, say, for 
the second primary endpoint) using NOT the approach suggested by Mehta and Pocock (2011), 
but rather the approach defined by Cui (1999), Equation 3.3 and later generalization, which 
guarantees no alpha inflation regardless of how the post-interim sample sizes (i.e., 
1 and 
2) 
are determined.  




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5.3. 
Safety Analysis Population  
The safety analysis population will contain all subjects in the Randomized Population who 
receive at least one dose of study drug and subjects will be analyzed according to treatment 
received in Part 1 (i.e., for Part 2, subjects who were on placebo and subjects who were on 
SNF472 in Part 1 will be analyzed separately in Part 2). The safety population will be used for 
analyses of safety endpoints. If there is any doubt whether a subject was treated or not, they 
will be assumed treated for the purposes of analysis. Any patient who receives at least one 
dose of SNF472 will be considered as treated with SNF472 for safety purposes.  
5.4. 
Modified Intent-to-Treat Population (mITT) 
The modified intent-to-treat (mITT) population will consist of all enrolled subjects who are 
randomized, receive at least one dose of study drug, and have at least one post-randomization 
efficacy evaluation. Efficacy evaluations include the BWAT-CUA score from Central Wound 
Rating, Pain VAS score, Wound-QoL score, BWAT total score, qualitative wound image 
evaluation, and opioid use. Subjects will be analyzed according to the treatment to which they 
were randomized. The mITT population will be the primary analysis population for efficacy 
endpoints.  
5.5. 
Intent-to-Treat Population (ITT) 
The intent-to-treat (ITT) population will consist of all enrolled subjects who are randomized. 
Supportive analyses of the two alternate primary endpoints BWAT-CUA score from Central 
Wound Rating and Pain VAS score, will be performed in this population. Subjects will be 
analyzed according to the treatment to which they were randomized. 
5.6. 
Per Protocol Population (PP) 
The per-protocol (PP) population will be the subset of subjects in the mITT population who do 
not have any major protocol deviations that will impact the efficacy assessment, have a Week 
12 measurement of at least one of the primary efficacy variables, and have received a pre-
specified minimum study drug exposure. Protocol deviations will be reviewed prior to 
unblinding to determine whether they are cause for exclusion of a subject from the Per 
Protocol population. This review will be fully blinded and without reference to efficacy or other 
data.  
The PP population will be used for supportive analyses of efficacy endpoints.  
6. 
GENERAL CONSIDERATIONS 
6.1. 
Reference Start Date and Study Day 
Study Day will be calculated from the reference start date and will be used to derive start/stop 
day of assessments and events.  


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Reference start date is defined as the day of the first dose of study drug; for subjects in Part 1, 
the reference start date is Week 1 Day 1; for subjects in Part 2 who were on placebo in Part 1, 
their reference start dates will be: reference start date 1 which is Week 1 Day 1 and reference 
start date 2 which is Week 13 Day 1. Study day will appear in every listing where an assessment 
date or event date appears. It is calculated as the difference between the event date and the 
reference start date.  
 If the date of the event is on or after the reference start date, then:  
 
Study Day = (date of event  reference start date) + 1 
 If the date of the event is prior to the reference start date, then:  
 
Study Day = (date of event  reference start date) 
In the situation where the event date is partial or missing, the date will appear partial or 
missing in the listings. 
6.2. 
Baseline 
Unless otherwise specified, baseline is defined as the Week 1 Day 1 pre-dose assessment. For 
BWAT and other endpoints except Pain VAS, if the assessment is missing, the last pre-dose 
assessment will be assigned as baseline. For Pain VAS, missing baseline data will be imputed 
last pre-dose Pain VAS value OR the mean 
baseline Pain VAS value among subjects in the same treatment arm. In the case where the date 
of assessment and the reference start date coincide, collection time, where available will be 
compared. The measurement will be considered pre-baseline unless the measurements were 
taken post-dialysis according to the schedule of events, such as vital signs, and the AEs and 
medications commencing on the reference start date will be considered post-baseline.  
6.3. 
Retests, Unscheduled Visits and Early Termination Data 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will be assigned to the nearest scheduled visit as per Table 2 (Part 
1) and Table 3 (Part 2), and will be fully listed by subject and nominal visit. If a measurement 
does not fall into a specified visit window, then that measure will be listed only and will be 
excluded from data summaries and analyses. When there are multiple measures falling into a 
given visit window, the non-missing measure closest to the nominal visit time point will be used 
in data summaries and analyses. All values within a visit window will contribute to the 
assessment of best/worst case value where required (e.g., shift table). 
In the case of a retest (same visit number assigned), the earliest available measurement for that 
visit will be used for by-visit summaries. 






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is no issue related to the point or interval estimation in the final analysis using the approach 
described above in Section 4.1. 
6.5. 
Common Calculations 
For quantitative measurements, change from baseline will be calculated as: 
 Test Value at Visit X  Baseline Value 
6.6. 
Multiple Wound Images 
In the instance where a single wound is large and must be imaged with greater than one photo, 
BWAT item scores will be calculated as the mean of the BWAT item scores for each of the 
images for a visit. Wound area will be calculated as the sum of the areas determined for each of 
the images for a visit. A qualitative review response will be determined by the mode of 
responses. If there is an equal number of different qualitative response types, the worst response 
will be used. 
6.7. 
Software Version 
All analyses will be conducted using SAS version 9.4 or higher. 
7. 
STATISTICAL CONSIDERATIONS 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses 
The following covariates and factors are used in the analyses. For details of their inclusion in the 
models, see the specific analysis section. 
 Factor 1: Sodium thiosulfate (STS, any formulation) use at baseline (Yes/No) 
 Factor 2: Treatment  
 Factor 3: Visit  
 Factor 4: Visit by Treatment interaction 
 Covariate 1: BWAT-CUA baseline score 
 Covariate 2: Pain VAS baseline score 
 Covariate 3: Wound  Quality of Life (Wound-QoL) baseline score 
 Covariate 4: BWAT total baseline score 
7.2. 
Multicenter Studies 
This study will be conducted by multiple investigators at multiple centers internationally. 
Randomization to treatment arms is not stratified by country/center. 


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When specified, statistical analysis will be adjusted for geographic region. Geographic region 
will be categorized as follows: 
Geographic Region 
Country 
North America 
United States 
Europe 
UK, Spain, Italy, Belgium, Germany, Poland 
Center pooling will not be carried out for use in analyses for this study. 
7.3. 
Missing data 
Missing safety and efficacy data will be handled as described in Sections 15 and 16 of this SAP.  
7.4. 
Multiple Comparisons/ Multiplicity 
To prevent any overall Type I error inflation, the alternate primary endpoints will be assessed 
using a Hochberg procedure with a 2-sided alpha level of 4%. If both alternate primary 
endpoints are met, the alpha apportioned will be recycled so that the secondary endpoints will 
be assessed hierarchically at the 5% alpha level, 2-sided. If only one alternate primary endpoint 
is met, the secondary endpoints will be assessed hierarchically at the 1% alpha level, 2-sided. 
In terms of incorporation of the interim analysis for SSRE (Section 4.1) into the Hochberg 
procedure to control overall Type I error, the Hochberg procedure will simply be applied to the 
combined z-values in the final analysis; if  represents the originally planned overall study 
sample size and the interim for sample size reassessment is to be performed with  subjects, 
then the final analysis  values for the two primary endpoints, 
 and 
, say, 
 will be assessed via the Hochberg 
procedure. 
7.5. 
Examination of Subgroups 
Subgroup analyses will be conducted as stated in the exploratory analysis sections. It should be 
noted that the study was not designed to detect treatment differences with statistical power 
within subgroups. 
The following subgroups may be assessed for the primary and secondary endpoints:  
 Sex:  
 Female 
 Male 
 Age (years): 
 
 
 
 


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 Race in groups: 
 Black/African American  
 Asian 
 Native Hawaiian/Other Pacific Islanders 
 American Indian/Alaska Native 
 White 
 Other 
 More than one 
 Region: 
 North America 
 Europe 
 Major comorbid conditions:  
 Diabetes mellitus (Yes/No) 
 Peripheral vascular disease (Yes/No) 
 Obesity (BMI > 30) (Yes/No) 
 Time on Dialysis (years:months) 
 Medication use at baseline 
 STS (Yes/No) 
 Calcimimetic (Yes/No) 
 Noncalcium-based phosphate binder (Yes/No) 
 Calcium-based phosphate binder (Yes/No) 
 Warfarin (Yes/No) 
 Vitamin K compound (Yes/No) 
 Vitamin D compound (Yes/No) 
 Opioids (Yes/No) 
8. 
OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore 
the format and content of the summary tables, figures, and listings to be provided by IDDI 
Biostatistics. 
9. 
DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study.  


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Subject disposition and withdrawals will be presented in a CONSORT diagram with footnotes as 
needed. Protocol deviations will be presented for the Randomized Population and outputs 
including inclusion and exclusion criteria for all subjects in the Enrolled Population will be 
provided.  
The number and percentage of subjects in each of the disposition categories will be 
summarized. For the End of Treatment and End of Study, subjects who have completed 
treatment for Part 1, continued into Part 2, completed treatment for Part 2, discontinued 
treatment in Part 1, discontinued treatment in Part 2, completed the study and reason for 
discontinuation will be summarized. A subject disposition listing including subjects who 
discontinued treatment and/or study early will be provided along with the reasons for 
discontinuations. The disposition will differentiate patients who: (1) had early cessation of 
therapy by physician/study staff; (2) were lost to follow-up; and (3) patients who withdrew 
consent for follow-up.  
The reasons for discontinuations include: 
 Adverse event 
 Lost to follow up 
 Pregnancy 
 Study terminated by sponsor 
 Withdrawal by subject 
 Physician decision 
 Death 
 Other 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the Randomized, 
Safety, and mITT Populations. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study:  
 Age (years) categorical based on subgroups: 
 
 
 
 
 
 
 
 
 Age (years) continuous  
 Major comorbid conditions 


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 Diabetes mellitus (Yes/No) 
 Peripheral vascular disease (Yes/No) 
 Hypoalbuminemia (Yes/No) 
 Obesity (BMI>30)(Yes/No) 
 Time on Dialysis (Years:months) 
 Hyperphosphatemia 
 Pain medication use at baseline 
 Opioids 
 NSAIDs 
 Anticonvulsants 
 Anesthetics 
 Other pain medications 
 Other medication use at baseline 
 STS (Yes/No) 
 Calcimimetic (Yes/No) 
 Noncalcium-based phosphate binder (Yes/No) 
  Calcium-based phosphate binder (Yes/No) 
 Warfarin (Yes/No) 
 Vitamin K compound (Yes/No) 
 Vitamin D compound (Yes/No) 
 Sex 
 Ethnicity 
 Race  
 Weight (kg)  
 Height (cm) 
 BMI (kg/m2) continuous  
 BMI (kg/m2) categorical (underweight, normal, overweight, obese) 
 Time since diagnosis (years) of end stage renal disease - calculated relative to date of 
consent 
 BWAT-CUA score 
 BWAT total score 
 Pain-VAS score 
 Wound-QoL score 


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10.1. 
Derivations 
 BMI (kg/ m2) = weight (kg)/ height (m)2 
11. 
PROCEDURE AND MEDICAL HISTORY 
Procedure and Medical History information will be presented for the Safety Analysis 
Population.  
 Medical and Procedure History will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) central coding dictionary, Version 23.1 or later. 
 Data captured on the Medical and Procedure History page of the case report 
form (CRF) will be presented by System Organ Class (SOC) and Preferred Term 
(PT).  
12. 
MEDICATIONS 
Medications will be presented for the safety population and coded using WHO Drug Dictionary 
Global Version September 2020 and summarized by Part 1 (prior and concomitant), Part 2 
(concomitant only) and overall. To distinguish between Parts 1 and 2, the medication start date 
 
Anatomical Therapeutic Chemical (ATC) class coding will be performed, and the medications 
will be summarized under the ATC Level 1 and 4 coding.  
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible 
to define a medication as prior and concomitant, the medication will be classified by the worst 
case, i.e., concomitant.  
 
of study drug and those that were taken during the past 30 days prior to the first 
dose of the study will be flagged.  
 
ions which started prior to, on or after the 
first dose of study drug which is Week 1 Day 1 and continues to be used during the 
trial. 
13. 
STUDY DRUG EXPOSURE 
Exposure to study drug in days will be summarized for the safety population. The summary will 
be for Part 1 subjects who were on a study drug and overall for both Parts 1 and 2. 
dosed will be considered the date of first study drug administration. The date of last study drug 


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hospitalizations when it may not be possible to administer study drug) and compliance are not 
considered for duration of exposure.  
13.1. 
Derivations 
Duration of exposure (days) = date of last study drug administration  date of first study drug 
administration + 1.  
13.2. 
Exposure 
The planned dose of SNF472 (7 mg/kg) will be administered three times weekly during dialysis 
in the Parts 1 and 2 of the trial. 
Compliance (number of doses administered/number of doses scheduled based on the duration 
-20%, >20-40%, >40-60%, >60-
80%, >80-100%, >100-120%. Compliance categories will be summarized with descriptive 
statistics by treatment group and overall in the mITT population. The number of doses 
scheduled will assume a week consisting of 2 days expect 1 dose, a week consisting of 4 days 
expect 2 doses, and a week of 5 days expect 3 doses. 100% compliance over 52 weeks consists 
of 156 doses. 
Any infusion interruptions, stopped infusions, missed infusions, discontinuations, and 
duration/number of infusions will be summarized for Part 1 and Part 2 separately, by visit (as 
 
14. 
STUDY DRUG COMPLIANCE  
Compliance to study drug will be presented for the safety population.  
The listing by subjects of planned and actual doses will be presented.  
The compliance will be 100% if the actual dose is equal to the planned dose. In case the two are 
not equal, the compliance will be calculated as (actual/planned)*100. The compliance will be 
presented for each part of the study separately across all subjects.  
15. 
EFFICACY OUTCOMES 
15.1. 
Primary Efficacy 
15.1.1. 
Primary Efficacy Variables & Derivations 
Primary efficacy analyses will be performed using the mITT population, and supportive 
analyses, using the ITT and PP populations.  
There are two alternate primary efficacy variables: 
The first primary efficacy variable is absolute change from baseline to Week 12 in the BWAT-
CUA score for the primary lesion. The BWAT-CUA score focuses on the 8 prototypical features 


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of CUA lesions which are necrotic tissue type, necrotic tissue amount, exudate type, exudate 
amount, skin color surrounding wound, peripheral tissue edema, peripheral tissue induration 
 8 to 40 which is the possible range of scores for BWAT-CUA. 
For the missing assessments on any one of the BWAT-CUA items when the other items are 
present, the scores will be imputed by using the median of available scores for a particular item 
within the given randomized treatment group at that visit. A sensitivity analysis will also be 
performed by imputing missing assessments on any one of the BWAT-CUA items with a worst-
 
The second primary efficacy variable is absolute change from baseline to Week 12 in Pain VAS 
score. The Pain VAS will be electronically administered, requiring the subject to mark a position 
on a 10-cm (100-mm) long horizontal line to indicate his/her worst wound-related pain over the 
last 24 hours. From this mark, the VAS score is electronically recorded in mm based on 
measurement along the line. The Pain VAS score is collected in the raw data in the CRF. 
15.1.2. 
Primary Analysis of Primary Efficacy Variables 
The comparison of absolute change from baseline to Week 12 in BWAT-CUA score between 
treatment groups will be achieved using a MMRM analysis to estimate the difference between 
randomized treatment groups least squares means (LS means) at 12 weeks. The model will 
include fixed effect terms for randomized treatment, visit (Week 2 Day 3, Week 4 Day 3, Week 
6 Day 3, Week 8 Day 3, Week 10 Day 3 and Week 12 Day 5) and visit by randomized treatment 
interaction; the model will also include baseline STS use as a fixed effect and baseline BWAT-
CUA score will be included as a covariate. Subject will be fitted as random effect and an 
unstructured variance-covariance matrix will be used. In case the unstructured variance-
covariance results in the lack of convergence, the following covariance structures will be tried in 
order until convergence is reached: toeplitz with heterogeneity, autoregressive with 
heterogeneity, toeplitz, and autoregressive. The difference in least square means (LS Means) 
with corresponding confidence intervals (as in Section 6.4) and estimated p-values will be 
presented.  
For the alternate primary efficacy endpoint, the comparison of absolute change from baseline 
to Week 12 in the Pain VAS score will be analyzed using an MMRM analysis to estimate the 
difference between randomized treatment group least squares means (LS means) at 12 weeks. 
The model will include fixed effect terms for randomized treatment, visit (as above), and visit by 
randomized treatment interaction; the model will also include baseline STS use as a fixed effect 
and baseline Pain VAS score will be included as a covariate. Subject will be fitted as random 
effect and an unstructured variance-covariance matrix will be used. In case the unstructured 
variance-covariance results in the lack of convergence, the following covariance structures will 
be tried in order until convergence is reached: toeplitz with heterogeneity, autoregressive with 
heterogeneity, toeplitz, and autoregressive. The difference in least square means (LS Means) 
with corresponding confidence intervals (as in Section 6.4) and estimated p-values will be 
presented. 


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Note, if only one alternate primary is met, a 98% 2-sided CI will also be presented for that 
alternate primary. 
15.1.3. 
Sensitivity Analysis of Primary Efficacy Variables 
15.1.3.1. Sensitivity Analyses with Regard to Missing Primary Endpoint Data 
The primary efficacy analyses using the MMRM are performed with the underlying assumption 
that missing data are MAR. To assess the robustness of the treatment effect under this 
assumption, sensitivity analyses will be performed in the mITT population under the 
assumption of MNAR. Pre-specification of a fully exhaustive list of reasons for missing data is 
difficult to formulate in advance as missing data can arise during trial conduct for a wide variety 
of reasons not all of which are predictable. However, relatively common reasons for loss of data 
include, but are not restricted to, dropout due to adverse event, dropout due to lack of efficacy, 
patient and/or investigator decision to withdraw consent or death. 
The first approach for the sensitivity analyses will employ a control-based pattern-mixture 
2011)  whereby missing observations in both the SN472 and 
placebo groups are imputed using only data observed in the control group; as such, this 
approach reflects 
 Mean changes from baseline in 
BWAT-CUA score will be analyzed based on data observed while the subject remains on study 
as well as data imputed using multiple imputation (MI) methodology for time points at which 
no value is observed. Imputation of values in the placebo arm will assume MAR. Imputation of 
values in the experimental treatment arm will be done as if the subject had been a member of 
the placebo arm. Imputed values in the experimental treatment arm will be sampled using the 
imputation model of the placebo arm, i.e., conditional on subject values observed at time 
points prior to discontinuation relative to the mean of the model for the placebo arm. This 
approach does not assume a sustained benefit of experimental treatment after discontinuation 
and limits a post-discontinuation effect to that of placebo and trial effect as reflected in 
estimated correlations between time points in the placebo arm. The approach will be 
implemented as follows: 
 Step 1: Non-monotone missing data will be imputed first based on the MAR 
assumption and a multivariate joint Gaussian imputation model using Markov chain 
Monte Carlo (MCMC) method using the MCMC statement in the SAS® PROC MI 
procedure. As a result, each imputed dataset will only have missing data at the end 
MI procedure will be used with multiple chains (option CHAIN=MULTIPLE), 100 burn-
in iterations, and a non-informative prior. A separate imputation model will be used 
for each treatment arm. The imputation models will include the STS use at 
randomization variable, baseline BWAT-CUA score, and BWAT-CUA scores at each 
time point. In case of non-convergence or non-estimability issues, a ridge prior and a 
single model will be considered with treatment arm added as explanatory variable to 
the model. 


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 Step 2: The remaining, monotone, missing data for all subjects who discontinue 
study prematurely will be imputed using sequential regression multiple imputation 
model estimated based on data from the placebo arm only. Each sequential 
regression model (i.e., for imputation of values at a given time point) will include 
explanatory variables for the STS use at randomization variable, baseline BWAT-CUA 
score, and all previous values of BWAT-CUA. Missing values at a given time point in 
placebo and the experimental treatment arm will be imputed from the same 
imputation model, conditional on subject values observed or imputed at previous 
time points. No rounding or range restrictions will be applied to imputed values. 
 Step 3: The change from baseline in BWAT-CUA score to each scheduled post-
baseline visit will be calculated, based on observed and imputed data. Each of the 
imputed complete datasets from Step 2 will be analysed with the same MMRM 
model used for the primary analysis (Section 15.1.2).  
 Step 4: The results of the analysis of each imputed dataset, i.e., treatment 
rules (Rubin, 1987) to produce pooled estimates of treatment differences, its 95% 
confidence interval and a pooled p-value. This will be done using SAS® MIANALYZE 
procedure.  
The core SAS code to perform this first sensitivity analysis is contained in Appendix 3. 
The second sensitivity analyses will be a tipping point analysis. This will assess the robustness of 
the alternate primary endpoint analyses by analyzing the penalty to the statistical significance 
of the primary analysis when adopting a MNAR approach. This will be applied to subjects in the 
statistical significance, being P<0.04 2-sided if both alternate primary endpoints are met or 
P<0.02 2-sided if only one alternate primary is met, is lost. Note, if neither alternate primary 
endpoint reaches statistical significance, tipping point analyses will not be applicable. The 
analyses require that the data has a monotone missingness pattern, thus, if necessary, a partial-
imputation method using MCMC will be used. This will be done using the SAS® PROC MI 
procedure, with sample code given originally above.  
The minimum shift parameter will be determined as a small fraction of the estimated treatment 
effect from the primary analysis; i.e., if the treatment effect estimate from the primary analysis 
of BWAT-CUA is , then the minimum shift parameter,
 will be set as 
 ; and 
the maximum shift parameter will be set as 
 , with tipping point 
analyses executed with no shift parameter (=primary analysis assuming MAR) and between 
(
 at intervals of 
 creating 40 imputed datasets. Each of these datasets will be 
analyzed as for the primary analysis using MMRM specified in Section 15.1.2. Results from each 
 
The p-values outputted from the models will be displayed along with the treatment effect 
estimates and associated CIs so that the tipping point for when the significance of the primary 
analysis is lost can be identified. If the initial shift parameters tested do not identify the tipping 


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point, the process will be repeated with different shift parameter values (e.g., 
until the tipping point is identified.  
The core SAS code perform this analysis is contained in Appendix 4. 
The third sensitivity approach will apply a further pattern-mixture analysis using the 
neighboring-case missing values (NCMV) method as described by Molenberghs and Kenward 
(2007) to capture different patterns of missingness over time. Imputation of missing data is 
similar to that described above for the control-based pattern-mixture (jump-to-reference) 
model. Imputation is made within each pattern of missingness. The analysis then proceeds as 
per control-based pattern-mixture approach. See the primary analysis Section 15.1.2 for more 
details and a description of the presentation. 
The core SAS code to perform this analysis is contained in Appendix 5. 
Similar sensitivity analyses for missing data will be conducted for change from baseline to 
Week 12 in Pain VAS, score, the other alternate primary endpoint.  
15.1.3.2. Sensitivity Analyses with Regard to Missing Baseline Primary Endpoint Data 
The primary analyses of BWAT and Pain VAS will be reperformed without the imputation of 
missing baseline values as described in Section 6.2.  
15.1.3.3. Sensitivity Analyses with Regard to Pain Medication Use Over Time 
Two supportive sensitivity analyses of the Pain VAS alternate primary endpoint will be made to 
assess the influence of pain medication use during the trial.  
The first approach will be an MMRM model with class terms for STS use, randomized 
treatment, visit (=week 2, 4, 6, 8, 10 and 12), randomized treatment by visit interaction, pain 
medication use (measured as morphine milligram equivalent), pain medication by visit 
interaction, randomized treatment by pain medication interaction and randomized treatment  
by pain medication by visit interaction; baseline Pain VAS score will be included as a covariate. 
An unstructured covariance matrix will be used to model the within-subject error. The chief foci 
of this analysis are (i) the randomized treatment by pain medication interaction term and (ii) 
the randomized treatment by pain medication by visit interaction term.  
The second approach will be a random coefficient MMRM model as described by Hedeker and 
Gibbons (2006). Class terms will be included for STS and randomized treatment. Visit (week   2, 
4, 6, 8, 10 and 12) and pain medication use will be included as continuous variables. The 
interaction between randomized treatment by pain medication interaction and randomized 
treatment by pain medication by visit interaction will be the chief foci of this analysis. Inference 
between randomized treatment will focus on the estimated rate of change of Pain VAS over 
time on SNF472 vs placebo.  
In line with Hedeker and Gibbons (2006), the analysis will be repeated decomposing the within 
and between subject effects associated with the pain medication time dependent covariate. In 
this analysis pain medication will be included in the model as (i) mean pain medication use by 


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subject over time and (ii) within subject mean corrected pain medication use by time. Inference 
will again focus on the estimated rate of change of Pain VAS over time on SNF472 vs placebo.  
The core SAS code for these sensitivity analyses is presented in Appendix 6.  
15.2. 
Secondary Efficacy 
The secondary efficacy analyses will be performed hierarchically for the mITT in the order that 
the parameters appear in the following sub-sections. 
15.2.1. 
Secondary Efficacy Variables, Derivations and Analysis 
15.2.1.1. Absolute Change from Baseline to Week 12 in the Wound-QoL Score 
The first secondary efficacy endpoint of the absolute change from baseline to Week 12 in 
Wound-QoL will be analyzed using an MMRM analysis. Wound-QoL (Wound-QoL, 2018) is a 
questionnaire consisting of 17 items on impairments. Answers to each item are coded with 
-QoL global score on 
overall disease-specific quality of life is computed by averaging all items. A global score can only 
be computed if at least 75% of the items have been answered, i.e., at least 13 in 17 items are 
valid (Short manual, Wound-QoL, 2018-05-29 [Wound-QoL, 2018]
scores will be added up and divided by 17. If there are missing assessments for any one of the 
17 items, the median of the scores for a particular item within the associated randomized 
treatment group will be used for the imputation purposes.  
Change from baseline in the Wound-QoL score will be evaluated using an MMRM method 
similar to the one specified for the primary analysis while substituting BWAT-CUA score related 
variables in the model with the corresponding Wound-QoL score related variables, such as 
baseline score and baseline score-by-study visit interaction. See the primary analysis 
Section 15.1.2 for more details and a description of the presentation. 
15.2.1.2. Absolute Change from Baseline to Week 12 in the BWAT Total Score for Primary 
Lesion 
The second secondary efficacy endpoint of the absolute change from baseline to Week 12 
wound healing assessed by the BWAT total score will be analyzed with MMRM. BWAT is a 
standardized quantitative assessment of wound healing that consists of 13 items where each 
is the sum of all 13 items with a possible range of scores from 9 to 65. Location and shape items 
collected in BWAT do not contribute to scoring. 
Change from baseline in BWAT total score will be evaluated using an MMRM method similar to 
the one specified for the primary analysis while substituting BWAT-CUA score related variables 
in the model with the corresponding BWAT total score related variables, such as baseline score 
and baseline score-by-study visit interaction. See the primary analysis Section 15.1.2 for more 
details and a description of the presentation.  


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15.2.1.3. Qualitative Wound Image Evaluation for the Primary Lesion (Worsened, Equal to, 
or Improved Relative to Baseline) at Week 12  
The wound image evaluation will be collected as part of the non-CRF guideline in qualitative 
comparison to baseline from Week 12.  
The third secondary efficacy endpoint will be analyzed using the generalized estimating 
equations (GEE) approach. A longitudinal logistic regression model will be fit to the response 
variable, categorized as an ordinal variable (worsened, equal to or improved). The model will 
include the predictors: baseline STS use, randomized treatment group, visit (Week 12 Day 5), 
and visit by randomized treatment interaction. The odds ratio of SNF472 vs placebo along with 
the associated 95% confidence intervals and p-values will be presented.  
The data will be analyzed using the Stuart-Maxwell test which will test the marginal 
homogeneity for all of the categories (worsened, equal to, or improved) simultaneously. 
15.2.1.4. Rate of Change in Opioid Use as Measured in MME from Baseline to Week 12 
For the fourth secondary endpoint, the daily average opioid dose in MME will be calculated for 
all subjects prior to randomization and post-randomization on a weekly basis. The calculation of 
the pre-specified list of opioids will be based on the formula: strength per unit × (number of 
units/days supply) × MME conversion factor = MME/day, as specified in the opioid MME 
conversion guide (CMS, 2017). The maintenance opioid dose will be defined as the average 
daily opioid dose in MME during the 7-day period prior to Screening Visit 2.  
To assess the extent to which opioid use may have differed between randomized treatment 
arms over time, the change from baseline in daily average MME value will be analyzed using a 
MMRM model analysis. MME data collected between Week 1 and Week 12 will be the 
dependent variable with random subject effects for intercepts and slopes. Fixed effects for 
randomized treatment, baseline MME value, week and randomized treatment-by-week 
interaction will be included, and an unstructured covariance matrix assumed to estimate the 
rate of change of opioid use over time for both SNF472 and placebo and assess whether the 
rate of change in use differs between randomized treatments. This is accomplished by using 
SAS® Proc Mixed statement with the response variable being MME data between Week 1 and 
Week 12 model fixed variables are treatment, MME baseline value, week and treatment by 
week interaction and random variables are intercept and week. The treatment effect will be the 
contrast between SNF472 and placebo slope estimates over 1 to 12 weeks.  
The associated slope estimates, difference in slopes, 95% CI, and 2-sided p-value will be 
extracted from the model and presented. 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variables 
As with the primary analysis, sensitivity analyses to explore the influence of missing data will be 
performed using multiple imputation, tipping-point analyses, and pattern mixture models. 
For the secondary endpoints absolute change from baseline to Week 12 in the wound-QoL 
score, absolute change from baseline to Week 12 in the BWAT total score for primary lesion 
and rate of change in opioid use as measured in MME from baseline to Week 12, the control-


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based pattern-
(2011) as described above for the 
primary endpoint will be applied. For the ordinal endpoint qualitative wound image evaluation 
for the primary lesion at Week 12, a similar approach will be employed with monotone logistic 
regression option in SAS PROC MI. 
15.3. 
Exploratory Efficacy  
The exploratory efficacy will be performed on the mITT.  
15.3.1. 
Exploratory Efficacy Variables, Derivations and Analysis 
15.3.1.1. Absolute Change from Baseline to Week 12 in Wound Size for the Primary Lesion 
The wound size for the primary lesion is collected as a continuous variable of the wound area as 
measured by imaging software by Tissue Analytics and verified by the reviewing wound expert. 
Change from baseline in the wound size will be evaluated using an MMRM method similar to 
the one specified for the primary analysis while substituting BWAT-CUA score related variables 
in the model with the corresponding wound size related variables, such as baseline wound size 
and baseline size-by-study visit interaction. See the primary analysis Section 15.1.2 for more 
details and a description of the presentation. 
15.3.1.2. Absolute Change from Baseline to Week 12 in Each BWAT Item for the Primary 
Lesion 
There are 13 items that comprise BWAT:  
 Size 
 Depth  
 Edges 
 Undermining 
 Necrotic tissue type 
 Necrotic tissue amount 
 Exudate type 
 Exudate amount 
 Skin color surrounding wound  
 Peripheral tissue edema 
 Peripheral tissue induration 
 Granulation tissue 
 Epithelialization 
Each item is rated on a scale 0 or 1 (best) to 5 (worst).  
Change from baseline for each individual item will be evaluated using an MMRM method 
similar to the one specified for the primary analysis (Section 15.1.2). 


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15.3.1.3. Absolute Change from Baseline in BWAT-CUA, BWAT Total, Pain VAS and Wound-
QoL Score by Visit 
 BWAT-CUA score is a total of the 8 items of the BWAT assessment, as specified in 
Section 15.1.1 
 BWAT total score is a total of the 13 items of the BWAT assessment, as specified in 
Section 15.2.1.2  
 Pain VAS score is a measurement as specified in Section 15.1.1 
 Wound-QoL score is a measurement as specified in Section 15.2.1.1 
Change from baseline to each visit (as defined above) for each of these four endpoints will be 
evaluated using an MMRM method similar to the one specified for the primary analysis while 
substituting BWAT-CUA score related variables in the model with the corresponding (BWAT 
Total, Pain VAS and Wound-QoL) score-related variables for the other endpoints, such as 
baseline score and baseline score-by-study visit interaction. The model will be restricted to 
baseline and the visit of interest as well as the intermediary visits. The least squares mean of 
the treatment difference at the visit of interest will be reported with the difference, confidence 
interval, and p-value included. See the primary analysis Section 15.1.2 for more details and a 
description of the presentation. 
15.3.1.4. Proportion of Subjects with the New CUA Lesions Between Baseline and Week 12 
The new CUA lesion will be collected in the New CUA Lesion (Wound) CRF page.  
The proportion of subjects with the new CUA lesions since baseline will be considered as a 
binary response (no new lesions vs 1 or more new lesions). The model will use exact logistic 
regression with stratification for STS use at baseline and include randomized treatment group, 
time of the lesion assessment (Week 6 or Week 12) and time-by-treatment interaction. The 
odds ratio estimate for SNF472: placebo at each time point (and overall at any time point) will 
be presented along with the associated confidence interval.
15.3.1.5. Absolute change from baseline to Week 12 in the Wound-QoL scores for the body, 
everyday life, and psyche 
The Wound-QoL subscale scores will be evaluated using an MMRM similar to that described for 
the Wound-QoL global score in Section 15.2.1.1. There are three subscales of Wound-QoL 
b
p
e
subscale can only be computed if no more than 1 item of the subscale is missing. For example, 
scores added up and divided by 4. If there are missing assessments for any one items within a 
subscale, the median of the scores for a particular item within the associated randomized 
treatment group will be used for the imputation purposes. Descriptive statistical summaries will 
be generated for individual questions as well. 


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15.3.1.6. Absolute Change from Baseline to Week 12 in the BWAT-CUA Score for the 
Secondary and Tertiary Lesions 
The BWAT-CUA score will be evaluated as specified in Section 15.1.1 for each of the secondary 
and tertiary lesions.  
Change from baseline in the BWAT-CUA score of the secondary and tertiary lesions will be 
evaluated using an MMRM method similar to the one specified for the primary analysis while 
substituting BWAT-CUA score of the primary lesion related variables in the model with the 
corresponding BWAT-CUA score for secondary and tertiary related variables, such as baseline 
score and baseline score-by-study visit interaction. See the primary analysis Section 15.1.2 for 
more details and a description of the presentation. 
15.3.1.7. Proportion of Subjects Requiring an Increase in Pain Medication Related to their 
CUA lesion(s) Between Baseline and Week 12 
CUA wound pain medication will be recorded on the CUA pain medication CRF.  
The proportion of subjects with an increase in pain medication will be considered as a binary 
response (pain medication increased since baseline vs pain medications decreased or stayed 
the same compared with baseline). The model applied and results presented will be the same 
as that described for new CUA lesions above (Section 15.3.1.4). 
15.3.1.8. Proportion of Subjects with a Decrease in Pain Medication Related to their CUA 
Lesion(s) Between Baseline and Week 12 
The proportion of subjects with a decrease in pain medication will be considered as a binary 
response (pain medication decreased since baseline vs pain medications increased or stayed 
the same compared with baseline). 
15.3.1.9. Absolute Change from Baseline to Week 12 in Opioid Use as Measured in MME 
Opioid use as measured in MME will be used as specified in Section 15.2.1.4. 
Change from baseline in the opioid use will be evaluated using an MMRM method similar to the 
one specified for the primary analysis while substituting BWAT-CUA score related variables in 
the model with the corresponding opioid use related variables, such as baseline score and 
baseline score-by-study visit interaction. See the primary analysis Section 15.1.2 for more 
details and a description of the presentation. 
15.3.1.10. Absolute Change from Baseline to Week 24 vs Week 12 in the BWAT-CUA Score for 
the Primary Lesion 
The absolute change from baseline to Week 24 vs Week 12 is the change from baseline at 
Week 24 minus change from baseline at Week 12. 
BWAT-CUA score is a total of the 8 items of the BWAT assessment, as specified in 
Section 15.1.1. 


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The paired t-test will be used to test the mean difference between the two sets of observations 
for the subjects in Part 2 between Week 24 and Week 12 for the BWAT-CUA score for the 
primary lesion. The mean of the differences, standard deviation, corresponding 95% confidence 
intervals and p-value will be presented. 
15.3.1.11. Absolute Change from Baseline to Week 24 vs Week 12 in the Pain VAS Score  
Pain VAS score is a measurement as specified in Section 15.1.1. 
Change from baseline in the VAS scores will be evaluated using a paired t-test method similar to 
the one specified in Section 15.3.1.10 while substituting BWAT-CUA score for the primary lesion 
related variables with the corresponding Pain VAS score related variables. 
15.3.1.12. Absolute Change from Baseline to Week 24 vs Week 12 in the Wound-QoL Score 
Wound-QoL score is a measurement as specified in Section 15.2.1.1. 
Change from baseline in the Wound-QoL scores will be evaluated using a paired t-test method 
similar to the one specified in Section 15.3.1.10 while substituting BWAT-CUA score for the 
primary lesion related variables with the corresponding Wound-QoL score related variables. 
15.3.1.13. Absolute Change from Baseline to Week 24 vs Week 12 in the BWAT Total Score 
for the Primary Lesion 
BWAT total score is a total of the 13 items of the BWAT assessment, as specified in 
Section 15.2.1.2.  
Change from baseline in the BWAT total scores will be evaluated using a paired t-test method 
similar to the one specified in Section 15.3.1.10 while substituting BWAT-CUA score for the 
primary lesion related variables with the corresponding BWAT total score related variables. 
15.3.1.14. Qualitative Wound Image Evaluation for the Primary Lesion at Week 24 vs Week 
12 (Worsened, Equal to, or Improved Relative to Baseline) for the Primary Lesion 
Qualitative wound image evaluation for the primary lesion (worsened, equal to, or improved 
relative to baseline) is measured as specified in Section 15.2.1.3. 
The data will be analyzed using the Stuart-Maxwell test which will test the marginal 
homogeneity for all of the categories (worsened, equal to, or improved) simultaneously. 
15.3.1.15. Absolute Change from Baseline to Week 24 vs Week 12 in Wound Size for the 
Primary Lesion 
The wound size for the primary lesion is collected as a continuous variable of the wound area as 
measured by imaging software by Tissue Analytics and verified by the wound expert review.  
Change from baseline in the wound size for primary lesion will be evaluated using a paired t-
test method similar to the one specified in Section 15.3.1.10 while substituting BWAT-CUA 
score for the primary lesion related variables with the corresponding wound size related 
variables. 


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15.3.1.16. Absolute Change from Baseline to Week 24 vs Week 12 of each BWAT Item for the 
Primary Lesion 
Each BWAT assessment contains 13 items as specified in Section 15.3.1.2 . 
Change from baseline in each BWAT individual item score will be evaluated using a paired t-test 
method similar to the one specified in Section 15.3.1.10 while substituting BWAT-CUA score for 
the primary lesion related variables with the corresponding BWAT individual item score related 
variables. 
15.3.1.17. Absolute Change from Week 24 to the Follow-up Visit in the BWAT-CUA Score for 
Primary Lesion 
Absolute change from baseline to Week 24 to the follow up visit is defined as change from 
baseline at follow-up visit value minus change from baseline at Week 24 visit value.  
BWAT-CUA score is a total of the 8 items of the BWAT assessment, as specified in 
Section 15.1.1. 
The paired t-test will be used to test the mean difference between the two sets of observations 
for the subjects in Part 2 between the follow-up visit and Week 12 for the BWAT-CUA score for 
the primary lesion. The mean of the differences, standard deviation, corresponding 95% 
confidence intervals and p-value will be presented. 
15.3.1.18. Absolute Change from Week 24 to the Follow-up Visit in the Pain VAS Score 
Pain VAS score is a measurement as specified in Section 15.1.1. 
Change from baseline in the Pain VAS scores will be evaluated using a paired t-test method 
similar to the one specified in Section 15.3.1.17 while substituting BWAT-CUA score for the 
primary lesion related variables with the corresponding Pain VAS score related variables.  
15.3.2. 
Missing Data Methods for Exploratory Efficacy Variables 
There will be no multiple imputation or tipping point analysis for the exploratory endpoints.  
16. 
SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the safety population.  
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section for Part 1. For Part 2, subjects who were on 
Placebo and subjects who were on SNF472 in Part 1 will be presented separately in Part 2. 
16.1. 
Adverse Events 
Adverse Events (AEs) will be coded using MedDRA version 23.1 or later.  
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in 
severity on or after the first dose of study drug. Part 1 TEAEs are those that started on or after 


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first dose in part 1 but before 1st dose in part 2. Part 2 TEAEs are those that started on or after 
1st dose in part 2, up to and including on the last day of dose in part 2. AEs that started after the 
last day of dose, but within 30 days of last dose will be considered as emergent during follow-
up. If patients do not proceed to part 2, then TEAEs will be defined for part 1 and follow-up 
only, using the same approach. 
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to 
define an AE as treatment emergent or not, the AE will be classified by the worst case, i.e., 
treatment emergent.  
An overall summary of number of subjects within each of the categories described in the sub-
section below, will be provided as specified in the templates.  
Listings will include TEAEs and Non-TEAEs. 
16.1.1. 
All TEAEs  
Incidence of TEAEs will be presented by treatment group, study period (Part 1, Part 2 and 
follow-up period of 30 days), System Organ Class (SOC) and Preferred Term (PT) and broken 
down further by maximum severity and relationship to study drug. 
16.1.1.1. Severity and Intensity  
The intensity is classified according to the Common Terminology Criteria for Adverse Events 
(CTCAE): Grade 1 is Mild, Grade 2 is Moderate, Grade 3 is Severe, Grade 4 is Life-threatening, 
and Grade 5 is Fatal. TEAEs with a missing severity will be classified as severe. If a subject 
reports a TEAE more than once within that SOC/ PT, the AE with the worst case 
severity/intensity will be used in the corresponding severity summaries. 
16.1.1.2. Relationship to Study Drug 
. TEAEs 
 
16.1.2. 
TEAEs Leading to Discontinuation of Study drug 
TEAEs leading to permanent discontinuation of study drug will be identified by using the 
question 
 
Adverse events will continue to be collected for 30 days after last dose of study drug from 
subjects who request early discontinuation from the study drug during Part 1 or Part 2 but 
continue to participate in the trial assessments for remaining visits. 
For TEAEs leading to discontinuation of study drug, summaries of incidence rates (frequencies 
and percentages) by treatment group, study period (Part 1, Part 2 and follow-up), SOC and PT 
will be prepared. 


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16.1.3. 
Serious Adverse Events 
page of the (e)CRF. A summary of serious TEAEs by treatment group, study period (Part 1, 
Part 2 and follow-up), SOC and PT will be prepared. 
16.1.4. 
Adverse Events Leading to Death 
page of the (e)CRF. A summary of TEAEs leading to death by treatment group, study period 
(Part 1, Part 2 and follow-up), SOC and PT will be prepared. 
16.1.5. 
CUA Wound-Related Adverse Events 
The CUA wound-
-related 
-related 
complications will be presented by the treatment group, SOC and PT for Part 1, and by SOC and 
PT for Part 2 and follow-up will be prepared. 
16.1.6. 
Treatment-Related Adverse Events 
Treatment-related AEs are the treatment-
the study drug. A summary of treatment-related AEs by study period (Part 1, Part 2 and follow-
up), SOC and PT will be prepared. 
16.2. 
Deaths 
information will be presented in a summary table and a data listing. 
16.3. 
Hemodialysis-Related Events 
HD-
using counts and percentages by treatment group and study period (Part 1, Part 2 and follow-
up).  
16.4. 
Laboratory Evaluations 
Results from the central laboratory will be included in the reporting of this study for 
hematology, chemistry (including ionized calcium, parathyroid hormone (PTH), high-sensitivity 
C-reactive protein (hs-CRP)), and serum pregnancy test for females of childbearing potential. A 
list of laboratory assessments to be included in the outputs is included in Table 4 of the 
protocol.  
Presentations will use SI Units.  
, below the lower limit of 
 
, above the upper limit of quantification (ULQ), will be 


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converted to X for the purpose of quantitative summaries, but will be presented as recorded, 
i.e., 
 
The following summaries will be provided for laboratory data: 
 Actual and change from baseline by visit (for quantitative measurements) by panel 
(hematology or chemistry), test, timepoint for Part 1, Part 2, Follow up as well as 
from Week 12 to Week 24 by panel and test. 
 Incidence of abnormal values according to normal range criteria by panel, test, 
treatment group and at any timepoint post-baseline but within 30 days after the last 
dose.  
 Individual patient changes in chemistry and hematology parameters will be shown 
with scatter plots comparing baseline value and post-baseline value for each post-
baseline timepoint. A 45-degree line and the upper and lower limits of normal will 
be displayed for reference. 
 Listing of subjects meeting abnormal criteria by panel, test, treatment group and 
time point.  
16.4.1. 
Laboratory Reference Ranges and Abnormal Criteria 
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and categorized as collected: 
 Low: Below the lower limit of the laboratory reference range.  
 Normal: Within the laboratory reference range (upper and lower limit included). 
 High: Above the upper limit of the laboratory reference range. 
16.5. 
Holter Monitoring and Electrocardiograms 
Holter data will be analyzed centrally by extracting triplicate ECGs from the records at each of 
the following timepoints: pre-dose, end of infusion (EOI), and end of dialysis. Holter monitoring 
during dialysis will be performed as part of Screening Visit 2 (may be conducted at any dialysis 
session during the last week of screening prior to Week 1 Day 1) and at Weeks 1, 6, 12, 13 and 
24. The baseline will be the last non-missing record of Holter monitoring prior to the first dose 
of the study drug. The mean of the three results will be used for the presentation purposes. 
Results from the centrally analyzed extracted ECGs will be included in the reporting of this 
study.  
The following ECG parameters will be reported for this study: 
 PR Interval (msec) 
 QRS Interval (msec) 
 RR Interval (msec) 
 QT Interval (msec) 




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 > 500 msec 
 Change from Baseline to each timepoint and any post-baseline ECG in Part 1 and 
Part 2, for QT interval, QTcB interval and QTcF will be classified as: 
 >30 msec increase from baseline 
 >60 msec increase from baseline 
Note: The ranges are not mutually exclusive. For example, if a subject has a value of more than 
500 msec, they will be counted in the >450, > 480, and >500 category. 
16.5.3. 
Holter Arrhythmia Analysis 
Holter reading will be performed centrally and parameters related to the following will be 
reported and summarized: 
 Rhythm profile 
 Arrhythmias, rate and RR interval trends 
 Holter events or findings 
16.6. 
Vital Signs 
The following Vital Signs measurements will be reported for this study: 
 Systolic Blood Pressure (mmHg) 
 Diastolic Blood Pressure (mmHg) 
 Heart Rate (bpm) 
 Respiratory Rate (breaths/min) 
 Temperature (°C) 
 Post-dialysis Weight (kg) 
The following summaries, will be provided for vital signs data: 
 Actual and change from baseline by treatment group and timepoint  
16.7. 
CUA Wound Care 
be listed by subject and summarized by treatment group 
16.8. 
Physical Examination  
Physical examination findings will be listed by subject.  


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17. 
DIALYSIS PARAMETERS 
Dialysis parameters include: 
 Calcium concentration in the dialysate 
 Dialysis frequency  
 Dialysis duration 
 Clearance time / volume (Kt/V) 
 Urea reduction ratio (URR) (%) 
The dialysis parameters will be summarized by a parameter, treatment group and visit. 
 


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18. 
REFERENCES 
CMS. Opioid Oral Morphine Milligram Equivalent (MME) Conversion Factors. 
https://www.cms.gov/Medicare/Prescription-Drug-
Coverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-Factors-
Aug-2017.pdf. Published 2017. Accessed February 17, 2021.  
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-857. 
Hedeker D, Gibbons RD. Longitudinal Data Analysis, 2006. New York: John Wiley & Sons. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med. 2011;30(28):3267-3284. 
Molenberghs G and Kenward MG Missing Data in Clinical Studies, 2007. New York: John Wiley & 
Sons. 
-mixture models using standard SAS/STAT 
procedures. PharmaSUG. https://www.pharmasug.org/proceedings/2011/SP/PharmaSUG-
2011-SP04.pdf. Published 2011. Accessed February 17, 2021. 
Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons, 
1987. 
SAS Institute Inc. Chapter 62: The MIANALYZE Procedure. SAS/STAT® 13.1 User's Guide. Cary, 
NC: SAS Institute Inc.; 2013:5171-5231. 
Wound-QoL. Wound-QoL Questionnaire on quality of life with chronic wounds. Short Manual. 
https://www.wound-qol.com/wp-content/uploads/Wound-QoL-ShortManual-2018-05.pdf. 
Published 2018. Accessed February 17, 2021. 
 
 
 
 


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APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 
IDDI OUTPUT CONVENTIONS 
Outputs will be presented according to the following:  
1. 
ABBREVIATIONS 
ASCII  American standard code for information interchange file format 
CGM  Computer graphics metafile 
ODS  
Output Delivery System 
RTF  
Rich text file format 
2. 
INTRODUCTION 
This document applies to standards used for outputting tables, listings and figures. It is 
intended to provide specifications to guide the statistician or statistical programmer in setting 
up specifications for programming tables, listings and figures. These standards should be used 
in the absence of customer specific standards. 
3. 
OUTPUT FILE NAMING CONVENTIONS 
As far as possible, output files should be in RTF format, although .DOC files are also permitted. 
The program, program log and output file name should reflect the type and number of the 
statistical output. If this is not possible, then the output name should be at least as descriptive 
as possible. A prefix can be used to distinguish between a Table, Listing and Figure document 
listing or figure in the place where 2 digits are possible, a leading zero should be added in the 
file name to make sorting consistent with the sequence (e.g., t14_3_01_1.rtf) 
4. 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter for the United States, otherwise A4. 
The page orientation should preferably be landscape, but portrait is also permitted. 
5. 
TABLE AND LISTING OUTPUT CONVENTIONS 
Univariate Statistics: 
 Statistics should be presented in the same order across tables  


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 Table statistics should line up under the N part of the (N=XXX) in the table header. 
All decimal points should line up. If the minimum and maximum are output on one 
line as Minimum, Maximum then the comma should line up with the decimal point. 
 If the original data has N decimal places, then the summary statistics should have 
the following decimal places: 
 Minimum and maximum: N 
 Mean, median and CV%: N + 1 
 SD: N + 2 
Frequencies and percentages (n and %): 
 Percent values should be reported inside parentheses, with one space between the 
count and the left parenthesis of the percentage. Parentheses should be justified to 
accept a maximum of 100.0 as a value and padded with blank space if the percent is 
less than 100.0. An example is given below: 
 77 (100.0%) 
 50 ( 64.9%) 
 0 ( 0.0%) 
 Percentages will be reported to one decimal place, except percents <100.0% but 
Rounding will be applied after the <0.1% and >99.9% rule. 
 <0.1% 
 6.8% 
 >99.9% 
Percentages may be reported to 0 decimal places as appropriate (for example, 
where the denominator is relatively small). 
 Where counts are zero, percentages of 0.0% should appear in the output. 
Confidence Intervals: 
 An example is given below: 
 (-0.12, -0.10) 
 (9.54, 12.91) 
P-values: 
 P-values should be reported to three decimal places, except values <1.000 but 
<0.001 will be 
will be applied after the <0.001 and >0.999 rule. 


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6. 
EXAMPLE 
 
 
7. 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-dd and hh:mm:ss. 
8. 
SPELLING FORMAT 
English US  
9. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables and Graphs 
SNF472 
SNF472 
Placebo 
Placebo 
Not Randomized 
Not Randomized 
Not Treated 
Not Treated 
10. 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
 


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Long Name (default) 
Short Name  
Screening Visit 1  
Scr1  
Screening Visit 2  
Scr2 
Baseline Week 1 Day 1  
BL  
Week 1 Day 3  
W1D1 
Week 1 Day 5 
W1D3 
Week 2 Day 1 
W2D1 
Week 2 Day 3 
W2D3 
Week 2 Day 5 
W2D5 
Week 3 Day 1 
W3D1 
Week 3 Day 3 
W3D3 
Week 3 Day 5 
W3D5 
Week 4 Day 1 
W4D1 
Week 4 Day 3 
W4D3 
Week 4 Day 5 
W4D5 
Week 5 Day 1 
W5D1 
Week 5 Day 3 
W5D3 
Week 5 Day 5 
W5D5 
Week 6 Day 1 
W6D1 
Week 6 Day 3 
W6D3 
Week 6 Day 5 
W6D5 
Week 7 Day 1 
W7D1 
Week 7 Day 3 
W7D3 
Week 7 Day 5 
W7D5 
Week 8 Day 1 
W8D1 


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Long Name (default) 
Short Name  
Week 8 Day 3 
W8D3 
Week 8 Day 5 
W8D5 
Week 9 Day 1 
W9D1 
Week 9 Day 3 
W9D3 
Week 9 Day 5 
W9D5 
Week 10 Day  
W10D1 
Week 10 Day 3 
W10D3 
Week 10 Day 5 
W10D5 
Week 11 Day 1 
W11D1 
Week 11 Day 3 
W11D3 
Week 11 Day 5 
W11D5 
Week 12 Day 1 
W12D1 
Week 12 Day 3 
W12D3 
Week 12 Day 5 
W12D5 
Week 13 Day 1 
W13D1 
Week 13 Day 3 
W13D3 
Week 13 Day 5 
W13D5 
Week 14 Day 1 
W14D1 
Week 14 Day 3 
W14D3 
Week 14 Day 5 
W14D5 
Week 15 Day 1 
W15D1 
Week 15 Day 3 
W15D3 
Week 15 Day 5 
W15D5 
Week 16 Day 1 
W16D1 


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Long Name (default) 
Short Name  
Week 16 Day 3 
W16D3 
Week 16 Day 5 
W16D5 
Week 17 Day 1 
W17D1 
Week 17 Day 3 
W17D3 
Week 17 Day 5 
W17D5 
Week 18 Day 1 
W18D1 
Week 18 Day 3 
W18D3 
Week 18 Day 5 
W18D5 
Week 19 Day 1 
W19D1 
Week 19 Day 3 
W19D3 
Week 19 Day 5 
W19D5 
Week 20 Day 1 
W20D1 
Week 20 Day 3 
W20D3 
Week 20 Day 5 
W20D5 
Week 21 Day 1 
W21D1 
Week 21 Day 3 
W21D3 
Week 21 Day 5 
W21D5 
Week 22 Day 1 
W22D1 
Week 22 Day 3 
W22D3 
Week 22 Day 5 
W22D5 
Week 23 Day 1 
W23D1 
Week 23 Day 3 
W23D3 
Week 23 Day 5 
W23D5 
Week 24 Day 1 
W24D1 


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Long Name (default) 
Short Name  
Week 24 Day 3 
W24D3 
Week 24 Day 5/Early Termination 
W24D5/ET 
Follow up 
FU 








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APPENDIX 3. 
A CONTROL-BASED PATTERN-MIXTURE MODEL SENSITIVITY 
ANALYSIS  
A control-based pattern-
(2011) whereby 
missing observations in both the SN472 and placebo groups are imputed using only data 
observed in the control group; this model reflects 
  
Several steps are required to execute this sensitivity analysis. 
In the first step, intermittently missing data (e.g., where a subject has week 2 and week 6 data 
recorded but has week 4 data missing) are imputed as non-monotone missing to generate a 
monotone missing pattern. The form of the associated SAS code is given below where the 
dataset DATAIN has already been sorted by randomized treatment (RANDTRT) and the 
stratification variable of intravenous STS use at of randomization: 
/*FIRST STEP IMPUTE NON-MONOTONE(INTERMITTENTLY)MISSING DATA*/ 
PROC MI DATA=DATAIN SEED=<VALUE> NIMPUTE=20 OUT=MI_OUT1; 
  VAR BASE W2 W4 W6 W8 W10 W12; 
MCMC CHAIN=MULTIPLE PRIOR=JEFFREYS IMPUTE=MONOTONE; 
BY RANDTRT STS; 
RUN; 
where  BASE = baseline BWAT-CUA score, and 
W12 = 
BWAT-CUA scores.  
The resulting dataset MI_OUT1 is then sorted by _IMPUTATION_ , RANDTRT and STS. In the 
second step, PROC MI is called again utilizing the regression method under MNAR to complete 
imputation of the monotone missing datasets resulting from the first step. The SAS code will be 
of the following form:  
 
    /*SECONDLY IMPUTE MONOTONE MISSING DATA AS MNAR JUMP TO PLACEBO*/ 
PROC MI DATA=MI_OUT1 SEED = <SEED> NIMPUTE = 1 OUT=MI_OUT2; 
BY_IMPUTATION_; 
CLASS RANDTRT STS; 
MONOTONE REG (W2 W4 W6 W8 W10 W12 = BASE STS / DETAILS); 
MNAR MODEL (W2 W4 W6 W8 W10 W12 / MODELOBS =(RANDTRT = 'PLACEBO')); 
VAR W2 W4 W6 W8 W10 W12 BASE STS; 
    RUN; 
 
The dataset MI_OUT2 contains the 20 complete imputed data sets. This dataset will be 
transformed in a third step such that, for each subject, each post-baseline time-point is 
represented by a separate record.  
/*THIRD STEP TRANSFORM IMPUTED DATASETS*/ 
DATA MI_OUT3; SET MI_OUT2;  
VISIT=2; BWATCUA_CHG_BL=W2-BASE; OUTPUT;  
VISIT=4; BWATCUA_CHG_BL=W4-BASE; OUTPUT;  


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VISIT=6; BWATCUA_CHG_BL=W6-BASE; OUTPUT;  
VISIT=8; BWATCUA_CHG_BL=W8-BASE; OUTPUT;  
VISIT=10; BWATCUA_CHG_BL=W10-BASE; OUTPUT;  
VISIT=12; BWATCUA_CHG_BL=W12-BASE; OUTPUT;  
RUN; 
The 20 complete datasets in MI_OUT3 will then be analyzed in a fourth step by MMRM via PROC 
MIXED as specified for the primary endpoint. The SAS code will be of the following form:  
/*FOURTH STEP MMRM ANALYSIS OF IMPUTED DATASETS*/ 
PROC MIXED DATA=MI_OUT3 METHOD=REML; 
BY _IMPUTATION_;     
CLASS PATIENT RANDTRT VISIT STS; 
MODEL BWATCUA_CHG_BL = BASE RANDTRT VISIT RANDTRT*VISIT STS /DDFM=KR; 
REPEATED VISIT / PATIENT = PATIENT TYPE = UN; 
LSMEANS RANDTRT*VISIT/SLICE=VISIT PDIFF DIFF ALPHA=0.04 CL;     
ODS OUTPUT DIFFS=DIFF LSMEANS=LSMEANS; 
RUN; 
To obtain overall LSmean and treatment effect estimates, the DIFF and LSMEANS datasets are 
via PROC MIANALYZE. The SAS code will be of the following form:  
/*FIFTH STEP MERGE DIFF AND LSMEANS DATASETS*/ 
DATA DIFF2; 
SET DIFF (IN=A) LSMEANS; 
IF A THEN COMPARISON=RANDTRT||' VS '||LEFT(_RANDTRT); 
ELSE COMPARISON=RANDTRT; 
RUN; 
 
PROC SORT DATA=DIFF2; 
BY COMPARISON _IMPUTATION_; 
RUN; 
 
/*SIXTH STEP COMBINE MI ESTIMATES VIA MERGE DIFF AND LSMEANS DATASETS*/ 
PROC MIANALYZE DATA=DIFF2; 
BY COMPARISON; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
ODS OUTPUT PARAMETERESTIMATES=MIESTS; 
RUN; 
 
The output dataset MIESTS contains the final, imputed results. The resulting multiply imputed 
means and difference in means between SNF472 and placebo will be presented, along with the 
associated SEs, CIs and 2-sided p-values. 


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Exactly the same approach will be used for the analysis of the alternate primary endpoint, Pain 
VAS score. 


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APPENDIX 4. 
TIPPING POINT SENSITIVITY ANALYSIS  
A tipping point analysis whereby missing data are imputed in the SNF472 arm with an 
penalization that renders a positive p-value for the principal analyses of the primary endpoint 
non-significant. 
All imputation steps are as described in Appendix 3 for the control-based pattern-mixture 
model above, apart from the second step where monotone missing data are imputed for 
patients randomized to SNF472 are adjusted using the ADJUST and SHIFT options:  
    /*SECONDLY APPYING TIPPING POINT IMPUTATION*/ 
PROC MI DATA=MI_OUT1 SEED = <SEED> NIMPUTE = 1 OUT=MI_OUT2<DELTA>; 
BY_IMPUTATION_; 
CLASS RANDTRT STS; 
MONOTONE REG (W2 W4 W6 W8 W10 W12 = BASE <COVS> STS / DETAILS); 
MNAR ADJUST (W2 W4 W6 W8 W10 W12 / SHIFT = <DELTA> ADJUSTOBS =(RANDTRT = 
'PLACEBO')); 
VAR W2 W4 W6 W8 W10 W12 BASE <COVS> STS; 
    RUN; 
The value of <DELTA> is progressively increased and the code re-run for each increase. This  
generates a series of MI_OUT2<DELTA> datasets. To each of these datasets, steps 3 to 6 as 
described for the control-based pattern-mixture model will be applied, thus giving rise to a 
multiply imputed treatment effect estimate for each value of <DELTA> for SNF472 vs placebo, 
along with its SE and CI. These treatment effect estimates and CIs will be plotted in a stacked 
forest plot format vs <DELTA>. The first value of <DELTA> whereby the CI includes zero will be 
identified as the tipping point.  
 
 


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APPENDIX 5. 
PATTERN MIXTURE NEIGHBORING-CASE SENSITIVITY ANALYSIS  
A second pattern-mixture analysis using the neighboring-case missing values (NCMV) method 
as described by Molenberghs and Kenward (2007). All imputation steps are as described in 
Appendix 3 apart from the second step where monotone missing data are imputed using the 
MNAR (MODELOBS=NCMV) option: 
  /*SECONDLY IMPUTE MONOTONE MISSING DATA VIA PATTERN-MIXTURE APPROACH WITH 
NEIGHBOURING-CASE MISSING VALUES APPROACH*/ 
PROC MI DATA=MI_OUT1 SEED = <SEED> NIMPUTE = 1 OUT=MI_OUT2; 
 BY _IMPUTATION_ RANDTRT STS; 
MONOTONE REG (W2 W4 W6 W8 W10 W12 = BASE <COVS> / DETAILS); 
MNAR MODEL (W2 W4 W6 W8 W10 W12 / MODELOBS =NCMV); 
VAR W2 W4 W6 W8 W10 W12 BASE <COVS>; 
   RUN; 
 
 


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APPENDIX 6. 
SENSITIVITY ANALYSES REGARDING PAIN MEDICATION USE  
Two supportive sensitivity analyses of the Pain VAS alternate primary endpoint. The first 
approach will be an MMRM model with class terms for STS use, randomized treatment, visit 
(=week 2, 4, 6, 8, 10 and 12), randomized treatment by visit interaction, pain medication use 
(measured as morphine milligram equivalent), pain medication by visit interaction, randomized 
treatment by pain medication interaction and randomized treatment by pain medication by 
visit interaction; baseline Pain VAS score will be included as a covariate. An unstructured 
covariance matrix will be used to model the within-subject error.  
The chief foci of this analysis are (i) the randomized treatment by pain medication interaction 
term and (ii) the randomized treatment by pain medication by visit interaction term.  
The core SAS code will be of the form: 
PROC MIXED DATA=DATAIN;   
   CLASS PATIENT RANDTRT VISIT STS PAIN;     
   MODEL  VAS_CHG_BL = BASE RANDTRT VISIT PAIN RANDTRT*VISIT  
   
VISIT*PAIN RANDTRT*PAIN RANDTRT*VISIT*PAIN; 
  
REPEATED VISIT / SUBJECT = PATIENT(RANDTRT) TYPE=UN;    
LSMEANS RANDTRT*PAIN/PDIFF DIFF ALPHA=0.04 CL;     
LSMEANS RANDTRT*VISIT*PAIN/SLICE=VISIT*PAIN PDIFF DIFF ALPHA=0.04 CL;     
ODS OUTPUT DIFFS=DIFF LSMEANS=LSMEANS; 
RUN;     
The second approach will be a random coefficient MMRM model as described by Hedeker and 
Gibbons (2006). Class terms will be included for STS and randomized treatment. Visit (=week 0, 
2, 4, 6, 8, 10 and 12) and pain medication use will be included as continuous variables. The 
interaction between randomized treatment by pain medication interaction and randomized 
treatment by pain medication by visit interaction will be the chief foci of this analysis. Inference 
between randomized treatment will focus on the estimated rate of change of Pain VAS over 
time on SNF472 vs placebo.  
The core SAS code will be of the form:  
DATA DATAIN;  
RANDTRT_VISIT = RANDTRT*VISIT;   
RUN;  
         
PROC MIXED DATA = DATAIN;      
  CLASS PATIENT;     
  MODEL VAS_CHG_BL = STS RANDTRT VISIT RANDTRT_VISIT PAIN /SOLUTION;    
  RANDOM INTERCEPT VISIT /SUB=PATIENT(RANDTRT) TYPE=UN G GCORR;      
RUN;   
 
In line with Hedeker and Gibbons (2006), a further analysis will be performed to decompose the 
within and between subject effects associated with the pain medication time dependent 
covariate. In this analysis pain medication will be included in the model as (i) mean pain 


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medication use by subject over time and (ii) within subject mean corrected pain medication use 
by time. Inference will again focus on the estimated rate of change of Pain VAS over time on 
SNF472 vs placebo.  
The core SAS code will be of the form: 
PROC SORT DATA = DATAIN;  
BY PATIENT VISIT;   
RUN;                 
 
PROC MEANS DATA = DATAIN NOPRINT;  
CLASS PATIENT;  
VAR PAIN;    
OUTPUT OUT = MEANPAIN_BY_PATIENT MEAN = MPAIN;    
RUN;      
  
DATA DATAIN;  
MERGE DATATIN MEANPAIN_BY_PATIENT;   
BY PATIENT;     
PAINI = PAIN  MPAIN;    
RUN;     
 
PROC MIXED DATA = DATAIN METHOD=ML COVTEST;      
  CLASS PATIENT;   
  MODEL VAS_CHG_BL = STS RANDTRT VISIT RANDTRT_VISIT MPAIN PAINI /SOLUTION;      
  RANDOM INTERCEPT VISIT /SUB=PATIENT(RANDTRT) TYPE=UN G GCORR;   
RUN;             
 
 




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ADDENDUM TO STATISTICAL ANALYSIS PLAN VERSION 1.3- SUMMARY OF 
CHANGES FROM VERSION 1.2 
There have been no updates to the Addendum. 
 
 


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ADDENDUM TO STATISTICAL ANALYSIS PLAN 
If due to operational issues, the sample size re-estimation (SSRE) takes place with >50% (33/66) 
of subjects, the Cui, Hung and Wang fixed weight methodology for the SSRE and primary 
endpoint analysis will remain the same. For example, if the SSRE takes place with p% (>50%) of 
subjects, the combination of patient data pre and post the SSRE will use weights of 
 and 
 , respectively. Regardless of the fraction of subjects included in the SSRE, the pre-
specified minimum and maximum final sample size of 66 and 99 subjects, respectively, will not 
change.