Conditions: Diffuse Cutaneous Systemic Sclerosis
Keywords: skin diseases systemic sclerosis phase 2 Scleroderma Health Assessment Questionnaire Disability Index Modified Rodnan Skin Score Combined Response Index in dcSSc (CRISS) diffuse cutaneous systemic sclerosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This was a phase 2, open-label, single-cohort, multicenter trial of belumosudil in participants with Diffuse Cutaneous Systemic Sclerosis (dcSSc). An estimated total of 12 to 15 participants would receive belumosudil 200 milligrams (mg) administered orally (PO) twice daily (BID) for 52 weeks. The primary analysis was at 24 weeks.

Detailed description:
The primary objective of this phase 2, open-label, single-cohort, multicenter trial was to evaluate the efficacy of belumosudil 200 mg BID using the Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) after 24 weeks of therapy. The duration of the study was approximately 14 months (4 weeks for screening, 52 weeks of dosing period, and 4 weeks of Follow-up)

Participants who had signed an Institutional Review Board/Independent Ethics Committee-(IRB/IEC)-approved informed consent form (ICF) and met all of the inclusion/exclusion criteria were enrolled. A total of 10 participants at 6 sites received belumosudil 200 mg in tablet form administered PO BID for 52 weeks. The total duration of the study is approximately 14 months: a 4-week screening period, a 52-week treatment period, and a 4-week follow-up.

The primary endpoint was analyzed using Week 24 data.

Efficacy was assessed throughout the 52-week dosing period using:

* Composite Response Index in Systemic Sclerosis (CRISS)
* Modified Rodnan Skin Score (mRSS)
* Pulmonary Function Tests (PFTs)
* Physician Global Assessment
* Patient Global Assessment

Safety was be assessed throughout the study and will include:.

* Physical examinations (PEs)
* Vital sign measurements
* Weight measurements
* Blood sample collection for hematology and chemistry; urinalysis
* Electrocardiograms (ECGs)
* Adverse event (AE) assessments
* Concomitant medication assessments
* Pregnancy testing for females of childbearing potential.

Reasons for discontinuation of treatment because of adverse events were documented. Careful monitoring of all adverse events was carried out. Dosing could be reduced 1 dose level. If the dose was not tolerated, then the participant was discontinued from the study. If there is an interruption of dosing, after 14 days the participant was discontinued from the study.

Participants were given a study drug diary to record the details of each dose of belumosudil 200 mg. Diaries were dispense/collected on each visit. Compliance with dosing was confirmed using participant diaries, which was examined at each visit by site staff to determine if dosing was as instructed per protocol and follow-up.

A 4-Week Safety Follow-up Visit occurred 28 days (± 3 days) after the last dose of study drug.

Arms:
arm 1: Participants received belumosudil 200 mg tablet orally PO, BID for 52 weeks.

Interventions: intervention 1: Belumosudil
Intervention descriptions: intervention 1: 10 participants with dcSSc received belumosudil 200 mg PO BID for 52 weeks

Protocol document:
Prot_000.pdf: 


Belumosudil (KD025) 
 
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Procedures in Case of Emergency 
 
Serious Adverse Events  
Any serious adverse event (SAE)* occurring in a subject while receiving study drug or 
within 28 days of receiving their last dose of study drug, even though the event may not 
appear to be study drug related, must be promptly reported (within 24 hours) by 
telephone, e-mail, or telefax to the sponsor (or designee).   
Emergency Contact Information:  
For medical questions contact the Kadmon Medical Monitor: 
Email:  medicalmonitor@kadmon.com 
Phone:  724-778-6125 
 
For SAE reporting, send the SAE form, pregnancy form or follow-up within 
24 hours of becoming aware to: 
Kadmon Pharmacovigilance 
clinicalSAEreporting@kadmon.com 
or 
Fax: 646-430-9549 
 
 
SAE CRITERIA 
* A SAE is any untoward medical occurrence that at any dose results in any of the following outcomes, 
regardless of relationship to study drug (see Section 9.3.1 Serious Adverse Events, for additional 
information): 
• Death 
• Life-threatening adverse drug event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• An important medical event that may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
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SPONSOR APPROVAL SIGNATURE PAGE  
 
I have read and approve this protocol. My signature, in conjunction with the signature of 
the Investigator, confirms the agreement of both parties that the clinical study will be 
conducted in accordance with the protocol and all applicable laws and regulations 
including, but not limited to, the International Conference on Harmonization Guideline 
for Good Clinical Practice (GCP) R2, the Code of Federal Regulations (CFR), and the 
ethical principles that have their origins in the Declaration of Helsinki. 
 
 
 
 
 
 
 
Date of Signature 
 
 
(DD MMM YYYY) 
Kadmon Corporation, LLC 
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE  
 
I have read and approve this protocol. My signature, in conjunction with the signature of 
the sponsor, confirms the agreement of both parties that the clinical study will be 
conducted in accordance with the protocol and all applicable laws and regulations 
including, but not limited to, the International Conference on Harmonization Guideline 
for Good Clinical Practice (GCP) R2, the Code of Federal Regulations (CFR), and the 
ethical principles that have their origins in the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide 
emergency medical care under applicable regulations.  
 
 
 
 
 
Investigator Signature 
 
Date of Signature 
 
 
(DD MMM YYYY) 
 
 
 
 
 
 
Name of Investigator (please print) 
 
 
 
 
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PROTOCOL SYNOPSIS  
Study Title 
A Phase 2, Open-label Multicenter Study to Evaluate the Efficacy and 
Safety of Belumosudil in Subjects with Diffuse Cutaneous Systemic 
Sclerosis 
Clinical Phase 
2 
Number of Study Centers 
5-6 sites 
Study Background 
Systemic sclerosis, also known as scleroderma, is a chronic autoimmune 
disease primarily affecting the skin, but with systemic manifestations. 
Diffuse cutaneous systemic sclerosis is a more serious form of the 
disease and is often rapidly progressive, involving not only the skin but 
also internal organs including kidney, heart, and lungs. 
The estimated annual incidence of systemic sclerosis in the United States 
is 20 cases per million with a prevalence of 240 cases per million 
population. Racial disparities exist and there is an increased incidence 
and severity in African-Americans. Women are far more likely to acquire 
the disease and make up 80%˗90% of the systemic sclerosis population. 
It has been estimated that up to 60% of systemic sclerosis patients will 
develop interstitial lung disease. This interstitial disease begins with an 
inflammatory alveolitis suggesting that anti-inflammatory therapy may 
be of benefit at early stages. 
Systemic sclerosis has the highest case-specific mortality among all 
systemic autoimmune diseases. Pulmonary hypertension, pulmonary 
fibrosis, and cardiac complications are the most frequent causes of death. 
The single most common cause of mortality is pulmonary fibrosis from 
interstitial lung disease. 
There remains a substantial unmet medical need for therapies with 
improved tolerability and effectiveness for patients with systematic 
sclerosis. 
The pathogenesis of diffuse cutaneous systemic sclerosis (dcSSc) 
involves a variety of abnormalities, including 
immunological/inflammatory activation and vascular injury. The 
important role of T lymphocytes is well established and involves both IL-
17-producing helper T cells (Th17) and regulatory T cell (Treg) subsets.  
Generally, Th17 cells upregulate inflammation and fibrosis while Treg 
cells provide an immunosuppressive opposing function.  An imbalance of 
these immunomodulatory cell types may contribute to the pathogenesis 
of dcSSc.   
Several signaling pathways are activated and converge to create the pro-
fibrotic state commonly seen in dcSSc.  Importantly, extracellular 
mediators such as transforming growth factor-beta (TGF-β) and Wnt10b 
cause fibroblast activation and differentiation into myofibroblasts 
resulting in increased extracellular matrix deposition, collagen cross-
linking, matrix remodeling, and tissue stiffness.  Thus, fibrotic 
mechanisms appear to play a central role in the pathogenesis of systemic 
sclerosis. 
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Study Rationale 
Rho-associated coiled-coil containing protein kinases (ROCK) are 
members of the serine/threonine kinase family, often studied for their 
role in cell morphology, motility, and shape through effects on the 
cytoskeleton. Two ROCK isoforms have been identified: ROCK1 and 
ROCK2. While both are involved in Rho-mediated changes in the 
actin/myosin cytoskeletal network, ROCK1 and ROCK2 are not 
redundant signaling molecules and may serve different functions within 
cells. Recent research has uncovered additional roles for ROCK 
signaling, in conditions including autoimmune disease aggravated or 
caused by a Th17-polarized T cell response and pulmonary fibrosis. Rho 
GTPase-mediated signaling pathways play a central role in coordinating 
and balancing T cell mediated immune responses, including T cell 
receptor-mediated signaling, cytoskeletal reorganization, and the 
acquisition of the appropriate T cell effector program. 
Studies have demonstrated that aberrant activation of ROCK2 leads to 
induction of interleukin (IL)-17 and IL-21 via interferon regulatory 
factor 4-dependent mechanism. In addition, ROCK activity was found to 
be up-regulated in patients with rheumatoid arthritis and systemic lupus 
erythematosus and inhibition of ROCK2 effectively decreased IL-17 
production in vivo and demonstrated efficacy in arthritis and lupus 
mouse models. Autoimmunity also involves alterations to regulatory 
T cells that suppress activation of the immune system and play a critical 
role in maintaining immunological tolerance to self-antigens and 
inhibiting autoimmune responses. ROCK2 inhibition may increase the 
suppressive function of regulatory T cells. 
ROCK is also downstream of several major pro-fibrotic mediators, 
including TGF-β, connective tissue growth factor (CTGF), and 
lysophosphatidic acid. A defining feature of pathologic fibrosis is the 
differentiation of fibroblasts to myofibroblasts, a process mediated by 
ROCK. In addition, ROCK mediates stress fiber formation and regulates 
the transcription of pro-fibrotic genes, including CTGF and alpha-smooth 
muscle actin. Further, ROCK inhibition has demonstrated anti-fibrotic 
activity in murine models. 
Study Objective(s) 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of 
belumosudil using the Combined Response Index in diffuse cutaneous 
Systemic Sclerosis (CRISS) at Week 24.  
 
Secondary Objectives  
• 
To assess CRISS at Weeks 8, 16, 36, and 52 
• 
To evaluate the efficacy of belumosudil at Week 24 for: 
o 
Modified Rodnan Skin Score (mRSS) 
o 
Forced Vital Capacity (FVC) 
o 
Physician Global Assessment 
o 
Patient Global Assessment 
o 
Scleroderma Health Assessment Questionnaire–Disability 
Index (SHAQ-DI) 
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• 
To evaluate the efficacy of belumosudil at Weeks 8, 16, 36, and 52 
compared to baseline for all subjects for the parameters in the bullet 
above 
• 
To assess the safety of belumosudil in subjects with dcSSc by 
examining the percentage of subjects with treatment-emergent 
adverse events (CTCAE v5.0) 
Exploratory Objectives 
• 
 
 
 
 
 
 
 
  
Study Design 
Phase 2, open-label, multicenter trial in subjects with dcSSc 
Methodology 
Subjects who have signed an Institutional Review Board/Independent 
Ethics Committee-approved informed consent form and met all of the 
inclusion/exclusion criteria will be enrolled.  A total of 12-15 subjects 
will receive orally administered belumosudil 200 mg twice daily (BID) 
for 52 weeks.  Study drug will be collected at the end of Week 52.  
The primary endpoint will be analyzed using Week 24 data. 
Efficacy will be assessed at baseline and throughout the 52 weeks of the 
treatment period using CRISS, mRSS, pulmonary function tests (PFTs), 
Physician Global Assessments, and Patient Global Assessments. Safety 
will be assessed throughout the study. 
Subjects will undergo evaluations as outlined in the Study Assessment 
table. A 4-Week Follow-Up visit will occur 28 days (± 3 days) after the 
last dose of study drug.  
Approximate Number of 
Subjects 
12 to 15 subjects will be enrolled. 
Approximate Duration of 
Subject Participation 
Approximately 14 months of study duration:  4-week screening period, 
52-week treatment period, and 4-week follow-up 
Diagnosis and Main 
Criteria for Inclusion and 
Exclusion 
Inclusion Criteria: 
1. Male and female subjects ≥ 18 years old with the diagnosis of dcSSc 
according to the 2013 American College of Rheumatology and 
European League Against Rheumatism criteria  
2. Must have disease duration (defined as interval from first 
non-Raynaud disease manifestation) of ≤ 6 years 
3. Must have mRSS of ≥ 15 but ≤ 40 
4. Must have active disease as determined by the Principal Investigator 
within the 6 months prior to screening  
5. Adequate organ and bone marrow functions evaluated during the 
28 days prior to enrollment as follows: 
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a. 
Absolute neutrophil count ≥ 1.5 × 109/L  
b. Platelet count ≥ 100 × 109/L  
c. 
Total bilirubin ≤ 1.0 × upper limit of normal (ULN) 
d. Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and serum creatinine 
≤ 1.5 × ULN. 
6. Female subjects of childbearing potential have a negative pregnancy 
test at screening.  Females of childbearing potential are defined as 
sexually mature women without prior hysterectomy or who have had 
any evidence of menses in the past 12 months. However, women 
who have been amenorrheic for 12 or more months are still 
considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, anti-estrogens, or ovarian 
suppression. 
a. 
Women of childbearing potential (i.e., menstruating 
women) must have a negative urine pregnancy test (positive 
urine tests are to be confirmed by serum test) documented 
within the 24-hour period prior to the first dose of study 
drug.  
b. Sexually active women of childbearing potential enrolled in 
the study must agree to use two forms of accepted methods 
of contraception during the course of the study and for 
3 months after their last dose of study drug.  Effective birth 
control includes (i) intrauterine device plus 1 barrier 
method; (ii) on stable doses of hormonal contraception for 
at least 3 months (e.g., oral, injectable, implant, 
transdermal) plus 1 barrier method; or (iii) 2 barrier 
methods.  Effective barrier methods are male or female 
condoms, diaphragms, and spermicides (creams or gels that 
contain a chemical to kill sperm), or a vasectomized 
partner. 
7. For male patients who are sexually active and who are partners of 
premenopausal women: agreement to use 2 forms of contraception 
as in criterion number 6b above during the treatment period and for 
at least 3 months after the last dose of study drug. 
8. Male subjects must not donate sperm for 3 months after last dose of 
study drug. 
9. Able to provide written informed consent prior to the performance of 
any study-specific procedures. 
 
Exclusion Criteria: 
1. Subject has corrected QT interval using Fridericia’s formula (QTcF) 
> 450 ms 
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2. Ongoing use or current use of concomitant medication known to 
have the potential for QTc prolongation 
3. Female subject who is pregnant or breastfeeding. 
4. Participated in another study with an investigational drug within 
28 days of study entry (for studies involving biologics, within three 
half-lives of the biologic). 
5. History or other evidence of severe illness or any other conditions 
that would make the subject, in the opinion of the Investigator, 
unsuitable for the study. 
6. Chronic heart failure with New York Heart Association Classes II, 
III, or IV. 
7. Acute or chronic liver disease (e.g., cirrhosis) 
8. Positive human immunodeficiency virus (HIV) test. 
9. Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive 
whole blood tuberculin test. 
10. Diagnosed with any malignancy within 3 years of enrollment, with 
the exception of basal cell or completely resected squamous cell 
carcinoma of the skin, resected in situ cervical malignancy, resected 
breast ductal carcinoma in situ, or low-risk prostate cancer after 
curative resection. 
11. Has had previous exposure to belumosudil or known 
allergy/sensitivity to belumosudil, or any other ROCK2 inhibitor. 
12. Scleroderma renal crisis within 4 months prior to enrollment. 
13. FVC ≤ 50%. Predicted. 
Test Article(s)  
Belumosudil will be provided as 200 mg tablets. 
Dosage and Administration  
All subjects will receive belumosudil 200 mg BID. 
Reference Therapy 
Not applicable   
Duration of Treatment 
Study drug dosing will be for 52 weeks. 
Concomitant Treatment 
 
All medications a subject receives from the signing of informed consent 
through the 28-Day Follow-up visit will be documented. 
• 
CYP3A4 inhibitors/inducers should be used with caution. 
  
• 
Subjects on concomitant medications known to have the potential for 
QTc prolongation will be excluded. 
Safety Evaluation 
Safety data will be collected from the time the subject signs the informed 
consent form (ICF) until 28 days after their last dose of study drug (the 
adverse event [AE] reporting period). The primary safety outcome will 
be the percentage of subjects experiencing treatment emergent AEs 
(TEAEs).   
Safety assessments will include AEs, serious adverse events (SAEs), 
physical; examinations (PEs), vital sign measurements (blood pressure, 
pulse rate, respiratory rate, and temperature), clinical laboratory 
evaluations (hematology, chemistry and urinalysis), and 
electrocardiograms (ECGs).  Reasons for treatment discontinuation 
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because of toxicity will be documented.  Careful monitoring of all 
toxicities will be carried out.   
Efficacy/Activity 
Evaluation 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the effect of belumosudil on CRISS, an 
exponential algorithm determining the predicted probability of 
improvement from baseline, incorporating changes in mRSS, FVC % 
predicted, physician and Patient Global Assessments, and SHAQ-DI.  
The outcome is a continuous variable between 0.0 and 1.0 (0-100%).  A 
higher score indicates greater probability of improvement.  A CRISS 
score ≥ 20% is considered a clinically meaningful improvement. 
 
Secondary Efficacy Endpoints 
Secondary efficacy outcomes include the change from baseline in mRSS, 
FVC, SHAQ-DI, Physician Global Assessment, and Patient Global 
Assessment for KD025-treated subjects.   
Progression of interstitial lung disease (if present) will be evaluated by 
the effect of belumosudil on the change in predicted FVC. 
 
Exploratory Endpoints 
 
   
Pharmacokinetics 
No pharmacokinetic analysis will be conducted in this study.  
Pharmacodynamics 
 
 
 
 
 
 
 
Statistical Analysis  
This study will inform future development of belumosudil in dcSSc. The 
sample size is not driven by hypothesis testing. 
Two populations will be employed in the analysis of study data:  
• 
The Modified Intent-to-Treat (mITT) Population will consist of 
all subjects who receive at least 1 dose of study drug.   
• 
The Evaluable for Efficacy/Activity Population will consist of 
subjects who have received at least 80% of expected study drug 
and have post-baseline efficacy data.   
The primary endpoint will be analyzed on the mITT Population. 
Demographics, subject disposition, and baseline characteristics will be 
summarized in each population. 
Efficacy will be evaluated by Week 24 CRISS scores.  Secondary 
endpoints will include changes in mRSS, FVC, SHAQ-DI, Physician 
Global Assessment, and Patient Global Assessment from baseline to 
Week 24. 
Treatment-emergent AEs will be evaluated using the CTCAE v 5.0 and 
will be summarized using the Medical Dictionary for Regulatory 
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Activities (MedDRA) Version 21.0 or higher System Organ Class (SOC) 
and Preferred Term (PT), classified from verbatim terms. The incidence 
and percentage of subjects with at least one occurrence of a PT will be 
included, according to the most severe grade using a 5-point scale (mild, 
moderate, severe, life threatening, or death). The number of events per 
PT will also be summarized.  Causality (relationship to study treatment) 
will be summarized separately. 
Adverse events, SAEs, related AEs, related SAEs, Grade ≥ 3 AEs, 
related Grade ≥ 3 AEs, and AEs leading to withdrawal, or treatment 
discontinuation will be summarized according to SOC and PT. Adverse 
events will also be presented in listings. Duration of AEs will be 
determined and included in listings, along with action taken and 
outcome. 
Laboratory results will be graded using the CTCAE v5.0. Incidence of 
laboratory abnormalities will be summarized.  The worst on-study grade 
after the first dose of study drug will be summarized.  The incidence of 
Grade ≥ 3 laboratory abnormalities under treatment and shifts in toxicity 
grading from baseline to highest-grade post-baseline will be displayed.   
Vital sign measurements and ECGs will be summarized at each 
scheduled time point using descriptive statistics and included in data 
listings. 
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Table of Contents  
 
CLINICAL STUDY PROTOCOL ..................................................................................... 1 
SPONSOR APPROVAL SIGNATURE PAGE ........................................................... 3 
INVESTIGATOR SIGNATURE PAGE ...................................................................... 4 
PROTOCOL SYNOPSIS ................................................................................................ 5 
1. 
Introduction ............................................................................................................... 18 
1.1 
Background ..................................................................................................... 18 
1.2 
Rho-Associated Protein Kinase ...................................................................... 18 
1.3 
Belumosudil Nonclinical Experience ............................................................. 19 
1.4 
Clinical Experience ......................................................................................... 20 
1.4.1 
Clinical Pharmacokinetics .......................................................................... 20 
1.4.2 
Clinical Summary ....................................................................................... 26 
1.5 
Study Rationale............................................................................................... 27 
1.6 
Dose Rationale ................................................................................................ 28 
2. 
Study Objectives ....................................................................................................... 29 
2.1 
Primary Objective ........................................................................................... 29 
2.2 
Secondary Objectives ..................................................................................... 29 
2.3 
Exploratory Objectives ................................................................................... 29 
3. 
Investigational Plan ................................................................................................... 30 
3.1 
Study Design................................................................................................... 30 
3.2 
Number of Subjects ........................................................................................ 30 
3.3 
Study Centers .................................................................................................. 30 
3.4 
Inclusion Criteria ............................................................................................ 30 
3.5 
Exclusion Criteria ........................................................................................... 32 
3.6 
Screening ........................................................................................................ 32 
3.7 
Withdrawal Criteria ........................................................................................ 33 
3.8 
Replacements .................................................................................................. 33 
3.9 
Treatment Discontinuation ............................................................................. 33 
4. 
Study Treatment ........................................................................................................ 35 
4.1 
Investigational Product ................................................................................... 35 
4.2 
Dosage and Administration ............................................................................ 35 
4.3 
Treatment Assignment .................................................................................... 35 
4.4 
Blinding .......................................................................................................... 35 
4.5 
Treatment Compliance ................................................................................... 35 
4.6 
Missed Doses .................................................................................................. 35 
4.7 
Product Accountability ................................................................................... 36 
4.8 
Concomitant Medication and Therapies ......................................................... 36 
4.9 
CYP3A4 Inhibitors/Inducers .......................................................................... 36 
4.10 
Drugs Prolonging the QTc Interval ................................................................ 36 
4.11 
Overdose ......................................................................................................... 36 
4.12 
Dose Modification Guidelines ........................................................................ 37 
5. 
Study Assessments and Procedures .......................................................................... 38 
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5.1 
Screening Period (Day -29 to -1) .................................................................... 38 
5.2 
Treatment Period ............................................................................................ 38 
5.2.1 
Week 1 Day 1 Visit (Baseline) ................................................................... 39 
5.2.2 
End of Week 2 (Day 15 ± 3) Visit .............................................................. 39 
5.2.3 
End of Week 4 (Day 29 ± 3 Days) Visit ..................................................... 40 
5.2.4 
End of Week 8 (Day 57 ± 3 Days) Visit ..................................................... 40 
5.2.5 
End of Week 12 (Day 85 ± 3 Days) Visit ................................................... 41 
5.2.6 
End of Week 16 (Day 113 ± 3 Days) .......................................................... 41 
5.2.7 
End of Week 20 (Day 141 ± 3 Days) Visit ................................................. 42 
5.2.8 
End of Week 24 (Day 169 ± 3 Days) Visit ................................................. 42 
5.2.9 
End of Weeks 28 and 32 (Days 197 and 225 ± 3 Days) Visits ................... 43 
5.2.10 End of Week 36 (Day 253 ± 3 Days) Visit ................................................. 43 
5.2.11 End of Week 40, 44, and 48 (Days 281, 309 and 337 ± 3 Day) Visits ....... 44 
5.2.12 End of Treatment (EOT) Or End of Week 52, (Day 365 ± 3 Days) ........... 44 
5.3 
28-day Follow-up Visit ................................................................................... 45 
5.4 
Unscheduled Visit........................................................................................... 46 
6. 
Efficacy and Safety Assessments.............................................................................. 47 
6.1 
Efficacy Endpoints ......................................................................................... 47 
6.1.1 
Primary Efficacy Endpoint ......................................................................... 48 
6.1.2 
Secondary Efficacy Endpoints .................................................................... 48 
6.1.3 
Exploratory Endpoints ................................................................................ 48 
6.2 
Safety Endpoints ............................................................................................. 49 
6.2.1 
Vital Signs ................................................................................................... 49 
6.2.2 
Physical Examination.................................................................................. 49 
6.2.3 
12-Lead ECG .............................................................................................. 49 
6.2.4 
Clinical Laboratory Parameters .................................................................. 50 
6.2.5 
Pregnancy Testing ....................................................................................... 51 
7. 
Pharmacokinetics ...................................................................................................... 52 
8. 
Pharmacodynamics ................................................................................................... 53 
9. 
Safety ........................................................................................................................ 54 
9.1 
Safety Parameters ........................................................................................... 54 
9.2 
Adverse Event Definition ............................................................................... 54 
9.3 
Evaluating Adverse Events ............................................................................. 55 
9.3.1 
Serious Adverse Events .............................................................................. 55 
9.3.2 
Protocol-related Adverse Events ................................................................. 56 
9.3.3 
Relationship to Study Drug ......................................................................... 56 
9.3.4 
Recording Adverse Events .......................................................................... 57 
9.3.5 
Hospitalization ............................................................................................ 57 
9.3.6 
Serious Adverse Event Reporting ............................................................... 57 
9.4 
Follow-up for Adverse Events ........................................................................ 60 
9.5 
Other Safety Considerations ........................................................................... 61 
9.5.1 
Laboratory Data .......................................................................................... 61 
9.5.2 
Medication Errors ....................................................................................... 61 
9.6 
Study  Stopping  Rules ................................................................................... 61 
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9.6.1 
Stopping Rules for Study ............................................................................ 61 
9.6.2 
Stopping Criteria for Subjects ..................................................................... 61 
9.7 
Statistical Considerations ............................................................................... 62 
9.7.1 
Hypothesis................................................................................................... 62 
9.7.2 
Sample Size ................................................................................................. 62 
9.7.3 
Analysis Populations ................................................................................... 62 
9.7.4 
Data Analysis .............................................................................................. 62 
9.7.5 
Interim Analysis .......................................................................................... 62 
9.8 
Efficacy Analysis ............................................................................................ 63 
9.8.1 
Primary Efficacy Endpoint ......................................................................... 63 
9.8.2 
Secondary Efficacy Endpoints .................................................................... 63 
9.8.3 
Exploratory Analyses .................................................................................. 63 
9.8.4 
Analysis Method ......................................................................................... 63 
9.9 
Safety Analyses .............................................................................................. 64 
9.10 
Pharmacokinetic Analyses .............................................................................. 64 
9.11 
Pharmacodynamic Analyses ........................................................................... 64 
9.12 
Data Quality Assurance .................................................................................. 65 
10. 
Regulatory Obligations .......................................................................................... 66 
11. 
Ethical Aspects....................................................................................................... 67 
11.1 
Local regulations ............................................................................................ 67 
11.2 
Informed Consent ........................................................................................... 67 
11.3 
Institutional Review Board ............................................................................. 68 
11.4 
Future Use of Subject Samples ....................................................................... 68 
12. 
Conditions for Modifying the Protocol .................................................................. 69 
13. 
Conditions for Terminating the Study ................................................................... 70 
14. 
Study Documentation, CRFs and Record Keeping................................................ 71 
14.1 
Investigator’s Files and Retention of Documents........................................... 71 
14.2 
Source Documents and Background Data ...................................................... 71 
14.3 
Audits and Inspections.................................................................................... 72 
14.4 
Electronic Case Report Forms ........................................................................ 72 
15. 
Monitoring of the study ......................................................................................... 73 
16. 
Confidentiality of Trial Documents and Subject Records ..................................... 74 
17. 
Publication of Data and Protection of Trade Secrets ............................................. 75 
18. 
References .............................................................................................................. 76 
19. 
Appendix A:  Schedule of Assessments ................................................................ 79 
20. 
Appendix B:  Calculation of Modified Rodnan Skin Score .................................. 81 
21. 
Appendix C:  Scleroderma Health Assessment Questionnaire .............................. 82 
22. 
Appendix D:  Physician Global Assessment ......................................................... 85 
23. 
Appendix E:  Patient Global Assessment .............................................................. 86 
24. 
Appendix F:  Determining Relationship of Adverse Events to Study Drug .......... 87 
25. 
Appendix G:  Drugs That Induce and Inhibit CYP3A4 ......................................... 89 
26. 
Appendix H:  Drugs Known to Have the Potential for QTc Prolongation ............ 90 
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List of Tables 
Table 1 
Cohorts (Treatment Groups in KD025-211 Study Design ............................. 23 
Table 2 
Guidelines for Management of Treatment-emergent Toxicities .................... 37 
Table 3 
Clinical Laboratory Panels ............................................................................. 50 
 
List of Figures 
No table of figures entries found. 
 
 
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List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BA/BE 
Bioavailability/Bioequivalence 
BID 
Twice daily 
BP 
Blood pressure 
BSC 
Best supportive care 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CPK 
Creatinine phosphokinase 
CRISS 
Combined Response Index in Diffuse Cutaneous Systemic Sclerosis 
cGVHD 
Chronic graft versus host disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTGF 
Connective tissue growth factor 
CYP3A4 
Cytochrome P450 3A4 
dcSSc 
Diffuse cutaneous systemic sclerosis 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
 
 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume (in the first second) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
ILD 
Interstitial lung disease 
IND 
Investigational New Drug 
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IP 
investigational product 
IPF 
Idiopathic pulmonary fibrosis 
IRB 
Institutional review board 
LFT 
Liver function tests 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mRSS 
Modified Rodnan Skin Score 
OECD 
Organisation for Economic Cooperation and Development 
PASI 
Psoriasis Area and Severity Index 
PD 
Pharmacodynamic 
PE 
Physical examination 
PFT 
Pulmonary function test 
PO 
Oral(ly) 
PPI 
Proton pump inhibitor 
PT 
Preferred Term 
QD 
Once daily 
QTc(F) 
Corrected QT interval using Fridericia's formula 
RNA 
Ribonucleic acid 
ROCK 
Rho-associated protein kinase 
SAE 
Serious adverse event 
SHAQ-DI 
Scleroderma Health Assessment Questionnaire—Disability Index 
SOC 
System organ class 
SSc 
Systemic sclerosis 
STAT 
Signal transducer and activator of transcription 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TGF 
Transforming growth factor 
Th17 
Helper T cells 
TLC 
Total lung capacity 
Treg 
Regulatory T-cells 
ULN 
Upper limit of normal 
VAS 
Visual Analog Scale 
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1. INTRODUCTION  
1.1 
BACKGROUND  
Systemic sclerosis, also known as scleroderma, is a chronic autoimmune disease 
primarily affecting the skin, but with systemic manifestations. Diffuse cutaneous 
systemic sclerosis is a more serious form of the disease and is often rapidly progressive, 
involving not only the skin but also internal organs including kidney, heart, and lungs.(1) 
The estimated annual incidence of systemic sclerosis in the United States is 20 cases per 
million with a prevalence of 240 cases per million population.(2,3,4) Racial disparities exist 
and there is an increased incidence and severity in African-Americans. Women are far 
more likely to acquire the disease and make up 80%˗90% of the systemic sclerosis 
population.(5) 
It has been estimated that up to 60% of systemic sclerosis patients will develop interstitial 
lung disease. This interstitial disease begins with an inflammatory alveolitis suggesting 
that anti-inflammatory therapy may be of benefit at early stages.(6,7) 
Systemic sclerosis has the highest case-specific mortality among all systemic 
autoimmune diseases. Pulmonary hypertension, pulmonary fibrosis, and cardiac 
complications are the most frequent causes of death. The single most common cause of 
mortality is pulmonary fibrosis from interstitial lung disease.(8) 
There remains a substantial unmet medical need for therapies with improved tolerability 
and effectiveness for patients with systematic sclerosis. 
1.2 
RHO-ASSOCIATED PROTEIN KINASE  
Rho-associated coiled-coil containing protein kinases (ROCK) are members of the 
serine/threonine kinase family, often studied for their role in cell morphology, motility 
and shape through effects on the cytoskeleton. Two ROCK isoforms have been identified, 
ROCK1 and ROCK2.(9,10,11,12) While both are involved in Rho-mediated changes in the 
actin/myosin cytoskeletal network, ROCK1 and ROCK2 are not redundant signaling 
molecules and may serve different functions within cells.(13,14,15) Recent research has 
uncovered additional roles for ROCK signaling, in conditions including autoimmune 
disease aggravated or caused by a helper T cell (Th17)-polarized T cell response(16) and 
pulmonary fibrosis.(17) Rho GTPase-mediated signaling pathways play a central role in 
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coordinating and balancing T cell mediated immune responses, including T cell receptor-
mediated signaling, cytoskeletal reorganization, and the acquisition of the appropriate 
T cell effector program.(18) 
Studies have demonstrated that aberrant activation of ROCK2 leads to induction of 
interleukin (IL)-17 and IL-21 via interferon regulatory factor 4-dependent mechanism.(19) 
In addition, ROCK activity was found to be up-regulated in patients with rheumatoid 
arthritis and systemic lupus erythematosus(20) and inhibition of ROCK2 effectively 
decreased IL-17 production in vivo and demonstrated efficacy in arthritis and lupus 
mouse models. Autoimmunity also involves alterations to regulatory T cells that suppress 
activation of the immune system and play a critical role in maintaining immunological 
tolerance to self-antigens and inhibiting autoimmune responses.(21) ROCK2 inhibition 
may increase the suppressive function of regulatory T cells. 
ROCK is also downstream of several major pro-fibrotic mediators, including 
transforming growth factor beta, connective tissue growth factor (CTGF), and 
lysophosphatidic acid. A defining feature of pathologic fibrosis is the differentiation of 
fibroblasts to myofibroblasts, a process mediated by ROCK. In addition, ROCK mediates 
stress fiber formation and regulates the transcription of pro-fibrotic genes, including 
CTGF and alpha-smooth muscle actin. Further, ROCK inhibition has demonstrated anti-
fibrotic activity in murine models. 
1.3 
BELUMOSUDIL NONCLINICAL EXPERIENCE  
In vitro, belumosudil has demonstrated an impact on the T-helper 17 (Th17) and regulatory 
T cells (Treg)-immune responses as well as on the actin/myosin cytoskeletal network and 
collagen formation. In vivo, belumosudil has demonstrated efficacy in a variety of clinically 
relevant animal models of disease including chronic graft versus host disease (cGVHD), 
scleroderma, idiopathic pulmonary fibrosis (IPF), and other autoimmune diseases. 
Good Laboratory Practice (GLP) compliant rat and dog general toxicology/toxicokinetic 
studies of acute, subchronic (1-and 3-month), and chronic (6-month rat and 9-month dog) 
duration have been completed. In addition, safety pharmacology (human ether-à-go go 
related gene [in vitro], central nervous system [rat], respiratory [rat], and cardiovascular 
[dog]), embryo-fetal toxicology [rat and rabbit], male/female fertility [rat]), genotoxicity, and 
phototoxicity studies have also been completed. The primary nonclinical toxicology finding 
at/near clinically relevant exposures were limited to changes in the cardiovascular (blood 
pressure [BP] lowering), hepatic (transaminitis, hypertrophy/increased organ weight, and 
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cholestasis/inflammation), renal (increased blood urea nitrogen [BUN], tubular changes, 
pigmentation, intracellular protein droplets in the epithelium), gastrointestinal (decreased 
appetite), and hematopoietic/immunologic (anemia with regeneration and thymic/splenic 
lymphoid depletion) systems. 
Belumosudil demonstrated embryo-fetal toxicity/teratogenicity as well as reduced male 
fertility (reduced fertility index/sperm concentration/motility and increased abnormal sperm 
percentage), and changes in the testes/epididymis (decreased organ weights and degenerative 
histopathology). Male fertility findings were generally at higher than clinically relevant 
exposures. 
All pivotal non-clinical safety studies (i.e., those studies identified in International 
Conference on Harmonisation guidelines as needing to be conducted in accordance with 
GLP) were conducted in a country that is a member of the Organisation for Economic 
Cooperation and Development (OECD) Mutual Acceptance of Data program in accordance 
with the OECD Test Guidelines and Principles of GLP. Study details and potential 
clinically relevant findings from these studies are summarized in the belumosudil 
Investigator’s Brochure (IB). 
1.4 
CLINICAL EXPERIENCE  
1.4.1 Clinical Pharmacokinetics  
Following a single oral dose of belumosudil 200 mg in the fed state, the mean absolute 
bioavailability (%F) was 64%. Systemic exposure of belumosudil was increased when 
administered in the fed state, and in ongoing and planned clinical studies, belumosudil 
should be taken with food or within 5 minutes of eating. 
Across all clinical studies, observed time to reach maximum concentration for 
belumosudil, belumosudilm1, and belumosudilm2 has ranged from 2-4 hours, and the 
belumosudil terminal elimination half-life averages ~7 hours following single or multiple 
dose administration. Exposure of belumosudil (maximum concentration observed and 
area under concentration curve) in healthy subjects appears to be slightly greater than 
dose proportional over the 20 to 500 mg once daily (QD) dose range, but less than dose 
proportional for doses above 500 mg. Little to no accumulation of belumosudil or 
metabolites, KD025m1 or KD025m2, was observed following multiple dose 
administration. KD025m1 and KD025m2 exposures are < 5% and ≤ 20%, respectively, 
of belumosudil exposure. 
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A [14C]-belumosudil human absorption, metabolism, and excretion study confirmed that 
the majority of radioactivity was recovered in feces (85%), with < 5% recovered in urine. 
This indicates minimal renal elimination and that the predominant route of clearance of 
belumosudil and associated metabolites is biliary and/or intestinal. 
Cytochrome P450 3A4 (CYP34A) likely plays a predominant role in the metabolism of 
belumosudil, and in a clinical drug-drug interaction study in healthy volunteers, co-
administration with itraconazole (CYP3A4 inhibitor) resulted in a modest 20-25% 
increase in belumosudil exposure, while co-administration with rifampicin (CYP3A4 
inducer) led to a 60-70% reduction in belumosudil exposure. 
A delay in absorption and a reduction in belumosudil exposure were observed when 
belumosudil was co-administered with proton pump inhibitors (PPI) rabeprazole (80-90% 
decrease) or omeprazole (50-70% decrease), consistent with the finding that increased pH 
leads to decreased solubility of belumosudil. The clinical relevance of this interaction 
with PPIs is being evaluated in ongoing studies. 
1.4.1.1 Chronic Graft Versus Host Disease  
KD025-208 is an ongoing phase 2a, dose-escalation, open-label study to evaluate the 
safety, tolerability, and activity of belumosudil in subjects with cGVHD who have 
previously received 1-3 prior lines of treatment.  The majority of subjects enrolled had 
cGVHD affecting at least 4 organs.  Preliminary data from Cohort 1 (200 mg QD, 
n = 17), Cohort 2 (200 mg twice daily [BID], n = 16), and Cohort 3 (400 mg QD, n = 18) 
show encouraging activity of belumosudil with response rates of 65%, 69% and 33%, 
respectively.  Responses have been durable.  Among responders in Cohort 1, 8/11 (73%) 
have sustained the response for ≥ 20 weeks.  Data continue to mature in this ongoing 
study.  Fifty-nine (59%) of subjects have achieved reductions in corticosteroid doses, 
with 10% discontinuing systemic corticosteroid therapy completely.  Across the 3 
cohorts, 61% of responders and 26% of non-responders have reported improvements in 
the Lee Symptom Scale score. KD025-213 is another study in cGVHD which is currently 
ongoing at multiple sites in the U.S. Over one hundred subjects have been enrolled and 
this study will be submitted as a potential registration study for cGVHD in 2020. 
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1.4.1.2 Idiopathic Pulmonary Fibrosis  
KD025-207 is an ongoing, randomized, phase 2, open-label, multicenter study to evaluate 
the safety, tolerability, and activity of belumosudil in subjects with IPF who have 
received pirfenidone and/or nintedanib or been offered both prior to enrollment.  Subjects 
are randomized 2:1 to receive 400 mg belumosudil QD or best supportive care (BSC). 
Forty subjects have been enrolled: 26 to the belumosudil arm and 14 subjects to the BSC 
arm.  Nine BSC subjects have crossed over to the belumosudil arm.  This study has been 
extended to enroll an additional 40 subjects. 
Preliminary results demonstrate clinical activity of belumosudil in the treatment of IPF.  
In the modified intent to treat (mITT) population, there was an absolute median change in 
forced vital capacity (FVC) of 50 mL at Week 24 in subjects treated with belumosudil, 
compared to -175 mL in subjects treated with BSC.  The decline in percentage predicted 
FVC was 1% with belumosudil versus 5% with BSC. 
Overall, at Week 24, 29% of belumosudil patients had experienced an FVC decline ≥ 5%, 
compared to 55% of BSC patients.  
1.4.1.3  Psoriasis  
In KD025-205, a study of 8 subjects with moderately severe psoriasis who had failed at 
least 1 line of systemic therapy, the mean Psoriasis Area and Severity Index (PASI) score 
decreased with 28 days of treatment by 1.1 (not statistically significant) from a mean 
baseline of 17.5.  Some subjects experienced slight improvement in scaling and softening 
of plaques. 
KD025-206 was a phase 2, open-label, safety and tolerability study of belumosudil 
dosing in 38 subjects with psoriasis vulgaris who had disease progression after at least 
one systemic therapy.  The mean baseline PASI score was 19.8.  The changes from 
baseline PASI scores were -8.8 (belumosudil 200 mg), -6.0 (belumosudil 400 mg QD) 
and -4.8 (belumosudil 400 mg BID) and were statistically significant for each treatment 
group and overall.  Reductions of 50% in PASI scores were observed in 42% (200 mg 
BID), 50% (400 mg QD), and 18% (400 mg BID) of subjects. 
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KD025-211 was a Phase 2, two-period, dose-finding study of the safety, tolerability, and 
efficacy of belumosudil for the treatment of adult male and female subjects with 
moderate to severe chronic plaque psoriasis who were candidates for systemic therapy or 
phototherapy. 
The first period (Week 1 through Week 16) was double-blind and placebo-controlled:  
the Double-blind Treatment Period.  Approximately 110 subjects were randomly 
assigned to each of 5 dose cohorts in a 1:1:1:1:1 manner and were treated for up to 
16 weeks (Table 1). 
Table 1 
Cohorts (Treatment Groups) in KD025-211 Study Design  
Cohort 
Number of Subjects 
Dose 
1 
22 
200 mg belumosudil QD 
2 
22 
200 mg belumosudil BID 
3 
22 
400 mg belumosudil QD 
4 
22 
600 mg belumosudil (400 mg in the morning; 200 mg in the evening) 
5 
22 
Matching placebo BID 
BID = twice daily; QD = once daily 
Study drug was administered orally (PO), with a meal or within 5 minutes of finishing a 
meal, in a double-blind fashion. 
The second period (Week 16 through Week 52) was an open-label study of belumosudil:  
the Open-label Treatment Period.  All subjects were given the option to receive 
belumosudil for an additional 32 weeks.  All subjects in the Open-label Period received 
belumosudil at 400 mg QD, regardless of initial randomization. 
Subject status was collected at screening, Week 1 Day 1 (baseline), and for the evaluation 
of primary and secondary study endpoints.  Response was assessed by PASI, PGA, and 
DLQI scores at scheduled time points throughout the study. 
Subjects underwent medical history evaluations; physical examinations ([PEs] including 
weight, skeletal, and neurological measurements); vital sign measurements; adverse event 
(AE) assessments; concomitant medication assessments; blood sample collection for 
hematology, chemistry, coagulation, lipid panel, and thyroid-stimulating hormone; 
urinalysis; pregnancy testing for females of childbearing potential; photography 
(optional); punch biopsy (optional); and electrocardiogram (ECGs).  
If a subject discontinued from the study prior to 16 weeks, an Early Termination Visit 
was performed, and procedures were conducted immediately upon discontinuation.  For 
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all subjects, including those who discontinued from the study prematurely, a Follow-Up 
Visit occurred 30 days (± 3 days) after the last dose of study drug. 
A placebo control was used in the Double-blind Period of this study.  No control was 
used for the Open-label Continuation Period of the study. 
A total of 110 subjects were randomized and included in the mITT Population: 
23 subjects in the belumosudil 200 mg QD cohort, 22 in the belumosudil 200 mg BID 
cohort, 21 in the belumosudil 400 mg QD cohort, 26 in the belumosudil 600 mg/day 
cohort, and 18 in the placebo cohort.  The Safety Population had the same number of 
subjects as the mITT Population.  Of the 110 subjects in the study, 27.3% (n = 30 
subjects) completed treatment: 39.1% (n = 9) in the belumosudil 200 mg QD cohort; 
27.3% (n = 6) in the 200 mg BID cohort; 42.9% (n = 9) in the 400 mg QD cohort; 15.4% 
(n = 4) in the 600 mg/day cohort; and 11.1% (n = 2) in the placebo cohort.  Overall, the 
most frequent reasons for early study termination were withdrawal by subject (40.9%; 
n = 45 subjects), followed by loss to follow-up (12.7%; n = 14 subjects), and elevated 
liver enzymes (5.5%; n = 6 subjects). 
The primary efficacy end point was the number (%) of subjects with a 75% decrease in 
PASI (PASI 75) by Week 16.  When including subjects who completed 16 weeks of 
treatment and carrying forward the last results of subjects who did not complete 16 weeks 
of treatment, all belumosudil-treated subjects and all belumosudil cohorts had a 
proportion of subjects with PASI 75.  Among all 92 KD025-treated subjects, 10.9% (95% 
confidence interval [CI]: 5.3%, 19.1%; n = 10 subjects) had a PASI 75 at Week 16.  Of 
the 18 subjects in the placebo cohort, 16.7% (95% CI: 3.6%, 41.4%; n = 3 subjects) had a 
PASI 75.  Each belumosudil cohort had a proportion of subjects with PASI 75:  8.7% 
(95% CI: 1.1%, 28.0%; 2/23 subjects) in the 200 mg QD cohort; 9.1% (95% CI: 1.1%, 
29.2%; 2/22 subjects) in the 200 mg BID cohort; 19.0% (95% CI: 5.4%, 41.9%; 4/21 
subjects) in the 400 mg QD cohort; and 7.7% (95% CI: 0.9%, 25.1%; 2/26 subjects) in 
the 600 mg/day cohort.  The proportion of subjects who had a PASI 75 among all 
belumosudil-treated subjects was less than for placebo (-5.8% [95% CI: -24.2%, 12.6%]) 
but the difference was not statistically significantly different (p = 0.4435).  None of the 
belumosudil-treated cohorts had a statistically significant difference compared to the 
placebo cohort: p = 0.6384 for the 200 mg QD cohort; p = 0.6419 for the 200 mg BID 
cohort; p > 0.9999 for the 400 mg QD cohort; and p = 0.3859 for the 600 mg/day cohort. 
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During the Entire Treatment Period, 92 subjects received belumosudil and 18 subjects 
received placebo.  The proportions of TEAEs among all 92 KD025-treated subjects were 
comparable to or less than those occurring among the 18 subjects in the placebo cohort 
were as follows: 
• Severe TEAE:  belumosudil = 8.7% (n = 8 subjects); placebo = 11.1% (n = 2 
subjects) 
• Grade ≥ 3 TEAEs:  belumosudil = 10.9% (n = 10); placebo = 11.1% (n = 2) 
• TEAEs related to study drug:  belumosudil = 30.4% (n = 28); placebo = 33.3% 
(n = 6) 
• Grade ≥ 3 TEAEs considered related to study drug:  belumosudil = 5.4% (n = 5); 
placebo = 5.6% (n = 1) 
• Grade 4:  belumosudil = 1.1% (n = 1); placebo = 0 
• SAEs:  belumosudil = 4.3% (n = 4); placebo = 5.6% (n = 1) 
• SAEs related to study drug:  belumosudil = 0; placebo = 0 
• TEAEs leading to discontinuation:  belumosudil = 16.3% (n = 15; includes SAE); 
placebo = 16.7% (n = 3) 
• Deaths:  belumosudil = 1.1% (n = 1); placebo = 0 
• Deaths related to study drug = 0 
The conclusions of the study were that PO administration of belumosudil improves the 
clinical symptoms of subjects with psoriasis as demonstrated by: 
• Improvement in PASI 75 score at 16 weeks, regardless of dosing regimen 
• Improvement in PASI 75 score at 48 weeks 
• Improvement in DLQI score at 16 weeks 
• Improvement in DLQI score at 48 weeks 
• Generally well-tolerated with no deaths or SAEs considered related to study drug 
1.4.1.4 Other Potential Indications  
Other potential indications include bronchiolitis obliterans and solid organ 
transplantation. 
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In addition to being a pulmonary manifestation of cGVHD, bronchiolitis obliterans is a 
form of chronic lung allograft dysfunction that affects a majority of lung transplant 
recipients and is the principal factor limiting long-term transplant survival. Bronchiolitis 
obliterans is characterized by progressive airflow obstruction unexplained by acute 
rejection, infection, or other coexistent condition.(22) 
Recent data have implicated IL-17 and Th17 cells in the development of autoimmunity 
and chronic rejection after lung transplantation in both animal models and humans.(23) A 
correlation between decreased regulatory T cells and the incidence of bronchiolitis 
obliterans has been reported in lung transplantation recipients.(23) 
There remains substantial unmet medical need for therapies for patients with bronchiolitis 
obliterans. 
The goal of achieving prolonged graft survival in the absence of immunosuppression has 
long been an aspiration of transplant physicians and researchers. One approach for 
inducing immune tolerance has been combined kidney and hematopoietic stem cell 
transplant. Upregulation of the Treg cells may result in higher levels of donor chimerism 
and lead to prolonged graft survival in the absence of immunosuppression in the HLA 
mismatched setting.(24) 
1.4.2 Clinical Summary  
As of 19 February 2020, more than 600 individuals have been dosed with belumosudil as 
participants of phase 1 and phase 2 Kadmon-sponsored studies. 
Single and multiple doses of belumosudil up to 1000 mg appear to be safe and well 
tolerated in phase 1 studies conducted in healthy volunteers. There were few SAEs, all 
unrelated to belumosudil. The most common AEs seen in Phase 1 studies were transient 
increases in transaminases which resolved after cessation of dosing. 
Analysis of Phase 2 safety data from subjects with cGVHD, IPF, and psoriasis suggests 
an acceptable, manageable safety profile for belumosudil. Overall, TEAEs have generally 
been consistent with those expected in the populations enrolled in each of the studies. 
Development of belumosudil is most advanced in the indication of cGVHD. Data from an 
early Phase 2 study, KD025-208, served as the basis for a Breakthrough Therapy 
Designation for belumosudil for the treatment of adult patients with cGVHD. These 
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results were also the basis for a subsequent study, KD025-213 (the ROCKstar Study). 
Subjects who had received 2 to 5 prior lines of systemic therapy for cGVHD were 
enrolled into the ROCKstar study, a population with significant unmet medical need. 
Overall, 132 subjects were randomized to receive either belumosudil 200 mg QD (Arm 
A, n=66) or belumosudil 200 mg BID (Arm B, n=66). Subjects enrolled reflected a real-
world population of complex, advanced cGVHD patients: median age 56 years; male 
57%; 49% had received at least 4 prior lines of systemic therapy; median time from 
transplant to study 29 months; severe cGVHD at baseline 67%; prior treatment with 
ibrutinib 35%. The primary endpoint was met in both dosing arms at the primary analysis 
(6 months after last patient enrolled): overall response rate (95% CI on a mITT basis was 
73.5% (95% CI: 65%, 81%). 
Taken together, the totality of the data support the continued development of 
belumosudil.  
1.5 
STUDY RATIONALE  
Belumosudil is an inhibitor of the ROCK2 isoform.  This family of kinases has been 
shown to have profound activity on cell morphology, motility, and shape through effects 
on the cytoskeleton.  Data show that ROCK2 inhibition has an anti-inflammatory effect 
predominantly through the down-regulation of signal transducer and activator of 
transcription 3 (STAT3) and the Th17 axis.  Thus IL-17, IL-21, and IL-22 are 
downregulated. 
Chronic fibrosis is characterized by myofibroblast resistance to apoptosis.  Inhibition of 
the ROCK pathway has demonstrated a beneficial effect on bleomycin induced fibrosis 
acting through the inhibition of activation of myofibroblasts.  Anti-inflammatory activity, 
coupled with anti-fibrotic activity, suggests that inhibiting the ROCK2 pathway may be 
an effective therapy for inflammatory fibrotic diseases such as lung disease, which is 
associated with the majority of subjects with systemic sclerosis (SSc).  Belumosudil has 
been shown to increase STAT5, which leads to an increase in the Treg population of 
lymphocytes and helps balance the immune system during inflammation. 
Nonclinical pharmacology studies have demonstrated the potential of belumosudil to 
have a therapeutic benefit in a number of indications, particularly in autoimmune and 
fibrotic diseases.  In vitro, belumosudil has demonstrated an impact on the Th17-type 
immune responses as well as on the actin/myosin cytoskeletal network and collagen 
formation.  In vivo, belumosudil has demonstrated efficacy in a variety of clinically 
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relevant animal models of disease including cGVHD, scleroderma, IPF, and other 
autoimmune diseases at clinically relevant drug exposures.  Belumosudil has also been 
shown to significantly decrease the GVHD score in the sclerodermatous GVHD mouse 
model. 
In a 3-month study in patients with moderate-to-severe psoriasis, belumosudil 
demonstrated both clinical and pharmacodynamic (PD) activity.  Similarly, in an open-
label study of belumosudil in the treatment of IPF, belumosudil slowed the decrease in 
lung function in IPF patients over 24 weeks of treatment when compared to best 
supportive care.  Finally, in a study of patients with steroid refractory or dependent 
cGVHD, approximately two-thirds of patients achieved a clinical response with 
belumosudil.  In this study, patients were able to reduce doses of steroids and 
immunosuppressant drugs during treatment with belumosudil.  It is noteworthy that 
cGVHD represents a paradigm for immune-inflammatory triggering of chronic fibrosis 
that shares important similarities with SSc. 
1.6 
DOSE RATIONALE  
Belumosudil was well-tolerated in Phase 1 studies of healthy volunteers at single doses 
up to 1000 mg, and with repeat doses up to 500 mg BID for 28 days. 
Phase 2 studies of belumosudil have been initiated, enrolling patients with IPF (KD025-
207), cGVHD (Study KD025-208 and Study KD025-213) and psoriasis (Study KD025-
205, Study KD025-206, and Study KD025-211). More than 600 subjects have been dosed 
with belumosudil for inflammatory or fibrotic diseases or as healthy volunteers at doses 
ranging from 20 mg to 1000 mg QD and 500 mg BID.   
Preliminary data from phase 2 studies of belumosudil indicate that the dose of 200 mg 
QD is associated with clinical efficacy and should be well-tolerated in an indication with 
immune and fibrotic manifestations (e.g., diffuse cutaneous systemic sclerosis [dcSSc]). 
This study will evaluate belumosudil at a dose of 200 mg BID in and open study in dcSSc 
to further evaluate safety and activity. 
Also, refer to the Belumosudil IB for more detailed information. 
 
 
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2. STUDY OBJECTIVES  
2.1 
PRIMARY OBJECTIVE  
The primary objective of this study is to evaluate the efficacy of belumosudil using the 
Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) at Week 24. 
2.2 
SECONDARY OBJECTIVES  
• To assess CRISS at Weeks 8, 16, 36, and 52 
• To evaluate the efficacy of belumosudil at Week 24 for: 
o 
Modified Rodnan Skin Score (mRSS) 
o 
FVC 
o 
Physician Global Assessment 
o 
Patient Global Assessment 
o 
Scleroderma Health Assessment Questionnaire–Disability Index (SHAQ-DI) 
• To evaluate the efficacy of belumosudil at Weeks 8, 16, 36, and 52 compared to 
baseline for all subjects for the parameters in the bullet above 
• To assess the safety of belumosudil in subjects with dcSSc by examining the 
percentage of subjects with treatment-emergent adverse events (Common 
Terminology Criteria for Adverse Events Version 5.0 [CTCAE v5.0]) 
2.3 
EXPLORATORY OBJECTIVES  
• 
 
 
 
 
 
 
 
 
 
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3. INVESTIGATIONAL PLAN  
3.1 
STUDY DESIGN  
This is a phase 2, open-label, single cohort, multicenter trial in subjects with dcSSc. 
The duration of the study will be approximately 14 months (4 weeks for screening, 52 
weeks of dosing period, and 4 weeks of follow-up). 
Subjects who have signed an Institutional Review Board/Independent Ethics Committee-
(IRB/IEC)-approved informed consent form and met all of the inclusion/exclusion 
criteria will be enrolled.  A total of 12 to 15 to subjects will receive belumosudil 200 mg 
administered PO BID for 52 weeks.  
Subjects will undergo evaluations as outline in the Study Schedule of Assessments 
(Appendix A).The primary endpoint will be analyzed using Week 24 data. 
Efficacy will be assessed throughout the 52-week dosing period using CRISS, mRSS, 
PFTs, Physician Global Assessment, and Patient Global Assessment. 
Follow-up Period 
A 4-Week Safety Follow-up Visit will occur 28 days (± 3 days) after the last dose of 
study drug.  Subjects will undergo PEs; vital sign measurements; weight measurement; 
blood sample collection for hematology and chemistry; urinalysis; ECGs; AE 
assessments; concomitant medication assessments; and pregnancy testing for females of 
childbearing potential.  In addition, subjects will also have efficacy assessment done as 
per Appendix A:  Schedule of Assessments. 
3.2 
NUMBER OF SUBJECTS  
Twelve to 15 male and female subjects will be enrolled. 
3.3 
STUDY CENTERS  
Approximately 5 to 6 centers will participate in this study. 
3.4 
INCLUSION CRITERIA  
1. Male and female subjects ≥ 18 years old with the diagnosis of dcSSc according to 
the 2013 American College of Rheumatology and European League Against 
Rheumatism criteria  
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2. Must have disease duration (defined as interval from first non-Raynaud disease 
manifestation) of ≤ 6 years 
3. Must have mRSS ≥ 15 but ≤ 40 
4. Must have active disease as determined by the Principal Investigator within the 
6 months prior to screening 
5. Adequate organ and bone marrow functions evaluated during the 28 days prior to 
enrollment as follows: 
a. Absolute neutrophil count ≥ 1.5 × 109/L  
b. Platelet count ≥ 100 × 109/L  
c. Total bilirubin ≤ 1.0 × upper limit of normal (ULN) 
d. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
serum creatinine ≤ 1.5 × ULN 
6. Female subjects of childbearing potential have a negative pregnancy test at 
screening.  Females of childbearing potential are defined as sexually mature 
women without prior hysterectomy or who have had any evidence of menses in 
the past 12 months. However, women who have been amenorrheic for 12 or more 
months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression. 
a. Women of childbearing potential (i.e., menstruating women) must have a 
negative urine pregnancy test (positive urine tests are to be confirmed by 
serum test) documented within the 24-hour period prior to the first dose of 
study drug.  
b. Sexually active women of childbearing potential enrolled in the study 
must agree to use two forms of accepted methods of contraception during 
the course of the study and for 3 months after their last dose of study 
drug.  Effective birth control includes (i) intrauterine device plus 1 barrier 
method; (ii) on stable doses of hormonal contraception for at least 
3 months (e.g., PO, injectable, implant, transdermal) plus 1 barrier 
method; or (iii) 2 barrier methods.  Effective barrier methods are male or 
female condoms, diaphragms, and spermicides (creams or gels that 
contain a chemical to kill sperm), or a vasectomized partner. 
7. For male patients who are sexually active and who are partners of premenopausal 
women: agreement to use 2 forms of contraception as in criterion 
number 6b above during the treatment period and for at least 3 months after the 
last dose of study drug. 
8. Male subjects must not donate sperm for 3 months after last dose of study drug. 
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9. Able to provide written informed consent prior to the performance of any 
study-specific procedures. 
3.5 
EXCLUSION CRITERIA  
1. Subject has corrected QT interval using Fridericia’s formula (QTcF) > 450 ms 
2. Ongoing use or current use of concomitant medication known to have the 
potential for QTc prolongation 
3. Female subject who is pregnant or breastfeeding. 
4. Participated in another study with an investigational drug within 28 days of study 
entry (for studies involving biologics, within three half-lives of the biologic). 
5. History or other evidence of severe illness or any other conditions that would 
make the subject, in the opinion of the Investigator, unsuitable for the study. 
6. Chronic heart failure with New York Heart Association Classes II, III, and IV. 
7. Active or chronic liver disease (e.g., cirrhosis). 
8. Positive human immunodeficiency virus (HIV) test. 
9. Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood 
tuberculin test. 
10. Diagnosed with any malignancy within 3 years of enrollment, with the exception 
of basal cell or completely resected squamous cell carcinoma of the skin, resected 
in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk 
prostate cancer after curative resection. 
11. Has had previous exposure to belumosudil or known allergy/sensitivity to 
belumosudil or any other ROCK2 inhibitor. 
12. Scleroderma renal crisis within 4 months prior to enrollment. 
13. FVC ≤ 50% Predicted. 
3.6 
SCREENING  
The screening period commences once the ICF is signed.  Adequate time must be 
allowed for the subject to ask questions and make a voluntary decision. The ICF must be 
signed before any study-specific samples are taken or study-specific tests or evaluations 
are conducted.   
Data regarding screen-failures will be captured in the electronic data capture (EDC) 
system. 
Screening assessments as summarized in the Schedule of Assessments (Appendix A) will 
be performed within 29 days of first dose of study drug (Week 1 Day 1 Visit [baseline]).   
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Study eligibility will be based on satisfying all of the study inclusion and exclusion 
criteria. 
Re-screening of subjects will be allowed only upon approval of the medical monitor. 
3.7 
WITHDRAWAL CRITERIA  
Subjects may be withdrawn from study treatment at any time by the Investigator if it is 
considered detrimental for the subject to continue in the study.  The reason for 
withdrawal must be captured in the electronic case report form (eCRF). 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution.  Every effort 
should be made to have such subjects attend end of treatment (EOT) and 28-day 
Follow-up Visits.  In the instances where a reason for withdrawal of consent is given, this 
will be captured in the eCRF.  Subject data up to withdrawal of consent will be included 
in the analysis of the study, and where permitted, publicly available data can be included 
after withdrawal of consent.  
3.8 
REPLACEMENTS  
Subjects withdrawn from the study before receiving any study drug will be replaced by 
enrolling additional subjects into the study. 
3.9 
TREATMENT DISCONTINUATION  
Treatment discontinuation reasons include the following: 
• An AE requiring permanent discontinuation of study drug  
• Investigator decision 
• Clinically significant disease progression.  For example: 
o mRSS increase ≥ 5 units 
o Absolute decrease in FVC (% predicted) ≥ 10% or absolute decrease in 
diffusing capacity of the lungs for carbon monoxide (DLco) (corrected for 
Hb) of ≥ 15% 
o Renal crisis 
• Study stopping rules for the sponsor (Section 9.6.1) 
• Subjects meeting criteria for discontinuation from the study (Section 9.6.2) 
• Voluntary withdrawal by subject 
• Noncompliance to protocol 
• Subject lost to follow-up 
• Termination of the study by sponsor 
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• 
Subject death 
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4. STUDY TREATMENT  
4.1 
INVESTIGATIONAL PRODUCT  
Belumosudil (2-(3-(4-(1H-indazol-5-ylamino) quinazolin-2-yl) phenoxy)-N-
isopropylacetamide-methane sulfonic acid salt) is an orally available ROCK2 selective 
inhibitor.  Belumosudil will be provided as 200 mg tablets. 
4.2 
DOSAGE AND ADMINISTRATION  
Subjects will receive belumosudil 200 mg PO BID for 52 weeks. 
4.3 
TREATMENT ASSIGNMENT  
This is a single-cohort study.  All subjects will receive belumosudil 200 mg PO BID for 
52 weeks. 
4.4 
BLINDING  
This is an open-label study.  No blinding will occur. 
4.5 
TREATMENT COMPLIANCE  
Subjects will be given a study drug diary to record the details of each dose of study drug. 
Diaries will be dispensed/collected on each visit. Compliance with PO dosing will be 
confirmed using subject diaries, which will be examined at each visit by site staff to 
determine if dosing is as instructed per protocol and follow-up with the subject 
accordingly. If the subject skips more than 7 consecutive days of drug dosing (other than 
those specified in the Dose Modification Guideline for Toxicity), the subject should be 
discontinued from the study unless approved by the medical monitor and Investigator. 
4.6 
MISSED DOSES  
Subjects should make every effort to take the study drug, belumosudil 200 mg PO BID, 
at the same scheduled time daily. In the event that the subject misses the planned dose, 
the following protocol should be followed: 
• If < 12 hours of time have elapsed after the scheduled dose, the drug should be 
taken. The subject should then resume the regular planned daily dosing schedule 
the following day. 
• If ≥ 12 hours of time have elapsed after the scheduled dose, the drug should be 
skipped for that day. The subject should then resume the regular planned dosing 
schedule the following day. 
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4.7 
PRODUCT ACCOUNTABILITY  
In accordance with regulatory requirements, study sites must document the amount of 
investigational product (IP) received from and returned to the sponsor, and the amounts 
of IP dispensed to study subjects, and the amount returned by study subjects.  Product 
accountability records must be maintained throughout the course of the study.  
4.8 
CONCOMITANT MEDICATION AND THERAPIES  
All concomitant medications taken during the study and relevant procedures will be 
recorded on the eCRFs.   
Subjects will be counseled to avoid non-prescribed medicines or complementary 
alternative medicines excluded by the study.  All medications a subject receives from the 
signing of the ICF through the 28-day Follow-up Visit will be documented. 
After discontinuation of study drug, any medication used in response to an AE is to be 
recorded on the appropriate eCRF. 
The concomitant medication names will be coded by the sponsor according to the World 
Health Organization Drug Dictionary and classified by anatomical therapeutic chemical 
categories 
4.9 
CYP3A4 INHIBITORS/INDUCERS  
CYP3A4 inhibitors/inducers should be used with caution (Appendix G). 
4.10 DRUGS PROLONGING THE QTC INTERVAL  
Subjects on concomitant medications known to have the potential for QTc prolongation 
will be excluded (Appendix H). 
4.11 OVERDOSE  
Doses of belumosudil considered to represent an overdose have not been defined.  In 
clinical studies of belumosudil, repeat dosing of 1000 mg QD for 7 days and 500 mg BID 
for 28 days were generally well tolerated in healthy volunteers.  There are no known 
antidotes to belumosudil, and no specific treatment is recommended in the event of a 
suspected overdose.  The treating Investigator should employ clinical judgment in 
managing subjects with suspected overdose.  Overdose should be reported as an AE. 
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4.12 DOSE MODIFICATION GUIDELINES  
Any clinically significant toxicity will necessitate consideration of either a pause or 
cessation of therapy.  Guidelines for management of treatment-emergent toxicities in 
subjects receiving belumosudil are outlined in Table 2: 
Table 2 
Guidelines for Management of Treatment-emergent Toxicities  
Toxicity 
Recommended Action 
Grade ≥3 LFTs (AST, 
ALT, or total 
bilirubin) 
• 
Complete the “Treatment-emergent LFT Elevations” eCRF 
• 
Discontinue belumosudil 
Other Grade ≥3 
clinically significant 
toxicities considered 
related to belumosudil 
• 
Discontinue belumosudil 
Grade 2 clinically 
significant toxicities  
• 
Consider pause or dose modification of therapy 
• 
Dose interruption for toxicity will be permitted up to 14 days. If 
toxicity resolves to Grade 1 or below then consider resuming 
belumosudil at current dose or 1 dose decrement as outlined in 
Table 3 
• 
If toxicity recurs, hold dose as above then consider resuming 
belumosudil at 1 dose decrement 
• 
If toxicity does not resolve to Grade 1 or below for 14 days, subjects 
will be discontinued from treatment 
ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; eCRF = electronic case report form; LFT = 
liver function tests 
 
Dose interruption for toxicity management for 14 days is permitted. Subjects requiring 
pauses of more than 14 days will be discontinued from the study unless approved by the 
medical monitor. 
 
Table 3. 
Belumosudil Dose Decrements  
Belumosudil Dose 
Dose Reduction 
200 mg BID 
200 mg QD  
200 mg QD 
200 mg QOD 
Abbreviations:  BID = twice daily; QD = once daily; QOD = once every other day 
 
If the reduced dose is tolerated for 1 complete cycle, then the dose may be escalated to 
the previous dose. 
 
 
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5. STUDY ASSESSMENTS AND PROCEDURES  
The Schedule of Assessments is outlined in Error! Reference source not found.   
CRISS assessments will not be performed on site for the study but rather will be 
calculated outside of EDC. 
5.1 
SCREENING PERIOD (DAY -29 TO -1)  
Informed consent must be obtained before any study-specific samples are taken or 
study-specific tests or evaluations are conducted.  The following assessments at the 
screening visit are to occur within 29 days of first dose of study drug (Week 1 Day 1 
Visit).  Study eligibility will be based on satisfying all the study inclusion and exclusion 
criteria.   
At the screening visit, information will be collected, and subjects will have clinical 
evaluations as follows: 
• Informed consent 
• Subject demography 
• Medical history 
• Inclusion/exclusion criteria 
• mRSS 
• FVC 
• Complete PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• 12-lead ECG 
• Pregnancy test 
• Concomitant medication assessment 
5.2 
TREATMENT PERIOD  
After completion of screening procedures, confirmation of subject eligibility and 
informed consent, the subject will be enrolled into the study and will undergo all 
subsequent evaluations required by the protocol. 
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5.2.1 Week 1 Day 1 Visit (Baseline)  
At the Week 1 Day 1 Visit, subjects will come to the clinic to have the following 
procedures: 
• Confirmation of inclusion/exclusion criteria 
• mRSS 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• PFT* 
• Skin biopsies 
• Complete PE 
• Vital signs 
• Weight 
• Hematology and chemistry* 
• Urinalysis* 
• 12-lead ECG 
• Pregnancy test 
• Dispense study diary 
• Study drug administration (belumosudil 200 mg):  review with subject 
• Dispense study drug 
• Concomitant medication assessment 
• AE assessment 
*These assessments do not need to be repeated if they were conducted within 
7 days of baseline. 
5.2.2 End of Week 2 (Day 15 ± 3) Visit  
Subjects will come to the clinic to have the following procedures: 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
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• Study drug administration 
• Concomitant medication assessment 
• AE assessment 
5.2.3 End of Week 4 (Day 29 ± 3 Days) Visit  
Subjects will come to the clinic to have the following procedures: 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Dispense and collect study diary  
• Study drug administration 
• Dispense and collect study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.4 End of Week 8 (Day 57 ± 3 Days) Visit  
Subjects will come to the clinic to have the following procedures: 
• CRISS 
• mRSS 
• FVC 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
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• Dispense and collect study diary  
• Study drug administration 
• Dispense and collect study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.5 End of Week 12 (Day 85 ± 3 Days) Visit  
Subjects will come to the clinic to have the following procedures: 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary 
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.6 End of Week 16 (Day 113 ± 3 Days)  
Subjects will come to the clinic to have the following procedures: 
• CRISS 
• mRSS 
• FVC 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
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• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary  
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.7 End of Week 20 (Day 141 ± 3 Days) Visit  
Subjects will come to the clinic to have the following procedures: 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary  
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.8 End of Week 24 (Day 169 ± 3 Days) Visit  
Subjects will come to the clinic to have the following procedures: 
• CRISS 
• mRSS 
• FVC (if PFT not performed at visit) 
• Skin biopsies 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• PFT (± 7 days) 
• Complete PE 
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• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary  
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.9 End of Weeks 28 and 32 (Days 197 and 225 ± 3 Days) Visits  
Subjects will come to the clinic to have the following procedures at each visit: 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary  
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
5.2.10 End of Week 36 (Day 253 ± 3 Days) Visit  
Subjects will come to the clinic to have the following procedures: 
• CRISS 
• mRSS 
• FVC 
• SHAQ-DI 
• Physician Global Assessment 
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• Patient Global Assessment 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary  
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
 
5.2.11 End of Week 40, 44, and 48 (Days 281, 309 and 337 ± 3 Day) Visits  
Subjects will come to the clinic to have the following procedures at each visit: 
• Symptom-directed PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and dispense study diary  
• Study drug administration 
• Collect and dispense study drug 
• Concomitant medication assessment 
• AE assessment 
 
5.2.12 End of Treatment (EOT) Or End of Week 52, (Day 365 ± 3 Days)  
Subjects will come to the clinic to have the following procedures:   
• CRISS 
• mRSS 
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• FVC (if PFT not performed at visit) 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• PFTs (± 7 days) 
• Skin biopsies 
• Complete PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect study diary  
• Collection of study drug  
• Concomitant medication assessment 
• AE assessment 
5.3 
28-DAY FOLLOW-UP VISIT  
Subjects will return to the clinic 28 days (± 3 days) after their last dose of belumosudil 
200 mg.  At this visit, the following procedures will be completed: 
• CRISS 
• mRSS 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• Complete PE 
• PFT 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
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• Concomitant medication assessment 
• AE assessment 
5.4 
UNSCHEDULED VISIT  
For subjects requiring an unscheduled visit, the following procedures may be performed 
at the Investigator’s discretion: 
• CRISS 
• mRSS 
• FVC (if PFT not performed at visit) 
• SHAQ-DI 
• Physician Global Assessment 
• Patient Global Assessment 
• PFTs 
• Complete PE 
• Vital signs 
• Weight 
• Hematology and chemistry 
• Urinalysis 
• 12-lead ECG 
• Pregnancy test 
• Collect and/or dispense study diary 
• Study drug administration (belumosudil 200 mg) 
• Collect and/or dispense study drug 
• Concomitant medication assessment 
• AE assessment 
 
 
 
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6. EFFICACY AND SAFETY ASSESSMENTS  
6.1 
EFFICACY ENDPOINTS  
Efficacy measurements will be performed as outlined in Appendix A. 
The primary efficacy endpoint is the effect of belumosudil 200 mg BID on the CRISS at 
the end of Week 24 in the mITT Population.  The CRISS exponential algorithm 
determines the predicted probability of improvement from baseline, incorporating 
changes in mRSS, FVC% predicted, SHAQ-DI, and physician and Patient Global 
Assessments.  The outcome is a continuous variable between 0.0 and 1.0 (0-100%).  A 
higher score indicates greater probability of improvement.  A CRISS score ≥ 20% is 
considered a clinically meaningful improvement.  The calculation of CRISS will be 
performed from data available from the EDC and will not be performed by the 
investigator (or designee) on site. 
Secondary efficacy endpoints include the change from baseline in mRSS, FVC, 
SHAQ-DI, Physician Global Assessment, and Patient Global Assessment. 
Other efficacy outcomes include the change from baseline in mRSS for KD025-treated 
subjects.  The mRSS is a measure of skin thickness rated with scores ranging from 
0 (normal) to 3 (severe skin thickening) across 17 different sites.  The total score is the 
sum of the individual skin scores in the 17 body areas (i.e., face, hands, fingers; proximal 
area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and 
distal area of the legs, feet), yielding a range of 0 to 51 units.  The mRSS has been 
validated for patients with SSc.  A negative change from baseline demonstrates 
improvement. 
The effect of belumosudil will be explored for the change in baseline for SHAQ-DI, 
which assesses 5 scleroderma-specific Visual Analog Scale (VAS) items to explore the 
impact of participant's disease. Each VAS item will be rated separately in scale of 0 to 
100 mm, with higher scores indicating more severe disease. The 5 items are: (1) intestinal 
disease, (2) breathing problem, (3) Raynaud syndrome, (4) finger ulcers, and (5) overall 
disease. 
Onset/progression of ILD will be evaluated by the effect of belumosudil in the change in 
predicted FVC, which is based on institutional standards and will be measured as part of 
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PFTs, including FEV1, FVC, DLCO, and total lung capacity (TLC).  The same equipment 
and tester should be used during the course of the study to the extent possible. The person 
responsible for conducting the PFTs will be required to comply with the study guidelines 
and the American Thoracic Society/European Respiratory Society joint criteria on lung 
function testing. 
6.1.1 Primary Efficacy Endpoint  
The primary efficacy endpoint of the study is the efficacy of belumosudil 200 mg BID for 
CRISS at Week 24. 
6.1.2 Secondary Efficacy Endpoints  
The secondary efficacy endpoints are: 
• Efficacy of belumosudil 200 mg BID CRISS at Weeks 8, 16, 36, and 52 
• Efficacy of belumosudil 200 mg BID at Week 24 for: 
o mRSS 
o FVC 
o Physician Global Assessment 
o Patient Global Assessment 
o SHAQ-DI 
• Efficacy of belumosudil 200 mg BID at Weeks 8, 16, 36, and 52 compared to 
baseline for: 
o mRSS 
o FVC 
o Physician Global Assessment 
o Patient Global Assessment 
o SHAQ-DI 
6.1.3 Exploratory Endpoints  
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6.2 
SAFETY ENDPOINTS  
The safety endpoints include (see Section 9 for additional detail on AEs): 
• The percentage of subjects with TEAEs and SAEs (CTCAE v5.0) 
• Hematological and clinical chemistry parameters 
• Urinalysis 
• Vital signs:  change from baseline in systolic blood pressure, diastolic blood 
pressure and heart rate  
• PEs (complete or symptom-directed) 
• 12-lead ECG:  mean and maximum change from baseline in QTc(F)  
• Pregnancy test 
6.2.1 Vital Signs  
Seated pulse rate and BP measurements will be performed as outlined in the Schedule of 
Assessments (Appendix A).  Measurements will be taken with the subject sitting, having 
rested in this position for at least five (5) minutes.  Vital signs should be taken before 
ECGs and other scheduled assessments. 
6.2.2 Physical Examination  
A complete PE is to include documentation of height (screening only), weight, body 
temperature, and vital signs (BP [sitting], pulse rate [sitting], and respiratory rate) and 
will be performed by a physician or staff member who is qualified to perform such 
examinations (e.g., physician’s assistant, nurse practitioner).  All PEs, whether focused 
on symptoms (symptom-directed) or complete, will include assessment of cardiac 
(including heart rate and vital signs), musculoskeletal (e.g., joints, muscles), and 
neurological (e.g., gait) systems. 
6.2.3 12-Lead ECG  
Twelve-lead ECGs will be performed as outlined in the Schedule of Assessments 
(Appendix A).  ECGs will be recorded after the subject has rested in the supine position 
for at least 5 minutes.  
The following ECG parameters will be collected:  PR interval, QRS interval, RR and 
QTc or QTcF.  The ECG findings will be evaluated by a qualified physician for the 
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presence of abnormalities (qualitative assessment).  The physician will assess each ECG 
as normal, abnormal/not clinically significant, or abnormal/clinically significant.   
Abnormalities in the ECG that lead to a change in subject management or result in 
clinical signs and symptoms are considered clinically significant for the purposes of this 
study and will be recorded in the AE eCRF. If ECG abnormalities meet criteria defining 
them as serious, they must be reported as an SAE (Section Error! Reference source not 
found.). 
6.2.4 Clinical Laboratory Parameters  
Clinical laboratory tests will be performed as outlined in the Schedule of Assessments 
(Appendix A).  Samples should be taken pre-dose and will be collected and assessed 
locally. 
Table 4 
Clinical Laboratory Panels  
 
Hematology 
Serum Chemistry 
Other 
• 
White blood cell count with 
differential (including at 
minimum: neutrophils, 
basophils, eosinophils, 
lymphocytes, monocytes) 
• 
Red blood cell count 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet count 
• 
MCV 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Chloride 
• 
CO2 
• 
Creatinine/GFR 
• 
CPK 
• 
Total and direct 
bilirubin 
• 
GGT 
• 
Globulin 
• 
Glucose 
• 
HBV (screening only) 
• 
HCV (screening only) 
• 
HIV (screening only) 
• 
Lactate dehydrogenase 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
• 
Whole blood tuberculin 
test (screening only) 
• 
Urinalysis 
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Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen, CPK = creatinine phosphokinase; GFR = glomerular filtration rate; GGT = gamma glutamyl 
transferase; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
MCV = mean corpuscular volume 
 
Abnormalities in clinical laboratory tests that lead to a change in subject management 
(e.g., dose delay, requirement for additional medication or monitoring) are considered 
clinically significant for the purposes of this study and will be recorded on the AE eCRF 
page. Laboratory results will be classified using the CTCAE v5.0. If laboratory values 
constitute part of an event that meets criteria defining it as serious, the event (and 
associated laboratory values) must be reported as an SAE (see Section Error! Reference 
source not found.). 
6.2.5 Pregnancy Testing  
Pregnancy tests (urine) will be done in women of childbearing potential. Positive urine 
results are to be confirmed with serum testing.  In the event of a positive urine test at 
baseline, serum testing results should be acquired within 48 hours prior to study start. 
In the event that a subject, or subject’s partner, becomes pregnant while on study, she will 
be monitored until the outcome of the pregnancy is known.  The baby will continue to be 
monitored for 30 days after delivery.  The data are reported on a pregnancy form within 
24 hours of becoming aware.
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7. PHARMACOKINETICS  
No pharmacokinetic analysis to be performed in this study. 
 
 
 
 
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8. PHARMACODYNAMICS  
 
 
 
 
 
 
 
 
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9. SAFETY  
9.1 
SAFETY PARAMETERS  
Safety data will be collected from the time the subject signs the ICF form until 28 days 
after their last dose of study drug (the AE reporting period).  The primary safety outcome 
will be the percentage of subjects experiencing TEAEs and SAEs.  
Safety assessments will include AEs, SAEs, PEs, vital sign measurements, clinical 
laboratory evaluations (hematology, chemistry, and urinalysis), and ECGs.  Reasons for 
treatment discontinuation because of toxicity will be documented.   
All AEs that occur in enrolled subjects during the AE reporting period must be recorded 
regardless of the relationship of the AE to study drug.  Any known untoward event that 
occurs beyond the AE reporting period that the Investigator assesses as possibly related 
to study drug also should be reported to Kadmon. 
Careful monitoring of all toxicities will be carried out.  Vital sign measurements, 
including BP, pulse rate, respiratory rate, and temperature will be monitored throughout 
the study. 
9.2 
ADVERSE EVENT DEFINITION  
An AE is defined as any untoward medical occurrence in a clinical trial subject 
associated with the use of a drug, whether or not considered drug related.  An AE can be 
an unfavorable and unintended sign (e.g., an abnormal laboratory value finding), a 
symptom, or a disease temporally associated with the use of a drug, without judgment as 
to causality.  An AE can arise from use of the drug (e.g., use in combination with another 
drug) and from any route of administration, formulation or dose, including an overdose. 
An AE also includes, but is not limited to, any clinically significant worsening of a 
pre-existing condition. Examples include: 
• Any sign, symptom, physical finding, or laboratory result that has worsened in 
nature, severity or frequency compared to baseline 
• Reactions from an investigational drug, including those occurring as a result of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity, or toxicity 
• Concurrent illness that was not present or worsens in nature, severity, or 
frequency compared to baseline 
• Injury or accident; and/or 
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• Exacerbation of a pre-existing condition 
For the purpose of data collection, all untoward events that occur after informed consent 
through 28 days after last dose of study drug are to be recorded on eCRFs by the 
investigational site.   
9.3 
EVALUATING ADVERSE EVENTS  
The Investigator will determine the seriousness, intensity, and causality of an AE 
associated with the use of the study drug (i.e., events where there is a reasonable 
possibility that the event may have been caused by the study drug) based on the 
definitions that follow. 
9.3.1 Serious Adverse Events  
The SAE definition and reporting requirements are in accordance with Title 21 Part Code 
of Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators 
Safety Reporting Requirements for Investigational New Drug (INDs) and 
Bioavailability/Bioequivalence (BA/BE) Studies. 
Serious adverse event assessments will be performed from the time when the ICF is 
signed. 
SAE: An AE is considered "serious" if, in the view of either the Investigator or sponsor, 
it results in any of the following outcomes: 
Death:  This includes any death that occurs while the subject is “on study” as well as any 
death that occurs within 28 days after study drug discontinuation.  
Note: Death is an outcome of an AE, and not an AE in itself.  The event(s) that caused 
death (e.g., illness, accident) is the SAE.  Death due to any other cause(s) must also be 
reported as an outcome of the reportable SAE. 
Life-threatening adverse event:  An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the Investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. It does not include an AE or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death.  
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Inpatient hospitalization or prolongation of existing hospitalization:  In the absence 
of an AE, the Investigator should not report hospitalization or prolongation of 
hospitalization. This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol 
• Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center 
• Hospitalization for survey visits or annual physicals 
In addition, a hospitalization planned before the start of the study for a pre-existing 
condition which has not worsened does not count as an SAE.  
• Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
• Congenital anomaly/birth defect 
• Important medical event:  An event that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, it may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.   
9.3.2 Protocol-related Adverse Events  
Adverse events that are not study drug related may nevertheless be considered by the 
Investigator or the medical monitor to be related to the conduct of the clinical study.  
That is, the event may be related to the fact that a subject is participating in the study.  
For example, a protocol-related AE may be an event that occurs during a washout period 
or that is related to a procedure required by the protocol. 
 
9.3.3 Relationship to Study Drug  
The Investigator will attempt to assess the relationship of the event to study drug using a 
5-point scale (not related, unlikely related, possibly related, probably related, or definitely 
related) (Appendix F). 
 
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9.3.4 Recording Adverse Events  
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF during the subject’s participation in the study. The severity of each AE 
will be graded using the CTCAE v5.0 scale. The date of onset as well as the end date of 
the event also should be recorded or the event should be entered as “ongoing”.  In 
addition, the method used to treat the AE and the outcome of the AE also will be noted. 
In the event that the grade of an AE worsens, an end date should be entered to the initial 
AE and a new AE entered with the updated grade and date of onset.  The Investigator will 
assess the relationship of the event to study drug. Note: All SAEs also are to be entered 
onto an SAE form and sent to sponsor or designee. 
9.3.5 Hospitalization  
In the absence of an AE, the Investigator should not report hospitalization or prolongation 
of hospitalization.  This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol. 
• Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center. 
• Hospitalization for survey visits or annual physicals. 
In addition, a hospitalization for elective procedures planned before or after the start of 
the study for a pre-existing condition that has not worsened does not count as an SAE. 
9.3.6 Serious Adverse Event Reporting  
9.3.6.1 Governing Regulatory Requirements  
Compliance with this request for prompt reporting is essential in that the sponsor is 
responsible for informing the US FDA as well as all other participating Investigators of 
the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the 
Guidance for Industry and Investigators Safety Reporting Requirements for INDs and 
BA/BE Studies, the sponsor is required to submit written documentation, in the form of 
an IND safety report, detailing: 
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• Any event associated with the use of the drug, that is both serious and unexpected, 
or  
• Any findings from clinical, epidemiological, or pooled analysis of multiple 
studies or any findings from animal or in vitro testing that suggest a significant 
risk in humans exposed to the drug.  
Written submission must be made by the sponsor to the FDA and the IRB/IECs as soon 
as possible and in no event later than 15 calendar days after the sponsor’s initial 
notification of the event.  Any unexpected death or life-threatening suspected adverse 
drug reaction must be reported to FDA no later than 7 calendar days after the sponsor’s 
initial receipt of the information.  The sponsor shall also inform all Investigators. 
Time Frame for Reporting 
Any death, SAE, pregnancy (including pregnancy of a partner), experienced by a subject 
while receiving or within 28 days of receiving study drug, regardless of relationship to 
study drug, or any death that occurs more than 28 days after receiving study drug, and is 
believed to be study drug-related, must be promptly reported (within 24 hours of the 
Investigator becoming aware of the event) by e-mail to the sponsor (or designee).  
Contact information for SAE reporting: 
For medical questions contact the Kadmon Medical Monitor: 
E-mail:  medicalmonitor@kadmon.com 
Phone:  724-778-6125 
For SAE reporting send the SAE form, pregnancy form, or follow-up within 24 
hours of becoming aware: 
Kadmon Pharmacovigilance 
Email: clinicalSAEreporting@kadmon.com   
or 
Fax: 1-646-430-9549 
In the event of a subject, or a subject’s partner, becomes pregnant while on study, she 
will be monitored until the outcome of the pregnancy is known.  The baby will continue 
to be monitored for 30 days after delivery.  The data are reported on a pregnancy form 
within 24 hours of becoming aware. 
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9.3.6.2 Information to be Provided by the Investigator  
Any SAE for all enrolled subjects must be recorded on the SAE form (during study 
participation). This requirement includes all SAEs that occur after informed consent and 
through 28 days after last dose of study drug, and in addition, any SAEs that are 
assessed as possibly related to study drug by the Investigator, even if the SAE occurs 
more than 28 days after the last dose of study drug must be reported to the Kadmon 
Corporation Pharmacovigilance Department (or designee). 
The minimum information required for SAE reporting includes identity of Investigator, 
site number, subject number, an event description, SAE term(s), onset date, the reason 
why the event is considered to be serious (i.e., the seriousness criteria) and the 
Investigator’s assessment of the relationship of the event to study drug. Additional SAE 
information including medications or other therapeutic measures used to treat the event, 
action taken with the study drug due to the event, and the outcome/resolution of the event 
will be recorded on the SAE form for reporting which will be provided to the study sites. 
In all cases, the Investigator should continue to monitor the clinical situation and report 
all material facts relating to the progression or outcome of the SAE. Furthermore, the 
Investigator may be required to provide supplementary information as requested by the 
Kadmon Corporation Drug Safety personnel or designee. 
When reporting SAEs, the following additional points should be noted: 
• When the diagnosis of an SAE is known or suspected, the Investigator should report 
the diagnosis or syndrome as the primary SAE term, rather than as signs or 
symptoms. Signs and symptoms may then be described in the event description. For 
example, dyspnea should not be used as an SAE term if the diagnosis which caused 
the dyspnea is known to be malignant pleural effusion.   
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless 
the event preceding the death is unknown. In the exceptional case where the events 
leading to death are unknown, then death may be used as an event term. If an autopsy 
was performed, the autopsy report should be provided.  
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do 
not require SAE reporting, as follows:  
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o Elective or previously scheduled surgery (e.g., a previously scheduled ventral 
hernia repair) 
o Procedures for pre-existing conditions that have not worsened after initiation 
of treatment 
o Pre-specified study hospitalizations for observation 
o Events that result in hospital stays of less than 24 hours and that do not require 
admission (e.g., an emergency room visit for hematuria that results in a 
diagnosis of cystitis and discharge to home on oral antibiotics) 
o SAEs must, however, be reported for any surgical or procedural complication 
resulting in prolongation of the hospitalization. 
 
9.3.6.3 Regulatory Reporting  
Kadmon Corporation Pharmacovigilance Department (or designee) will process and 
evaluate all SAEs as soon as the reports are received. For each SAE received, Kadmon 
Corporation will determine whether the criteria for expedited reporting have been met. 
Kadmon Corporation (or designee) will submit SAEs that meet the criteria for expedited 
reporting to the Regulatory Authorities in accordance with local regulations governing 
safety reporting. Reporting of SAEs by the Investigator to his or her IRB/IEC will be 
done in accordance with the standard operating procedures and policies of the IRB/IEC. 
Adequate documentation must be maintained showing that the IRB/IEC was properly 
notified. 
9.4 
FOLLOW-UP FOR ADVERSE EVENTS  
Any SAE or AE assessed as at least possibly related that led to treatment discontinuation 
(including clinically significant abnormal laboratory values that meet these criteria) and 
is ongoing 28 days after last dose of study drug must be followed until either resolution 
of the event or determination by the Investigator that the event has become stable or 
irreversible. This follow-up guidance also applies to possibly related SAEs that occur 
more than 28 days after last dose of study drug. The status of all other continuing AEs 
will be documented as of 28 days after last dose of study drug.   
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9.5 
OTHER SAFETY CONSIDERATIONS  
9.5.1 Laboratory Data  
All laboratory data obtained during the course of the study should be reviewed. Any 
abnormal value that leads to a change in subject management (e.g., dose reduction or 
delay, requirement for additional medication or monitoring) or is considered to be of 
clinical significance by the Investigator should be reported as an AE and/or SAE as 
appropriate, unless this value is consistent with the subject’s present disease state or is 
consistent with values obtained before entry into the study. 
Laboratory results will be classified using the CTCAE v5.0. 
9.5.2 Medication Errors  
Any medication error that results in an AE, even if it does not meet the definition of 
serious, requires reporting within 24 hours to the safety monitor. 
9.6 
STUDY  STOPPING  RULES  
9.6.1 Stopping Rules for Study  
Kadmon reserves the right to discontinue the trial at any time for the following reasons:  
1. Failure to meet expected enrollment goals 
 
2. Emergence of any safety information that could significantly affect continuation 
of the trial  
 
3. Violation of GCP (R2), the Clinical Trial Program, or the contract by a trial site or 
Investigator, or any other administrative reasons, disturbing the appropriate 
conduct of the trial 
 
4. Results from other competing clinical trials make this trial not worthy to continue 
 
9.6.2 Stopping Criteria for Subjects  
Subjects will be discontinued from the study at any time for the following reasons: 
 
1. Grade ≥ 3 LFT increase (AST, ALT, or total bilirubin) 
 
2. Grade ≥ 3 clinically significant toxicity considered related to belumosudil 
 
3. QTc > 500 ms or AE of Torsades de pointes 
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9.7 
STATISTICAL CONSIDERATIONS  
9.7.1 Hypothesis  
This study will explore the efficacy of belumosudil 200 mg BID on proposed primary and 
secondary endpoints. The main focus is to provide guidance for follow-up studies. 
9.7.2 Sample Size  
This is an exploratory study.  Sample size and power are not driven by hypothesis testing. 
Twelve to 15 subjects will be enrolled to receive PO administered belumosudil 200 mg 
BID.    
9.7.3 Analysis Populations  
Two populations will be employed in the analysis of study data: 
• Modified Intent-to-Treat (mITT) Population:  All subjects who receive at least 1 dose 
of belumosudil 200 mg. 
• Safety Population:  As with the mITT Population, all subjects who received at least 
1 dose of belumosudil 200 mg.   
Efficacy analyses will be performed on the mITT Population.  Safety analyses will be 
performed on the Safety Population. 
9.7.4 Data Analysis  
All pre-specified analyses will be described in a Statistical Analysis Plan. 
Demographics, subject disposition, and screening and baseline characteristics will be 
summarized in each population. 
9.7.5 Interim Analysis  
No interim analysis is planned.  However, an interim analysis may be performed to 
examine early data, if appropriate. 
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9.8 
EFFICACY ANALYSIS  
9.8.1 Primary Efficacy Endpoint  
The primary efficacy analysis is of the CRISS at Week 24 for subjects administered 
belumosudil 200 mg BID in the mITT Population. 
9.8.2 Secondary Efficacy Endpoints  
Secondary efficacy analyses of belumosudil 200 mg BID performed on the mITT 
Population are: 
• CRISS at Weeks 8, 16, 36, and 52 
• The following analyses for Week 24: 
o mRSS 
o FVC 
o Physician Global Assessment 
o Patient Global Assessment 
o SHAQ-DI 
• The following analyses at Weeks 8, 16, 36, and 52 compared to baseline: 
o mRSS 
o FVC 
o Physician Global Assessment 
o Patient Global Assessment 
o SHAQ-DI 
 
9.8.3 Exploratory Analyses  
 
 
 
 
 
 
 
 
 
9.8.4 Analysis Method  
Descriptive statistics will be provided for all endpoints by visit as described above. 
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9.9 
SAFETY ANALYSES  
Treatment exposure will be summarized. 
The TEAEs will be evaluated using CTCAE v5.0.  A single cohort of 12 to 20 subjects 
will receive belumosudil 200 mg PO BID.  
The TEAEs will be summarized using Medical Dictionary of Regulatory Activities 
(MedDRA; Version 21.0 or higher), System Organ Class (SOC) and Preferred Term 
(PT), classified from verbatim terms. The incidence and percentage of subjects with at 
least 1 occurrence of a PT will be included, according to the most severe grade using a 
5-point scale (mild, moderate, severe, life-threatening, or death). The number of events 
per PT will also be summarized. Causality (relationship to study treatment) will be 
summarized separately. 
Adverse events, SAEs, related AEs, related SAEs, Grade ≥ 3 AEs, related Grade ≥ 3 
AEs, and AEs leading to withdrawal, or treatment discontinuation will be summarized 
according to SOC and PT. Adverse events will also be presented in listings. Duration of 
AEs will be determined and included in listings, along with action taken and outcome. 
Laboratory results will be graded.  Incidence of laboratory abnormalities will be 
summarized.  The worst on-study grade after the first dose of study drug will be 
summarized.  The incidence of Grade ≥ 3 laboratory abnormalities under treatment and 
shifts in toxicity grading from baseline to highest-grade post-baseline will be displayed.   
Vital sign measurements and ECGs will be summarized at each scheduled time point 
using descriptive statistics and included in data listings. 
9.10 PHARMACOKINETIC ANALYSES  
No PK analysis will be performed in this study. 
9.11 PHARMACODYNAMIC ANALYSES  
Changes in biomarkers of endothelial cell dysfunction, fibrosis, immune system function, 
and cytokine alterations from subjects receiving belumosudil will be analyzed as will 
histology and gene expression from skin biopsies taken from subjects at baseline, 
Week 24, and Week 52. 
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9.12 DATA QUALITY ASSURANCE  
Accurate and reliable data collection will be ensured by verification and cross check of 
the eCRFs against the Investigator’s records by the study monitor (source document 
verification) and by the maintenance of a drug–dispensing log by the Investigator.  
Collected data will be entered into a computer database and subject to electronic and 
manual quality assurance procedures. 
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10. REGULATORY OBLIGATIONS  
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, and in general, consistent with the most recent 
version of the Declaration of Helsinki.  In addition, the Investigator agrees to adhere to 
all applicable local laws and regulatory requirements relevant to the use of new 
therapeutic agents in the countries involved. 
The study is to be conducted in compliance with the protocol.  The appropriate 
IRBs/IECs must approve the protocol and any amendments, and the subject ICF form 
before implementation.   
Freely given written informed consent must be obtained from every subject before 
participation in this clinical trial.  The rights, safety, and well-being of participating 
subjects are the most important considerations and should prevail over interests of 
science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, 
and experience to perform their respective task(s).  This trial will not use the services of 
study personnel where sanctions have been invoked or where there has been scientific 
misconduct of fraud (e.g., loss of medical licensure, debarment). 
 
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11. ETHICAL ASPECTS  
11.1 LOCAL REGULATIONS  
The study must fully adhere to the principles outlined in Guideline for Good Clinical 
Practice ICH E6(R2) Integrated Addendum to ICH E6(R1) (March 2018), and in general, 
be conducted in a manner consistent with the most recent version of the Declaration of 
Helsinki.  The Investigator will ensure that the conduct of the study complies with the 
basic principles of GCP as outlined in the current version of 21 CFR, subpart D, Part 312, 
“Responsibilities of Sponsors and Investigators”, Part 50, “Protection of Human 
Subjects”, and Part 56, “Institutional Review Boards”. 
11.2 INFORMED CONSENT  
Sample ICFs will be supplied to each site.  Kadmon Corporation or its designee must 
review any ICF prior to submission for review by the IRB/IEC.  The final 
IRB/IEC-approved document must be provided to Kadmon Corporation for regulatory 
purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to 
obtain written informed consent from each subject (or the subject’s legally authorized 
representative) participating in this study after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study in accordance with 
federal and state regulations.  In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion.  After the 
subject has orally consented to participation in the trial, the witness’ signature on the 
form will attest that the information in the ICF was accurately explained and understood.  
A copy of the ICF must be provided to the subject.  If applicable, it will be provided in a 
certified translation of the local language. 
The eCRF for this study contains a section for documenting informed subject consent, 
and this must be completed appropriately.  Signed ICFs must remain in each subject’s 
study file and must be available for verification by study monitors at any time.  If new 
safety information results in changes in the risk/benefit assessment, the consent form 
should be reviewed and updated as necessary.  All subjects (including those already being 
treated) should be informed of the new information, should be given a copy of the revised 
form, and should give their consent to continue in the study. 
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11.3 INSTITUTIONAL REVIEW BOARD  
This study is being conducted under a United States IND application.  This protocol (and 
any modifications) and appropriate consent procedures must be reviewed and approved 
by an IRB/IEC.  This board must operate in accordance with the current federal or local 
regulations.  The Investigator will send a letter or certificate of IRB/IEC approval to 
Kadmon Corporation (or designee) before subject enrollment and whenever subsequent 
modifications to the protocol are made. 
11.4 FUTURE USE OF SUBJECT SAMPLES  
Not all of the tissue and blood components obtained during this study may be required for 
the tests that are part of the clinical trial.  Following the conclusion of the study, the 
samples may be used for additional research.  This research will help to understand 
disease subtypes, drug response and toxicity, and possibly identify new drug targets or 
biomarkers that predict subject response to treatment.  The use of the samples for internal 
research will be done according to the guidelines defined by the FDA guidance for 
In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not 
Individual Identifiable (issued April 25, 2006) and/or the European Medicines Agency 
Reflection Paper on Pharmacogenetic Samples, Testing and Data Handling 
(EMEA/CHMP/PGxWP/201914/2006). 
If a subject requests destruction of their tissue and blood samples and the samples have 
not yet been de-identified, Kadmon Corporation will destroy the samples as described in 
this FDA guidance.  Kadmon Corporation will notify the Investigator in writing that the 
samples have been destroyed. 
Once all samples have been analyzed for additional research, the samples will be 
discarded and will not be stored for future research. 
 
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12. CONDITIONS FOR MODIFYING THE PROTOCOL  
Protocol modifications will be reviewed and approved by Kadmon Corporation 
representatives. 
All protocol modifications must be submitted to the IRB/IEC for information and 
approval in accordance with local requirements, and to regulatory agencies if required.  
Approval must be obtained before any changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to study subjects, or when the change 
involves only logistical or administrative aspects of the trial (e.g., change in monitor, 
change of telephone number). 
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13. CONDITIONS FOR TERMINATING THE STUDY  
Kadmon Corporation has the right to terminate the study at any time.  In terminating the 
study, Kadmon Corporation and the Investigator will ensure that adequate consideration 
is given to the protection of the subjects’ interests. 
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14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING  
14.1 INVESTIGATOR’S FILES AND RETENTION OF DOCUMENTS  
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into 2 separate categories as follows: (1) Investigator’s 
study files and (2) subject clinical source documents. 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, 
query forms, IRB/IEC, and governmental approval with correspondence, sample ICF, 
drug records, staff curriculum vitae and authorization forms, and other appropriate 
documents and correspondence. 
Subject clinical source documents (usually predefined by the project to record key 
efficacy and safety parameters independent of the eCRFs) may include subject 
hospital/clinic records, physician and nurse’s notes, appointment book, original 
laboratory reports, ECG, electroencephalogram, X-ray, pathology and special assessment 
reports, signed ICFs, consultant letters, and subject screening and enrollment logs.  The 
Investigator must keep these 2 categories of documents on file for at least 2 years 
following the marketing application approval date for the study drug and for the 
indication being investigated or for 2 years after the investigation is discontinued and the 
FDA notified.  After that period of time, the documents may be destroyed subject to local 
regulations with prior written permission from Kadmon Corporation.  If the Investigator 
wants to assign the study records to another party or move them to another location, 
Kadmon Corporation must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or 
all of the documents, special arrangements must be made between the Investigator and 
Kadmon Corporation to store these in a sealed container outside of the study site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  When source 
documents are required for the continued care of the subject, appropriate copies should be 
made for storing outside of the study site. 
14.2 SOURCE DOCUMENTS AND BACKGROUND DATA  
Upon request, the Investigator will supply Kadmon Corporation with any required 
background data from the study documentation or clinic records.  In case of special 
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problems or governmental queries or requests for audit inspections, it is also necessary to 
have access to the complete study records, provided if subject confidentiality is protected. 
14.3 AUDITS AND INSPECTIONS  
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Kadmon Corporation Quality 
Assurance Unit (or designee), or to health authority inspectors after appropriate 
notification.  The verification of the eCRF data must be by direct inspection of source 
documents. 
14.4 ELECTRONIC CASE REPORT FORMS  
Clinical trial data for this study will be captured on electronic eCRF.  The Investigator 
agrees to provide all information requested on the eCRF in an accurate manner according 
to instructions provided.  Electronic CRFs are designed for computer processing and 
analysis.  The Investigator should ensure the accuracy, completeness, and timeliness of 
the data reported to Kadmon Corporation (or designee) in the eCRF and in all required 
reports. 
An eCRF is required to be submitted for every subject who receives any amount of study 
drug.  This includes submission of retrievable data on subjects who withdraw before 
completion of the study.  The eCRFs must be reviewed for completeness and accuracy, 
and electronically signed where indicated, by the principal Investigator or authorized 
delegate from the study staff.  If a subject stops treatment or terminates from the study, 
the dates and reasons must be noted on the eCRF. 
 
 
 
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15. MONITORING OF THE STUDY  
It is understood that the responsible monitor (or designee) will contact and visit the 
Investigator regularly and will be allowed on request to inspect the various records of the 
trial (eCRFs and other pertinent data) provided subject confidentiality is maintained in 
accordance with local requirements. 
It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency, and 
accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other subject records needed to verify the entries on the eCRF.   
The Investigator (or designee) must agree to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 
 
 
 
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16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS  
The Investigator must ensure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On eCRFs or other documents 
submitted to Kadmon Corporation, subjects should be identified by an identification code 
and not by their names.  The subjects’ personal information should be redacted on all 
source documents prior to submission to Kadmon Corporation (or designee).  The 
Investigator should keep a subject enrollment log showing codes, names, and addresses.   
The Investigator should maintain documents not for submission to Kadmon Corporation 
(e.g., subjects’ written consent forms) in strict confidence. 
 
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17. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS  
The results of this study may be published or presented at scientific meetings.  The 
Investigator agrees to submit all manuscripts or abstracts to Kadmon Corporation for 
review at least 30 days before submission.  This allows Kadmon Corporation to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the Investigator. 
In the event that Kadmon Corporation coordinates a publication or presentation of study 
results from all study sites, the participation of Investigator or other representatives of 
study site as a named author shall be determined in accordance with Kadmon Corporation 
policy and generally accepted standards for authorship. 
 
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18. REFERENCES  
 
1. Sticherling M. Systemic sclerosis-dermatological aspects. Part 1: Pathogenesis, 
epidemiology, clinical findings. J Dtsch Dermatol Ges. 2012;10(10):705-718; quiz 
716. 
2. Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of 
systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 
2008;37(4):223-235. 
3. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis 
and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 
2008;58(1):15- 25. 
4. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 2003;29(2):239-
254. 
5. Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, 
survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 
2012;24(2):165-170. 
6. Sanchez-Cano D, Ortego-Centeno N, Callejas JL, et al. Interstitial lung disease in 
systemic sclerosis: data from the spanish scleroderma study group. Rheumatol Int. 
2018; 38(3):363-374. 
7. Schoenfeld SR, Castelino FV. Interstitial lung disease in scleroderma. Rheum Dis 
Clin North Am. 2015;41(2):237-248. 
8. Poudel DR, Jayakumar D, Danve A, Sehra ST, Derk CT. Determinants of mortality in 
systemic sclerosis: a focused review. Rheumatol Int. 2018;38(10):1847-1858. 
9. Pelosi M, Marampon F, Zani BM, et al. ROCK2m positively control the maturation 
of the myogenic program. Mol Cell Biol. 2007;27(17):6163-6176 
10. Olson J, Olson L, Olson M. Rho-associated coiled-coil containing kinases (ROCK): 
structure, regulation, and functions. Small GTPases. vol. 5 (2014): e29846. 
doi:10.4161/sgtp.29846 
11. Tybulewicz VL, Henderson RB Rho family GTPases and their regulators in 
lymphocytes. Nat Rev Immunol. 2009;9(9):630–644. 
12. Riento K, Ridley AJ, Rocks: Multifunctional kinases in cell behaviour. Nat Rev Mol 
Cell Biol. 2003;4(6):446–456. 
13. Herskowitz JH, Feng Y, Mattheyses AL, et al. Pharmacologic inhibition of ROCK2 
suppresses amyloid-beta production in an Alzheimer's disease mouse model. J 
Neurosci. 2013;33(49):19086-19098 
14. Noguchi M, Hosoda K, Fujikura J, et al. Genetic and pharmacological inhibition of 
Rho- associated kinase II enhances adipogenesis. J Biol Chem. 
2007;282(40):29574-29583. 
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15. Shi J, Surma M, Zhang L, Wei L. Dissecting the roles of ROCK isoforms in 
stress- induced cell detachment. Cell Cycle. 2013;12(10):1492-1500. 
16. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor 
down- regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent 
mechanism. Proc Natl Acad Sci U S A. 2014;111(47):16814-16819. 
17. Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive 
signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. 
J Clin Invest. 2013;123(3):1096-1108. 
18. Tybulewicz VL, Henderson RB Rho family GTPases and their regulators in 
lymphocytes. Nat Rev Immunol. 2009;9(9):630–644. 
19. Biswas PS, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and 
IL-21 production and the development of autoimmunity in mice. The 
Journal of clinical investigation. vol. 2010;12(9): 3280-95. 
doi:10.1172/JCI4285610 
20. Isgro J, et al. Enhanced rho-associated protein kinase activation in patients 
with systematic lupus erythematosus. Arthritis and Rheumatism 
2013:65(6):1592-602. 
21. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and 
immune tolerance. Cell. 2008;133;775-787. 
22. Todd JL, Palmer SM. Bronchiolitis obliterans syndrome: the final frontier for 
lung transplantation. Chest. 2011;140(2):502-508.  
23. Shilling RA, Wilkes DS. Role of Th17 cells and IL-17 in lung transplant 
rejection. Semin Immunopathol. 2011;33(2):129-134.  
24. Chhabra, AY, HSCT- Based Approaches for tolerance induction in renal 
transplant. Transplantation 2017;101(11): 2682–2690 
25. Clements PJ, Lachenbruch, Seibold JR, et al.  Skin thickness score in systemic 
sclerosis: an assessment of interobserver variability in 3 independent studies.  J 
Rheumatol. 1993 Nov; 20(11):1892-96. 
26. Merkel PA, Herlyn K, Martin RW, et al.  Measuring disease activity and functional 
status in patients with scleroderma and Raynaud’s Phenomenon.  Arthritis Rheum 
2002 Sep; 46(9):2410-20. 
27. Adapted from Cobert B.  Cobert’s Manual of Drug Safety and Pharmacovigilance 
(2nd Ed).  Massachusetts:  Jones & Bartlett Learning, LLC.  2012. 
28. Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. 
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https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/drugi
nteractionslabeling/ucm093664.htm.  Accessed 19 Aug 2020. 
29. Credible Meds. Combined list of drugs that prolong QT and/or cause Torsades de 
Pointes (TDP). https://crediblemeds.org/pdftemp/pdf/combinedlist.pdf.  
Accessed  24Aug 2020. 
 
 
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19. APPENDIX A:  SCHEDULE OF ASSESSMENTS  
Assessment 
Screening 
Visit 
Week 1 
(Baseline) 
End of 
Week 2 
End of 
Week 4 
End of 
Week 8 
End of 
Week 
12 
End of 
Week 
16 
End of 
Week 
20 
End of 
Week 24 
End of 
Weeks 
28, 32 
End of 
Week 
36 
End of 
Weeks 
40, 44, 48 
End of 
Week 
52/EOT 
28-Day 
Safety 
Follow-up 
Unsched
uled 
Visit 
Study Day Window 
-29 to -1 
1 
15 
(± 3 
days) 
29 
(± 3 
days) 
57 
(± 3 
days) 
85 
(± 3 
days) 
113 
(± 3 
days) 
141 
(± 3 
days) 
169 
(± 3 
days) 
197, 225 
(± 3 
days) 
253 
(± 3 
days) 
281, 309, 
337 
(± 3 days) 
365 
(± 3 days) 
(± 3 days) 
 
Informed consentA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFFICACY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRISS 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
mRSSB 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
FVCB 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SHAQ-DIB 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Physician Global 
AssessmentB 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Patient Global 
AssessmentB 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
PFTsC 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Skin biopsiesD 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
SAFETY 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete PEE 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Symptom-directed 
PEE 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Vital signsF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistryG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study diary 
(dispense/collect) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
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Assessment 
Screening 
Visit 
Week 1 
(Baseline) 
End of 
Week 2 
End of 
Week 4 
End of 
Week 8 
End of 
Week 
12 
End of 
Week 
16 
End of 
Week 
20 
End of 
Week 24 
End of 
Weeks 
28, 32 
End of 
Week 
36 
End of 
Weeks 
40, 44, 48 
End of 
Week 
52/EOT 
28-Day 
Safety 
Follow-up 
Unsched
uled 
Visit 
Study Day Window 
-29 to -1 
1 
15 
(± 3 
days) 
29 
(± 3 
days) 
57 
(± 3 
days) 
85 
(± 3 
days) 
113 
(± 3 
days) 
141 
(± 3 
days) 
169 
(± 3 
days) 
197, 225 
(± 3 
days) 
253 
(± 3 
days) 
281, 309, 
337 
(± 3 days) 
365 
(± 3 days) 
(± 3 days) 
 
Study drug 
administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Dispense and collect 
study drug 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Collect study drug 
and study diary 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Concomitant 
medication 
 
At All Visits 
Adverse events 
 
Throughout Study 
 
 
Abbreviations:  CPK = creatinine phosphokinase; CRISS = Combined Response Index in Diffuse Cutaneous Systemic Sclerosis; DLCO = diffusing capacity of the lungs for carbon monoxide; ECG = electrocardiograph; 
EDC = electronic data capture; EOT = end of treatment; FEV1 = forced expiratory volume (in the first second); FVC = forced vital capacity; Hb = hemoglobin; ICF = informed consent form; ILD = interstitial lung 
disease; mRSS = modified Rodnan Skin Score; PE = physical examination; PFT = pulmonary function test; SHAQ—DI = Scleroderma Health Assessment Questionnaire—Disability Index; TLC = total lung capacity; 
UNS = unscheduled 
A.        The ICF must be signed before any study procedure begins. 
B.        mRSS, SHAQ-DI, FVC, Physician Global Assessment and Patient Global Assessment will be performed at baseline Day 1, Day 57, Day 113, and Day 169, and then after their last dose of study drug (4-Week 
Follow-up Visit).  mRSS and FVC will also be performed at screening as one of the inclusion criteria. FVCs do not need to be repeated when done at the same time point that PFT is scheduled.  
C.        PFTs, to include FEV1, FVC, DLCO (corrected for Hb), TLC, and RV, will be performed at baseline and Day 169 (± 7 days).  In addition, full PFTs will be performed after their last dose of study drug (4-week 
Follow-up Visit).  If the PFTs is performed within one month of the EOT visit, it does not need to be done again at the EOT visit.     
D.        Double punch skin biopsies are mandatory for all subjects on Day 1, Day 169, and at EOT or Week 52
   
E.        A complete PE is to include documentation of height (screening only), weight, body temperature, and vital signs (blood pressure [sitting], pulse rate [sitting], and respiratory rate) and will be performed by a 
physician or staff member who is qualified to perform such examinations (e.g., physician’s assistant, nurse practitioner).   All PEs will include assessment of cardiac (including heart rate, vital sign), musculoskeletal (i.e., 
muscle aches), and neurological (i.e., gait) systems. 
F.         Sitting blood pressure, heart rate to be obtained (after 5 minutes of rest) 
G.         See Section 6.2.4 for a complete list of laboratory safety assessments. 
H.        Women of childbearing potential must have a negative urine pregnancy test.  Positive results are to be confirmed with serum testing.  In the event of a positive urine test at baseline, serum testing results should be 
acquired within 48 hours prior to study start. 
Note:  At Week 1 Day 1 visit, if screening was completed within 7 days of baseline, only the complete PE and vital sign measurements need to be repeated.  
Note:  CRISS will not be performed on site but rather will be calculated outside of EDC. 
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22. APPENDIX D:  PHYSICIAN GLOBAL ASSESSMENT  
 
  
 
 
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23. APPENDIX E:  PATIENT GLOBAL ASSESSMENT  
 
 
 
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24. APPENDIX F:  DETERMINING RELATIONSHIP OF ADVERSE 
EVENTS TO STUDY DRUG  
Determination the relationship of AEs to study drug is displayed below:(27) 
1 
NOT RELATED 
This category applies to those AEs, which, after careful medical consideration, are clearly felt to 
be due to extraneous causes (e.g., disease, environment, etc.) that are unrelated to the 
administration of study drug. 
 
2 
UNLIKELY RELATED (must have first 2) 
This category applies to those AEs, which, after careful medical consideration, are felt unlikely to 
be related to the administration of the study drug.  The relationship of an AE to the study drug can 
be considered unlikely if: 
• 
It does not follow a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been a result of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
• 
It does not follow a known response pattern to the suspected drug. 
• 
It does not reappear or worsen when the drug is re-administered. 
3 
POSSIBLY RELATED (must have first 2) 
This category applies to those AEs, which, after careful medical consideration, are felt unlikely to 
be related to the administration of the study drug, but the possibility cannot be ruled out with 
certainty.  The relationship of an AE to the study drug can be considered possible if: 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been a result of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
• 
It follows a known response pattern to the suspected drug. 
4 
PROBABLY RELATED (must have first 3) 
This category applies to those AEs, which, after careful medical consideration, are felt with a 
high degree of certainty to be related to the administration of the study drug.    The relationship of 
an AE to the study drug can be considered probable if: 
• 
It follows a reasonable temporal sequence from administration of the drug.    
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
subject. 
• 
It disappears or decreases upon cessation of drug or reduction in dose.* 
• 
It follows a known response pattern to the suspected drug. 
 
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5 
DEFINITELY RELATED (must have first 3) 
This category applies to those AEs, which, after careful medical consideration, are felt to be 
related to the administration of the study drug.  The relationship of an AE to the study drug can be 
considered related if: 
• 
It follows a reasonable temporal sequence from administration of the drug or drug levels 
have been established in body fluids or tissues. 
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the 
subject. 
• 
It disappears or decreases upon cessation of drug or reduction on dose and appears upon 
rechallenge.* 
• 
It follows a known response pattern to the suspected drug. 
 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug 
relatedness clearly exists. 
 
 
 
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25. APPENDIX G:  DRUGS THAT INDUCE AND INHIBIT CYP3A4  
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with belumosudil.(28) 
Examples of Clinical Inducers / Inhibitors of CYP3A4 
 
Strong 
Moderate 
Weak 
Inducers 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenytoin 
Rifampin 
St.   John’s wort 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Armodafinil 
Rufinamide 
Inhibitors 
Boceprevir 
Cobicistat 
Conivaptan 
Danoprevir 
Dasabuvir 
Elvitegravir 
Grapefruit juice 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Paritaprevir 
Ombitasvir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Tipranavir 
Troleandomycin 
Voriconazole 
Aprepitant 
Cimetidine 
Ciprofloxacin 
Clotrimazole 
Crizotinib 
Cyclosporine 
Dronedarone 
Erythromycin 
Fluconazole 
Fluvoxamine 
Imatinib 
Tofisopam 
Verapamil 
Chlorzoxazone 
Cilostazol 
Fosaprepitant 
Istradefylline 
Ivacaftor 
Lomitapide 
Ranitidine 
Ranolazine 
Tacrolimus 
Ticagrelor 
 
 
 
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26. APPENDIX H:  DRUGS KNOWN TO HAVE THE POTENTIAL 
FOR QTC PROLONGATION  
Drugs known to have the potential for prolonging of QTc are prohibited.  The list below is not 
comprehensive.  All concomitant medications should be evaluated for possible interactions with 
belumosudil.(29) 
Generic Name 
• 
Aclarubicin 
• 
Iloperidone 
• 
Amiodarone 
• 
Levofloxacin 
• 
Anagrelide 
• 
Levomepromazine 
• 
Arsenic trioxide 
• 
Levomethadyl acetate 
• 
Astemizole 
• 
Levosulpiride 
• 
Azithromycin 
• 
Mesoridazine 
• 
Bepridil 
• 
Methadone 
• 
Chloroquine 
• 
Moxifloxacin 
• 
Chlorpromazine 
• 
Ondansetron 
• 
Cilostazol 
• 
Oxaliplatin 
• 
Ciprofloxacin 
• 
Papaverine HCl 
• 
Cisapride 
• 
Pentamidine 
• 
Citalopram 
• 
Pimozide 
• 
Clarithromycin 
• 
Probucol 
• 
Disopyramide 
• 
Procainamide 
• 
Dofetilide 
• 
Propofol 
• 
Domperidone 
• 
Quinidine 
• 
Donepezil 
• 
Roxithromycin 
• 
Dronedarone 
• 
Sevoflurane 
• 
Droperidol 
• 
Sotalol 
• 
Erythromycin 
• 
Sparfloxacin 
• 
Escitalopram 
• 
Sulpiride 
• 
Flecainide 
• 
Sultopride 
• 
Fluconazole 
• 
Terfenadine 
• 
Gatifloxacin 
• 
Terlipressin 
• 
Grepafloxacin 
• 
Terodiline 
• 
Halofantrine 
• 
Thioridazine 
• 
Haloperidol 
• 
Vandetanib 
• 
Ibogaine 
 
• 
Ibutilide 
 
 
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SAP_001.pdf: 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Kadmon 
Corporation and any unauthorized use or disclosure of such information without the prior written 
authorization of Kadmon Corporation is expressly prohibited. 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Open-label Multicenter Study to Evaluate the Efficacy and Safety 
of Belumosudil in Subjects with Diffuse Cutaneous Systemic Sclerosis (dcSSc) 
Protocol Number: 
KD025-215/ACT17634 
Study Drug: 
Belumosudil (KD025) 
IND Number: 
IND 140383 
Phase: 
2 
Sponsor: 
Kadmon, a Sanofi Company 
450 East 29th Street 
New York, NY 10016 
Version 2: 
20 January 2023 
NCT04680975


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SIGNATURE PAGE 
 
 
 
Prepared by: 
 
Senior Statistician  
Tigermed 
 Date of Signature 
(DD MMM YYYY) 
 
 
 
Reviewed by: 
 
Study Statistician 
Sanofi 
 Date of Signature 
(DD MMM YYYY) 
 
 
 
Reviewed by: 
 MD, PhD 
Medical Monitor 
Sanofi 
 Date of Signature 
(DD MMM YYYY) 




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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................ 1 
SIGNATURE PAGE ................................................................................................................... 2 
DOCUMENT HISTORY ............................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
1 
INTRODUCTION .................................................................................................................. 8 
2 
STUDY SUMMARY .............................................................................................................. 8 
2.1 
Study Objectives .......................................................................................................... 8 
2.1.1 Primary objective ......................................................................................................... 8 
2.1.2 Secondary objectives................................................................................................... 8 
2.2 
Study Design ............................................................................................................... 9 
2.3 
Visit Schedule and Study Assessment ......................................................................... 9 
3 
STATISTICAL METHODS .................................................................................................... 9 
3.1 
General Methods ......................................................................................................... 9 
3.1.1 Computing Environment .............................................................................................. 9 
3.1.2 Sample Size Justification ............................................................................................. 9 
3.1.3 General Considerations ............................................................................................... 9 
3.1.4 Study Day ...................................................................................................................10 
3.1.5 Baseline .....................................................................................................................10 
3.1.6 Handling of Incomplete or Missing Data .....................................................................10 
3.2 
Analysis Populations ..................................................................................................11 
3.3 
Subject Disposition and Evaluability ...........................................................................12 
3.4 
Protocol Deviations .....................................................................................................12 
3.5 
Demographics and Baseline Characteristics ...............................................................12 
3.5.1 Demographics and Other Characteristics ...................................................................12 
3.5.2 Medical History ...........................................................................................................13 
3.6 
Concomitant Medications ...........................................................................................13 
3.7 
Treatment Compliance and Exposure .........................................................................13 
3.8 
Definition of Efficacy Endpoints ..................................................................................14 
3.8.1 Primary Efficacy Endpoint: CRISS ..............................................................................14 
3.8.2 Secondary Efficacy Endpoints ....................................................................................15 


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3.9 
Safety Analysis ...........................................................................................................17 
3.9.1 Adverse Events ..........................................................................................................17 
3.9.2 Clinical Laboratory Evaluation ....................................................................................18 
3.9.3 Vital Signs ..................................................................................................................18 
3.9.4 ECG ...........................................................................................................................18 
REFERENCES .........................................................................................................................19 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ADI 
Actual dose intensity 
ANCOVA 
Analysis of covariance 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
BID 
Twice daily 
CI 
Confidence interval 
CM 
Concomitant medication 
CRF  
Case report form 
CRISS 
Combined Response Index in Diffuse Cutaneous Systemic Sclerosis 
CTCAE  
Common Terminology Criteria for Adverse Events 
dcSSc  
Diffuse cutaneous systemic sclerosis 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
ECG  
Electrocardiogram 
EOT  
End of Treatment 
FEV1  
Forced expiratory volume (in the first second) 
FVC 
Forced vital capacity 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
Hb 
Hemoglobin 
HLGT 
High level group term 
HRCT  
High-resolution computerized tomography 
IEC  
Independent Ethics Committee 
ILD  
Interstitial lung disease 
IND  
Investigational New Drug 
IRB  
Institutional review board 
ICH 
International Conference on Harmonisation  
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treatment 
MMRM 
Mixed-effects Model of Repeated Measures 
Ms 
Millisecond 
mRSS 
Modified Rodnan Skin Thickness Score 
PA 
Primary analysis 


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PD 
Pharmacodynamic 
PDI 
Planned dose intensity 
PE 
Physical exam 
PFTs 
Pulmonary function tests 
PK  
Pharmacokinetic 
PT 
Preferred term 
QD 
Once daily 
QTcF 
Corrected QT interval using Fridericia's formula 
RDI 
Relative dose intensity 
RV 
Residual volume 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SHAQ-DI 
Scleroderma Health Assessment Questionnaire-Disability Index 
SOC  
System organ class 
SSc 
Systemic sclerosis 
TEAE 
Treatment emergent adverse event 
TLC 
Total lung capacity 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes data-handling and statistical procedures to be 
used for Study KD025-215/ACT17634 as specified in protocol (Amendment No. 2, 01 July 2021): 
A Phase 2, Open-label Multicenter Study to Evaluate the Efficacy and Safety of Belumosudil in 
Subjects with Diffuse Cutaneous Systemic Sclerosis (dcSSc) 
Exploratory objectives analyses (biomarkers analysis, histology and gene expression analyses) 
will be described in separate documents. 
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the most recent ICH-E3 Guideline, entitled “Guidance for 
Industry: Structure and Content of Clinical Study Reports.”  
2 
STUDY SUMMARY 
2.1 
Study Objectives 
2.1.1 
Primary objective 
• 
To evaluate the efficacy of belumosudil using the Combined Response Index in diffuse 
cutaneous Systemic Sclerosis (CRISS) at Week 24. 
2.1.2 
Secondary objectives 
• 
To assess the CRISS at Weeks 8, 16, 36 and 52 
• 
To evaluate the efficacy of belumosudil at Week 24 for: 
o Modified Rodnan skin thickness score (mRSS) 
o Forced vital capacity (FVC) 
o Physician global assessment 
o Patient global assessment 
o Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) 
• 
To evaluate the efficacy of belumosudil at Weeks 8, 16, 36 and 52 compared to baseline 
for all subjects for the parameters in the bullet above  
• 
To assess the safety of belumosudil in subjects with diffuse cutaneous systemic 
sclerosis (dcSSc) by examining the percentage of subjects with Treatment-emergent 
AEs (TEAEs) (Common Terminology Criteria for Adverse Events [CTCAE] v5.0)  


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2.2 
Study Design 
KD025-215/ACT17634 is a Phase 2, open-label, multicenter trial in subjects with dcSSc.   
 
Subjects who have signed an Institutional Review Board/Independent Ethics Committee-
approved informed consent form and met all of the inclusion/exclusion criteria will be enrolled. A 
total of 12-15 subjects will receive orally administered belumosudil 200 mg twice daily (BID) for 
52 weeks. Study drug will be collected at the end of Week 52. The primary endpoint will be 
analyzed using Week 24 data. 
 
Efficacy will be assessed at baseline and throughout the 52 weeks of the treatment period using 
CRISS, mRSS, pulmonary function tests (PFTs), Physician Global Assessments, and Patient 
Global Assessments. Safety will be assessed throughout the study.  
Subjects will undergo evaluations as outlined in the Study Assessment table. A 4-Week Follow-
Up visit will occur 28 days (± 3 days) after the last dose of study drug. 
Efficacy will be assessed throughout the 52-week dosing period using CRISS, mRSS, PFTs, 
physician global assessment, SHAQ-DI. 
2.3 
Visit Schedule and Study Assessment 
The flow chart of visit schedule and study assessments is given in Appendix A of the Study 
Protocol. 
3 
STATISTICAL METHODS 
3.1 
General Methods 
3.1.1 
Computing Environment 
All statistical analyses will be performed using SAS® Version 9.4 or higher for Windows. 
3.1.2 
Sample Size Justification 
This is an exploratory study. Sample size and power are not driven by hypothesis testing. 
Twelve to 15 subjects will be enrolled to receive PO administered belumosudil 200 mg BID.  
3.1.3 
General Considerations  
General considerations for descriptive statistics, presentation, and analysis model (for efficacy 
analysis) used for continuous and categorical data are given below.  


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3.1.3.1 
Continuous variables 
Continuous variables will be described by using these descriptive statistics: number of 
observations (n), mean, standard deviation (SD), median, minimum and maximum.  
The means, medians, and standard deviation (SD) will be reported to one decimal place more 
than the data reported on the case report form (CRF) or by the laboratory/vendor.  Minimum and 
maximum will be reported to the same number of decimal places displayed on the CRF or by 
the laboratory/vendor.   
3.1.4 
Study Day 
The study day for all assessments prior to the first study drug administration is calculated as the 
difference between the date of the event or measurement (e.g., adverse event [AE] onset date, 
assessment date, sample collection date, etc.) and the start date of study treatment. The day 
before the start of study treatment is Study Day -1. 
The study day for all post assessments after the first study drug administration is calculated as 
the difference between the date of the event or measurement (e.g., AE onset date, assessment 
date, sample collection date, etc.) and the start date of study treatment plus one day. The first 
day of study treatment is Study Day 1. 
3.1.5 
Baseline 
Baseline value is defined as the valid and last non-missing value obtained within 29 days prior 
to subject receiving the first study medication, unless otherwise stated under the related 
assessment section. Baseline can be the day before the first study medication or on the same 
day as the first study medication if a pre-dose assessment is available. Subjects without data on 
a parameter before the first study medication will have a missing baseline for this parameter.  
3.1.6 
Handling of Incomplete or Missing Data 
There will be no imputation for missing efficacy values. Missing start and end dates for AE and 
concomitant medication (CM)  
The assumption will be the worst or most conservative judgment when imputing AE and CM 
start and end dates. The purpose of imputing a start date is to help define whether the AE/CM 
started while taking study drug. 
For a partial or missing start date: 


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• 
If the day is missing, the first day of the month will be imputed. If the missing day is the 
same as the month of first dose of study drug, then the first dose date will be imputed. 
• 
If the day and month are missing, the first day of January will be imputed. If the year is 
the same as the first dose date, then the first dose date will be imputed. 
• 
If the day is completely missing, the first dose date will be imputed. If the end date 
suggests it could have started prior to this, the first day of January of the same year as 
the end date will be imputed. 
• 
When imputing a start date, the start date will ensure that the new imputed date is 
sensible, i.e., is prior to the end date of the AE or CM. 
For a partial or missing end date: 
• 
If the day is missing, the last day of the month or the last assessment date, whichever is 
earlier, will be imputed. 
• 
If the day and month are missing, the 31st of December or the last assessment date, 
whichever is earlier, will be imputed. 
• 
If the date is completely missing, there will be a need to look at whether the AE/CM is 
still ongoing before imputing a date. If the ongoing flag is missing, then it will be 
assumed that AE is still present, or CM is still being taken (i.e., do not impute a date). If 
the AE/CM has stopped, then the last assessment date will be imputed. 
These data imputations are for categorization purpose only and will not be used in listings. 
If the assessment of the relationship of the AE to belumosudil is missing, then it will be assumed 
that the AE is related to belumosudil and the AE considered as such in the frequency tables of 
possibly related AEs. No imputation should be done at the data level. 
3.2 
Analysis Populations 
Three populations will be employed in the analysis of study data: 
• 
The Modified Intent-to-treat (mITT) Population will consist of all subjects who receive at 
least 1 dose of belumosudil 200 mg. 


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• 
The Safety Population is defined as all subjects who receive at least 1 dose of 
belumosudil 200 mg. In this study, the Safety Population is equivalent to the mITT 
Population. 
The primary endpoint will be analyzed on the modified Intent-to-Treat (mITT) Population. 
Demographics, subject disposition, baseline characteristics, and efficacy analyses will be 
summarized in mITT Population and by group. 
All safety analyses will be performed on the safety population. 
3.3 
Subject Disposition and Evaluability 
A disposition of all enrolled subjects will be summarized. The number of subjects screening 
failed, discontinuing from study treatment, discontinuing from study and the primary reason for 
discontinuation will be summarized.  
3.4 
Protocol Deviations 
All protocol deviations will be identified and classified as major or minor before the clinical 
database lock and will be presented in a listing.  
Major Deviation: Protocol deviation that may impact the accuracy, and/or reliability of the study 
data or that may impact subject rights, safety or well-being. 
Minor Deviation: Protocol deviation that does not impact the accuracy, and/or reliability of the 
study data or subject rights, safety or well-being. 
3.5 
Demographics and Baseline Characteristics 
3.5.1 
Demographics and Other Characteristics 
A summary table and a by patient listing will be generated for patient demographics and other 
characteristics.  Variables to be included are:  age, sex, race, ethnicity, height, weight, child 
bearing potential, and other variables as applicable based on indication/study design.   
Demographics and other baseline characteristics will be summarized in each population.  


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3.5.2 
Medical History 
Medical history will be summarized by primary system organ class (SOC) and preferred term 
(PT). Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 22.0 or higher) terminology. 
Medical history will be presented in a listing by patient and summarized in the Safety Population.  
3.6 
Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary.  
Concomitant medications are all medications taken after the start of study consent, during the 
treatment period (day 1 until 28 days after last dose), including those started before but ongoing 
at the start of study treatment.  
Concomitant medications will be summarized according to Anatomical Therapeutic Class (ATC) 
and preferred drug name. 
Concomitant medications will be presented in a listing by patient and summarized in the Safety 
Population.  
3.7 
Treatment Compliance and Exposure 
The relative dose intensity (RDI) will be used to assess the treatment compliance.  The RDI is 
defined as: 
 
RDI (%) = 100 × ADI (mg/day) / PDI (mg/day), 
where ADI and PDI are the actual dose intensity and planned dose intensity, respectively: 
 
PDI (mg/day) = planned cumulative dose (mg) / duration of exposure (days), 
 
ADI (mg/day) = actual cumulative dose (mg) / duration of exposure (days). 
The planned cumulative dose is the planned daily dose amount multiplied by the duration of 
exposure, while the actual cumulative dose is the sum of actual total daily dose amount over the 
duration of exposure.  The actual total daily dose will need the information of dose modifications 
(increased and reduced) and dose interruption (held) captured in CRF (Dose Modifications and 
Interruptions).  If a subject does not take any study drug, the actual RDI by definition is zero. 
The duration of exposure is defined as: 


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Duration of exposure (days) = (Date of last dose – Date of first dose) + 1, regardless of 
unplanned intermittent discontinuations. 
One summary table will be generated for treatment exposure and compliance, including: 
treatment duration (weeks), treatment duration categories (0 to 12 weeks, 12 to 24 weeks, 24 to 
28 weeks, 28 to 40 weeks, 40 to 52 weeks), actual cumulative dose, ADI, RDI, and RDI 
categories (>80%, <=80%; >95%, <=95%).   
Another summary table will be generated for dose increased, dose reduced, dose held, and the 
reasons. 
A by patient listing will be generated for the detailed exposure information.  
It will be summarized in Safety Population and by group. 
3.8 
Definition of Efficacy Endpoints  
3.8.1 
Primary Efficacy Endpoint: CRISS 
The primary efficacy endpoint is Combined Response Index in Diffuse Cutaneous Systemic 
Sclerosis (CRISS).  
CRISS is a 2-step process for use in a clinical trial.  
Step 1: patients who develop new onset of renal crisis, new onset or worsening of lung fibrosis, 
new onset of pulmonary arterial hypertension, new onset of left ventricular failure during the trial 
are considered as not improved and assigned a probability of improving equal to 0.0. 
Step 2: For the remaining patients, step 2 involves computing the predicted probability of  
improving for each individual, using the equation shown below.  
 
where ΔMRSS indicates the change in mRSS from baseline to follow up, ΔFVC% denotes the 
change in FVC% predicted from baseline to follow up, ΔPt-glob indicates the change in patient 
global assessment,  ΔMD-glob denotes the change in physician global assessment, and ΔHAQ-DI is 
the change in HAQ-DI. All changes are absolute change (Time2-Timebaseline). 


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As patient global assessment and physician global assessment are based on a VAS of 0 
(Extremely Poor)-100 (Excellent) in CRF.   When calculating the CRISS score, these 2 scores 
should be divided by 10 firstly to make it in a 0-10 scale.   
The outcome is a continuous variable between 0.0 and 1.0 (0-100%). A higher score indicates 
greater probability of improvement. A CRISS score ≥ 20% is considered as the minimal 
detectable difference and will be described as CRISS20 in the SAP. A CRISS score >= 60% is 
considered as the minimally important difference and will be described as CRISS60 in the SAP. 
This will be the primary variable for efficacy.  
Analysis of the primary efficacy endpoint will be conducted using the mITT population.  The 
number and percentage of patients achieving CRISS60 response at week 24 will be 
summarized.  
The following analysis on CRISS will also be provided as supportive evidence for the primary 
analysis.  
• 
The number and percentage of patients who develop new onset of renal crisis, new 
onset or worsening of lung fibrosis, new onset of pulmonary arterial hypertension, new 
onset of left ventricular failure during the trial are considered as not improved and 
assigned a probability of improving equal to 0.0. 
• 
The numerical CRISS Score at week 24. 
3.8.2 
Secondary Efficacy Endpoints 
3.8.2.1 
CRISS 
The numerical and categorical CRISS score will also be summarized for Weeks 8, 16, 36, and 
52 on the mITT population. 
3.8.2.2 
mRSS 
The mRSS is a measure of skin thickness rated with scores ranging from zero (0; normal) to 
three (3; severe skin thickening) across 17 different sites. The total score is the sum of the 
individual skin scores in the 17 body areas (e.g., face, hands, fingers; proximal area of the arms, 
distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, 
feet), giving a range of 0-51 units. A negative change from baseline demonstrates improvement.  


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MRSS total score, change from baseline, percent improvement will be summarized as a 
continuous endpoint at all scheduled assessment visits. 
3.8.2.3 
PFTs 
Onset/progression of ILD will be evaluated by the effect of belumosudil in the change in 
predicted FVC, which is based on institutional standards and will be measured as part of PFTs, 
including FEV1, FVC, DLCO, TLC, and RV.  
FVC (%) and change from baseline will be summarized as a continuous endpoint at all 
scheduled assessment visits.  
FEV1, FVC, DLCO, TLC, RV and their change from baseline will be summarized as a continuous 
endpoint at all scheduled assessment visits. 
3.8.2.4 
Physician Global Assessment 
Physician global assessment is physician’s assessment of patient's overall health during the last 
week based on a VAS of 0 (Extremely Poor)-100 (Excellent). A positive change from baseline 
demonstrates improvement.  
Physician global assessment score, change from baseline, percent improvement will be 
summarized as a continuous endpoint at all scheduled assessment visits. 
3.8.2.5 
Patient Global Assessment 
Patient global assessment is patient’s assessment of their overall health during the last week 
based on a VAS of 0 (Extremely Poor)-100 (Excellent). A positive change from baseline 
demonstrates improvement. 
Patient global assessment score, change from baseline, percent improvement will be 
summarized as a continuous endpoint at all scheduled assessment visits. 
3.8.2.6 
Scleroderma Health Assessment Questionnaire-Disability Index (SHAQ-DI) 
SHAQ-DI includes the general HAD-DI assessment and 6 scleroderma-specific Visual Analog 
Scale (VAS) items to explore the impact of participant's disease.  The general HAD-DI 
assessment includes 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and 
activities.  The 6 VAS items will be rated separately in scale of a 0−100 millimeters [mm], with 
higher scores indicating more severe disease. The 6 items are: 1) pain, 2) intestinal disease, 3) 


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breathing problem, 4) Raynaud syndrome, 5) finger ulcers, and 6) overall disease. A negative 
change from baseline demonstrates improvement. 
SHAQ-DI total score, each of the 6 VAS scores and their change from baseline, percent 
improvement will be summarized as a continuous endpoint at all scheduled assessment visits. 
3.8.2.7 
Treatment Emergent Adverse Events 
Treatment emergent adverse events in subjects with dcSSc at baseline will be presented by 
number (N) and percentage (%).  
3.9 
Safety Analysis 
Safety assessments include AEs, serious adverse events (SAEs), vital sign measurements, 
clinical laboratory evaluations (hematology, chemistry, urinalysis, pregnancy tests) and 
electrocardiograms (ECGs).  Unscheduled visits for safety assessments will not be presented in 
by visit summary tables but will be in listings and shift tables. All safety analyses will be 
performed using the safety population.  
Clinically significant PE findings will be captured as AEs. 
3.9.1 
Adverse Events 
AEs will be coded using the MedDRA dictionary (Version 22.0 or higher). TEAEs are any AEs 
occurring or worsening in severity after the first administration of study medication.  All AEs 
(including SAEs) will be graded using the 5-point CTCAE V5.0 scale (mild, moderate, severe, 
life threatening, or death).  Causality with study treatment will be classified as: definitely related; 
probably related; possibly related; unlikely related; not related.  
The number (N) and percentage (%) of patients who experienced at least one TEAE will be 
summarized by: 
• 
SOC and PTs within each SOC in decreasing total frequency 
• 
PT in decreasing total frequency 
• 
SOC, PTs, and maximum severity 
• 
SOC, PTs, and relationship to study drug 
These analyses will be repeated for Grade ≥3 TEAEs, SAE, TEAEs leading to dose modification, 
TEAES leading to dose interruption, and AE leading to study drug discontinuation. 


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Subject listings will be provided for AEs, SAEs, AEs resulting in study drug discontinuation and 
deaths. Time to onset and duration of AEs will be included in listings, along with action taken 
and outcome. 
3.9.2 
Clinical Laboratory Evaluation 
The summary statistics (including number, mean, SD, median, minimum and maximum) of all 
laboratory variables and changes from baseline will be calculated for each scheduled 
assessment visit. 
For parameters of white blood cell counts, neutrophils (absolute count), lymphocytes (absolute 
count), monocytes (absolute count), Hb, platelets, ALP, ALT, AST, GGT, total bilirubin, GFR, 
plots of mean / mean changes from baseline with the corresponding standard error will be 
displayed.  
For shift tables, laboratory results will be classified using the CTCAE V5.0. All graded laboratory 
parameters will be summarized separately for hematology and biochemistry. Corresponding 
shift tables to compare baseline to the worst post-baseline grade within the treatment period will 
be provided.   
A by patient by lab tests by visit listing will be generated for lab results with CTC grade >=3. 
3.9.3 
Vital Signs 
Descriptive statistics for vital signs (weight, heart rate, body temperature, systolic and diastolic 
blood pressure, pulse rate, and respiratory rate) values and the change from baseline will be 
presented for each scheduled assessment visit. 
A by patient by visit listing will be generated for vital signs. 
3.9.4 
ECG 
Descriptive statistics for ECG parameters (i.e., heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTcF interval) at each time point with triplicate ECGs will be presented for the 
values and change from baseline scores (QTcF is the QT interval using Fridericia’s correction 
which is calculated by QTcF = QT/RR1/3). In addition the maximum change from baseline will be 
calculated for each subject and summarized for each scheduled assessment visit.  
The number and percentage of subjects with observed QTcF values that satisfy the following 
conditions will be presented: 
• 
≤ 450 millisecond (ms)  


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• 
>450 to ≤ 480 ms 
• 
>480 to ≤ 500 ms 
• 
> 500 ms 
The number and percentage of subjects having change from baseline QTcF values that satisfy 
the following conditions will be presented: 
• 
≤ 0 ms 
• 
>0 to ≤ 30 ms 
• 
>30 to ≤ 60 ms 
• 
> 60 ms 
A by patient by visit listing will be generated for ECG results. 
 
REFERENCES 
1. Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, et al. The 
American College of Rheumatology provisional composite response index for clinical trials in 
early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2016;68(2):299–311. 
2. Spiera R, Hummers L, Chung L, Frech TM, Domsic R, Hsu V, Furst DE, Gordon J, Mayes M, 
Simms R, Lafyatis R. Safety and efficacy of lenabasum in a phase II, randomized, 
placebo‐controlled trial in adults with systemic sclerosis. Arthritis & Rheumatology. 2020 
Aug;72(8):1350-60.