Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Pulmonary Fibrosis Fibrosis Idiopathic Interstitial Pneumonias Lung Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 76
Healthy volunteers: no

Brief summary:
This Phase 2 study is to be conducted to evaluate the safety, tolerability, and activity of 400 mg of belumosudil orally (PO) once-daily (QD) compared to Best Supportive Care (BSC) in male and postmenopausal/surgically sterilized female subjects with Idiopathic Pulmonary Fibrosis (IPF). The primary objectives are to evaluate the:

* Change in Forced Vital Capacity (FVC) from baseline to 24 weeks after dosing with belumosudil 400 mg PO QD in subjects with IPF compared to BSC
* Safety and tolerability of belumosudil 400 mg PO QD when administered for 24 weeks to subjects with IPF compared to BSC

Detailed description:
Study KD025-207 is a Phase 2, randomized, 2-part, open-label, crossover study in subjects with IPF.

The purpose of the study is to evaluate the safety, tolerability, and activity of 400 mg of belumosudil administered orally (PO) every day (QD) compared to Best Standard of Care (BSC) in subjects with IPF who have previously been treated with or declined treatment with pirfenidone or nintedanib.

The primary objectives are to evaluate the change in Forced Vital Capacity (FVC), and the safety and tolerability from baseline to 24 weeks in subjects with IPF after dosing with belumosudil 400 mg PO QD compared to BSC.

Part 1: Randomized, Open-label for 24 Weeks

Approximately 81 eligible subjects with IPF are to be enrolled, in 10 to 15 sites, and randomized in a 2:1 ratio (belumosudil:BSC) to 1 of the following 2 groups:

* Belumosudil-R (Investigational Group): Belumosudil 400 mg PO QD for 24 weeks
* BSC-R (Control Group): BSC for 24 weeks

The study plan is for 54 subjects to be entered into the Belumosudil-R Treatment Group and 27 subjects into the BSC-R Treatment Group. This sample size provides over 90% power at the 2-sided 0.05 significance level to detect a 20% difference between treatment groups at 24 weeks in percentage change from baseline in FVC assuming a standard deviation (SD) in percentage change from baseline in FVC of 17%. The sample size of 54 subjects receiving belumosudil provides over 90% probability of ≥ 1 subject in the study experiencing an AE that had an underlying rate of ≥ 5%.

Part 2: Continuation of Belumosudil Therapy or Crossover to Belumosudil Therapy Subjects in the Belumosudil-R group who complete 24 weeks of treatment with belumosudil 400 mg PO QD have the option of continuing therapy with belumosudil 400 mg PO QD up to an additional 72 weeks if there are no safety signals and if clinical progress continues. No subject in the Belumosudil-R group is to be permitted to receive therapy with belumosudil greater than a total of 96 weeks.

Subjects in control group BSC-R who complete 24 weeks of BSC have the option of crossing over to therapy with belumosudil 400 mg PO QD for up to 96 weeks if there are no safety signals and if clinical progress continues. No subject in control group BSC-R is to be permitted to receive belumosudil 400 mg PO QD therapy greater than 96 weeks.

Follow-up Period:

Follow-up Visits are to occur 30 days (± 3 days) after the last dose of belumosudil during which subjects are to undergo safety assessments. (A Follow-up Visit is not necessary for subjects receiving BSC.)

Duration of Study for Individual Subjects:

1. Subjects randomized to belumosudil: total up to 104 weeks (4-week screening, 96-week treatment with belumosudil, and 4-week follow-up)
2. Subject randomized to BSC: total up to 128 weeks (4-week screening; up to 24-week treatment with BSC, 96-week treatment with belumosudil, and 4-week follow-up)

Efficacy Assessments

* FVC
* FVC% Predicted
* 6-minute Walking Distance (6MWD)
* Diffusing Capacity of Carbon Monoxide (DLCO)
* Lung Fibrosis (by HRCT and Radiologist's Visual Assessments)
* Time to Acute Exacerbation
* Time to Progression of IPF
* Time to Respiratory-related Hospitalization
* Time to Respiratory-related Death
* St. Georges Respiratory Questionnaire (SGRQ)

Biomarker Assessments

* Matrix Metalloproteinase-7 (MMP7)
* Chemokine Ligand 18 (CCL18)
* Surfactant Protein-D (SPD)

Safety Assessments

* Adverse event (AE)
* Serious adverse event (SAE)
* Physical examination (PE)
* Vital signs (VS)
* Clinical laboratory evaluations (hematology, chemistry, and urinalysis)
* Electrocardiogram (ECG)
* Reason for treatment discontinuation due to toxicity

Analyses

Efficacy and safety are to be analyzed at the end of Part 1 (Week 24) and for the Entire Treatment Period (Parts 1 and 2). Analyses of study subjects are to be grouped and defined as follows:

* Belumosudil-R: subjects randomized to belumosudil
* BSC-R: subjects randomized to BSC
* Belumosudil-WC: subjects randomized to belumosudil plus subjects randomized to BSC and who cross over to treatment with belumosudil
* BSC-NC: subjects randomized to BSC and who cross over to treatment with belumosudil but have data censored by the date of crossover

Arms:
arm 1: Subjects receive two 200 mg tablets of belumosudil (400 mg) PO QD for 24 weeks. Subjects may also continue treatment with belumosudil 400 mg PO QD after 24 weeks.

No subject may receive more than 96 weeks of treatment with belumosudil arm 2: Subjects receive best supportive care as determined by the physician. Subjects may later crossover to treatment with belumosudil 400 mg PO QD. No subject may receive more than 96 weeks of treatment with belumosudil.

Interventions: intervention 1: Belumosudil intervention 2: BSC
Intervention descriptions: intervention 1: None intervention 2: Treatment/drug as determined by each subject's prescribing physician

Protocol document:
Prot_000.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. 
 
                                          
 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the 
Safety, Tolerability, and Activity of KD025 in Subjects with Idiopathic 
Pulmonary Fibrosis (IPF) 
 
 
Protocol Number: 
KD025-207 
Study Drug: 
KD025 
IND Number: 
128024 
Phase  
2 
 
Sponsor: 
Kadmon Corporation 
 
450 East 29th Street 
 
New York, NY  10016 
Medical Monitor: 
 Sanjay Aggarwal, M.D.  
Date of Protocol: 
Original, Final, 22 September 2015 
 
Amendment No. 1, Final, 17 November 2015 
 
Amendment No. 2, Final, 04 December 2015 
 
Amendment No. 3, Final, 04 January 2016 
 
Amendment No. 4, Final, 01 February 2016 
 
Amendment No. 5, Final 07 April 2017 
 
 
Amendment No. 6, Final, 16 October 2017 
 
Amendment No. 7, Final, 22 December 2017 
 
Amendment No. 8, Final, 20 September 2019 
 
Amendment No. 9, Final, 03 March 2020 
 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Serious and Unexpected Adverse Events  
Any serious adverse event (SAE)* or suspected unexpected serious adverse reaction (SUSAR)** 
occurring in a subject while receiving study drug or within 30 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  
 
 
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 13.1, 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. 
**  A suspected unexpected SUSAR is any untoward and unintended responses to an investigational product related to any 
dose administered, of which the nature, or severity, is not consistent with the applicable product information (see also Section 
13.1 of this document; Suspected Unexpected Serious Adverse Reactions).  All suspected adverse reactions related to an 
investigational medicinal product which occur in the concerned trial and that are both unexpected and serious are subject to 
expedited reporting.   
 
For SAE/SUSAR reporting: 
For any other questions or to  
contact the medical monitor: 
 
APCER Life Sciences, LLC 
Fax: 646-430-9549 
 
In the event of an issue with the fax line, forward 
SAE/SUSAR via email to: 
ClinicalSAEReporting@kadmon.com 
 
Sanjay Aggarwal, M.D. 
Kadmon Corporation, LLC 
55 Cambridge Parkway, Suite 300E 
Cambridge, MA 02142 
Telephone:  724-778-6129   
Cell:  857-253-8642  
E-mail:  Sanjay.Aggarwal@kadmon.com 




KD025 
IND Number 128024 
Protocol Number KD025-207
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INVESTIGATOR SIGNATURE 
 
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) 
E6 (R2), 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) 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
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1. 
SYNOPSIS 
Study Title 
A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the 
Safety, Tolerability, and Activity of KD025 in Subjects with Idiopathic 
Pulmonary Fibrosis (IPF)  
Clinical Phase 
2 
Number of Study 
Centers/Sites 
Approximately 10-15 
Study Background 
Idiopathic pulmonary fibrosis is a chronic, progressive, irreversible, and 
often fatal lung disease of unknown cause. With a prevalence of 2 to 
29 per 100,000 people and an incidence of approximately 10 per 
100,000/per year, IPF meets the criteria for classification as an orphan 
disease. It affects older adults with peak prevalence around 65 years of 
age.  
The natural history for patients with IPF varies. While most patients 
progress slowly and gradually over many years, others have an 
accelerated decline often associated with episodes of acute respiratory 
worsening. The median survival time is 2 to 4 years from diagnosis and 
the 5-year survival rate ranges between 30% and 50%. Its mortality rate 
is higher than that of most cancers.  
The commonly accepted method of determining disease progression is to 
identify a decline in forced vital capacity (FVC). Functionally stable 
patients show a FVC decline of a maximum of 5% of the baseline value 
over 6 to 12 months. A decline in FVC of 5% to 10% indicates 
prognostically relevant progression, while a decline of ≥ 10% in 
6 months is associated with a 4- to 8-fold increase in the risk of death in 
the subsequent 12 months. Regular lung function checks to measure FVC 
and diffusing capacity are recommended at intervals of 3 to 6 months.  
Acute exacerbations are an important aspect of clinical progression. 
These are defined by a subacute or acute increase in shortness of breath 
over a period of 30 days and a high-resolution computed tomography 
([HRCT] slice thickness ≤ 2.0 mm, no contrast media) showing new 
infiltration of the lungs with no identifiable cause. Acute exacerbation 
frequency is 5% to 15% per year and acute exacerbations are associated 
with high mortality. After an acute exacerbation of IPF, approximately 
50% of patients die within 3 months, and approximately 80% to 90% 
within 12 months. 
There is no cure for IPF and treatment options are limited. Historically, 
available pharmacological therapies have had limited efficacy/activity 
and potential serious side effects. However, recently both nintedanib and 
pirfenidone have been shown to slow decline in FVC in separate Phase 3 


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clinical trials, and both received Food and Drug Administration approval 
in October 2014. 
Study Rationale 
This study is being conducted to evaluate the safety, tolerability, and 
activity of 400 mg of KD025 once-daily (QD) compared to best 
supportive care (BSC) in subjects with IPF.  
Rho-associated 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 isoforms of ROCK have been identified, ROCK1 and ROCK2. 
Early work with nonspecific ROCK inhibitors (eg, fasudil) suggested that 
both ROCK1 and ROCK2 are involved in Rho-mediated changes in the 
actin/myosin cytoskeletal network. However more recent research has 
uncovered additional relevant roles for ROCK signaling, particularly 
ROCK2, in conditions including IPF. Matrix stiffening and 
myofibroblast resistance to apoptosis are cardinal features of chronic 
fibrosis. The ROCK pathway, which is necessary for contraction and 
force generation in fibroblasts and for downstream actin polymerization, 
may therefore be a molecular driver for the formation and progression of 
pulmonary fibrosis 
The possibility that pulmonary fibrosis could be directly treated by 
inhibitors of ROCK has been investigated in mouse models. In a 
bleomycin-induced model of lung fibrosis, intratracheal (IT) 
administration of bleomycin in mice induces changes similar to those of 
diffuse pulmonary fibrosis or fibrosing alveolitis in humans, making this 
a good model of pulmonary fibrosis for testing of new IPF therapies. In 
particular, bleomycin causes increased deposition and net synthesis of 
collagen in the lungs. A study conducted in bleomycin-treated mice, 
showed that fasudil reduced pulmonary fibrosis even when administered 
14 days after IT bleomycin when fibrosis was presumably already 
present. Treatment with fasudil, an inhibitor of ROCK1 and ROCK2, 
significantly reduced the levels of alpha-smooth muscle actin and 
collagen content of the lungs. This study in bleomycin-treated mice also 
demonstrated that ROCK inhibitors may be effective for treating 
pulmonary fibrosis through more than 1 mechanism. Fasudil blocked 
actin cytoskeletal reorganization, fibroblast acquisition of contractile 
activity, and megakaryoblastic leukemia (translocation) 1 (MKL1) 
nuclear translocation, preventing the differentiation of fibroblasts into 
matrix/collagen depositing myofibroblasts in vitro.  
Kadmon Corporation has internally evaluated the efficacy/activity of 
13 days of therapy with KD025 in a bleomycin-induced pulmonary 
fibrosis model in mice. C57Bl/6 mice were treated with KD025 or 
vehicle (0.4% carboxymethyl cellulose) beginning 8 days after IT 


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treatment with 2.25 U/kg of bleomycin. At the initiation of treatment, 
pulmonary fibrosis was already established. Unlike vehicle control 
therapy, oral QD treatment with 100 mg/kg and 150 mg/kg of KD025 
significantly reduced pulmonary fibrosis and inflammation. 
Matrix metalloproteinase (MMPs) have been found to be increased in the 
lung and bronchoalveolar lavage (BAL) fluid of patients with IPF. A 
matrix metalloproteinase-7 (MMP7) previously implicated in the 
pathogenesis of IPF, is significantly increased in plasma, serum, BAL 
fluid, and lung tissue of IPF patients, suggesting that MMP7 may be a 
biomarker for IPF disease progression or mortality. The MMP7 levels 
will therefore be studied in this clinical trial, in addition to other potential 
future biomarkers for patient selection and pharmacodynamic response; 
chemokine ligand 18 (CCL18) and surfactant protein-D (SPD). 
Dose Rationale 
This study will evaluate KD025 at a dose of 400 mg QD.  Preliminary 
data from an ongoing study of KD025 in patients with moderate to severe 
psoriasis suggests that the dose of 400 mg QD for 12 weeks is associated 
with clinical efficacy/activity and is well tolerated. This study will 
examine the safety and clinical efficacy/activity of the 400 mg QD dose 
in subjects with IPF as compared to BSC. 
The administration of this dose to subjects with IPF who have disease 
progression after receiving both nintedanib and pirfenidone is supported 
by the data from a previous KD025 trial in subjects with psoriasis as well 
as by the clinical situation of subjects to be enrolled into this study. The 
safety data from KD025 psoriasis study indicate that the dose of 400 mg 
QD for 12 weeks was tolerable with an acceptable safety profile.  Finally, 
subjects with IPF who have disease progression after receiving both 
nintedanib and pirfenidone have a poor clinical prognosis, as poor as 
some types of aggressive cancer. Thus the risk to benefit ratio in these 
subjects favors the use of the 400 mg QD dose level which has 
demonstrated tolerability and clinical activity in previous clinical studies. 


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Study Objective(s)/ 
Purpose 
Primary objectives 
 
To evaluate the change in FVC from baseline to 24 weeks after 
dosing with KD025 400 mg QD in subjects with IPF compared 
with BSC 
 
To evaluate the safety and tolerability of KD025 400 mg QD 
when administered for 24 weeks to subjects with IPF compared 
to BSC 
Secondary objectives  
 
To evaluate the change in 6-minute walk distance (6MWD) from 
baseline to 24 weeks 
 
To evaluate the occurrence of acute exacerbation of IPF 
(frequency and severity) throughout treatment 
 
To evaluate change in severity of lung fibrosis as measured by 
quantitative HRCT 
 
To evaluate the percentage of subjects with disease progression 
before or at 24 weeks 
Exploratory Objective 
 
To evaluate the change in MMP7, CCL18, and SPD serum levels 
Trial Design 
Phase 2, randomized (2:1), open-label, multicenter in subjects with IPF 
Methodology 
Approximately 81 eligible subjects will be enrolled and randomized to 
treatment with KD025 400 mg QD for 24 weeks (Treatment Group 1) or 
BSC for 24 weeks (Treatment Group 2) in a 2:1 ratio (KD025 to BSC). 
Subjects in Treatment Group 1 who complete 24 weeks of treatment with 
KD025 400 mg QD will have the option of continuing therapy with 
KD025 400 mg QD up to an additional 72 weeks if there are no safety 
signals and if clinical progress continues.  No subject in Treatment 
Group 1 will be permitted to receive therapy with KD025 greater than a 
total of 96 weeks. 
Subjects in Treatment Group 2 who complete 24 weeks of BSC will have 
the option of crossing over to therapy with KD025 400 mg QD for up to 
96 weeks if there are no safety signals and if clinical progress continues.  
No subject in Treatment Group 2 will be permitted to receive KD025 
400 mg QD therapy greater than 96 weeks. 
For subjects from Treatment Group 2 who switch to KD025, prior to 
receiving their first dose of KD025, Investigators should perform the 
Week 1, Day 1 assessments (except for safety labs [hematology and 
chemistry] if performed within 1 week of this visit and PFTs if 


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performed within 4 weeks) and all subsequent visits as outlined in Table 
1, Study Assessments.   
All subjects will receive the same assessments. 
Subjects will undergo medical history evaluations, physical examinations 
(PEs), vital sign measurements, weight measurements, adverse event 
(AE) assessments, concomitant medication and procedures assessments, 
blood sample collection for hematology (including coagulation) and 
chemistry, urinalysis, thyroid function assessment (TSH), HRCT, and 
electrocardiogram (ECG), as outlined in the Study Assessments table 
(Table 1).  
Additionally, FVC, residual volume (RV), diffusing capacity of the lungs 
for carbon monoxide (DLCO), 6MWD, and MMP7, CCL18, and SPD 
serum levels will be measured. The 6MWD, weight, heart rate, blood 
pressure, and pulse oximeter oxygen saturation (SpO2) will be recorded 
before and after the walk. 
Occurrence of acute exacerbation (frequency and severity) of IPF will be 
assessed throughout the study.  
Follow-up visits will occur 30 days (± 3 days) after the last dose of 
KD025. (A Follow-up visit is not necessary for subjects receiving BSC.)  
Subjects will undergo the following safety assessments: Complete PEs, 
vital signs measurements, weight measurements, AE assessments, 
concomitant medication and procedures assessments, blood sample 
collection for hematology (including coagulation), chemistry and thyroid 
function (TSH), PFTs, and urinalysis. If another therapy is started within 
30 days after the last dose of study drug, the Follow-up visit will be 
conducted before the start of the other therapy. 
Number of Subjects 
Approximately 81 subjects with IPF. 
Approximate Duration of 
Subject Participation 
Subjects in Treatment Group 1, KD025 400 mg QD for 24 weeks, will 
have the option of continuing therapy with KD025 400 mg QD.  Subjects 
who do not continue KD025 400 mg QD after 24 weeks may remain 
on-study up to 32 weeks: 4 weeks for screening, 24 weeks of KD025 
400 mg QD, and 4 weeks of Follow-up.  Subjects who choose to continue 
therapy with KD025 400 mg QD after 24 weeks may remain on-study up 
to 104 weeks: 4 weeks for screening, a total of 96 weeks of KD025 
400 mg QD (an initial 24 weeks of KD025 400 mg and an additional 
72 weeks of KD025 400 mg QD), and 4 weeks of Follow-up.  No subject 
will receive more than 96 weeks of treatment with KD025 400 mg QD. 
Subjects in Treatment Group 2, BSC for 24 weeks, will have the option 
of crossing over to treatment with KD025 after 24 weeks.  Subjects who 


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Protocol Number KD025-207
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do not crossover will remain on-study up to 32 weeks: 4 weeks for 
screening, 24 weeks of BSC, and 4 weeks of Follow-up.  Subjects who 
do crossover to KD025 therapy may remain on-study up to 128 weeks: 
4 weeks for screening, 24 weeks of BSC, 96 weeks of KD025 400 mg 
QD, and 4 weeks of Follow-up.  No subject will receive more than 
96 weeks of treatment with KD025 400 mg QD. 
Criteria for Inclusion 
and Exclusion  
Inclusion Criteria 
1. Adult male and postmenopausal/surgically sterilized female subjects 
at least 18 years of age (if female, is surgically sterilized [ie, total 
hysterectomy, or bilateral salpingo-oophorectomy]) 
2. Able to provide written informed consent before the performance of 
any study specific procedures 
3. IPF diagnosis within 5 years before study entry, proven according to 
the American Thoracic Society/European Respiratory Society 
consensus conference criteria, with surgical lung biopsy.  In the 
absence of a surgical lung biopsy, HRCT must be consistent with 
usual interstitial pneumonitis.   
4. Resting state SpO2 ≥ 88% with or without supplemental oxygen, 
FVC % ≥ 50% normal predicted value, and DLCO ≥ 30% normal 
predicted value at baseline 
5. Men with partners of childbearing potential must be willing to use 
2 medically acceptable methods of contraception during the trial and 
for 3 months after the last dose of study drug. Effective birth control 
includes (a) intrauterine device (IUD) plus 1 barrier method; 
(b) stable doses of hormonal contraception for at least 3 months (eg, 
oral, injectable, implant, transdermal) plus 1 barrier method; 
(c) 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 (d) vasectomy.    
6. Have adequate bone marrow function: 
a. absolute neutrophil count > 1500/mm3 
b. Hemoglobin > 9.0 g/L 
c. Platelets > 100,000/mm3  
7. Willing to complete all study measurements and assessments in 
compliance with the protocol 
8. Has either received pirfenidone and/or nintedanib or has been offered 
both treatments (with last dose administered at least 1 month before 
the expected start of study drug dosing). If either or both pirfenidone 
and nintedanib treatment has not been given, then documentation that 
the subject was offered both treatments must be documented. 
Exclusion Criteria 
1. Interstitial lung disease caused by conditions other than IPF 


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2. Severe concomitant illness limiting life expectancy (< 1 year) 
3. DLCO < 30% predicted 
4. Residual volume ≥ 120% predicted 
5. Obstructive lung disease:  FEV1/ FVC ratio < 0.70 
6. Documented sustained improvement of the subject’s IPF condition 
up to 12 months before study entry with or without IPF-specific 
therapy 
7. Pulmonary or upper respiratory tract infection within 4 weeks before 
study entry 
8. Acute or chronic impairment (other than dyspnea) limiting the 
ability to comply with study requirements (eg, pulmonary function 
tests) 
9. Chronic heart failure with New York Heart Association Class III/IV 
or known left ventricular ejection fraction < 25% 
10. Moderate to severe hepatic impairment (ie, Child-Pugh Class B or 
C) 
11. Estimated creatinine clearance < 30 mL/min 
12. Aspartate aminotransferase (AST) and/or alanine 
aminotransaminase (ALT) > 2.0 × upper limit of normal (ULN) 
13. Hemoglobin < 75% of the lower limit of normal 
14. Systolic blood pressure < 100 mmHg 
15. Female subject who is pregnant or breastfeeding 
16. Men whose partner is pregnant or breastfeeding  
17. Current drug or alcohol dependence 
18. Chronic treatment with the following drugs (within 4 weeks of study 
entry and during the study) 
a. Immunosuppressive or cytotoxic drugs including 
cyclophosphamide and azathioprine 
b. Antifibrotic drugs including pirfenidone, nintedanib, 
D penicillamine, colchicine, tumor necrosis factor α 
blockers, imatinib and interferon-γ 
c. Chronic use of N-acetylcysteine prescribed for IPF 
(> 600 mg/day) 
d. Oral anticoagulants prescribed for IPF 
19. Treatment with endothelin receptor antagonists within 4 weeks 
before study entry 


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20. Systemic treatment within 4 weeks before study entry with 
cyclosporine A or tacrolimus, everolimus, or sirolimus (calcineurin 
or mammalian target of rapamycin inhibitors) 
21. Previous exposure to KD025 or known allergy/sensitivity to KD025 
or any other ROCK2 inhibitor 
22. Planned treatment, or treatment with another investigational drug 
within 4 weeks before study entry 
23. Subject is taking a medication that has the potential for QTC 
prolongation 
24. Subject is taking a drug that is a sensitive substrate of CYP enzymes 
25. Subject is taking a strong inducer of CYP3A4 
26. Subject has consumed an herbal medication (eg, St. John’s Wort) or 
grapefruit/grapefruit juice within 14 days prior to the Week 1, Day 1 
visit 
Test Drug  
Oral KD025. KD025 will be provided as 200-mg tablets.   
Dosage and 
Administration  
 
KD025 400 mg (two 200-mg tablets) will be administered orally QD. 
Subjects should take KD025 within 5 minutes of completing a meal.   
Reference Therapy  
Best supportive care (BSC) as deemed appropriate by the Investigator.  
Subjects randomized to BSC will undergo the same procedures and 
assessments as subjects on KD025.  
Concomitant Treatment 
 
Subjects will be counseled to avoid non-prescribed medicines or 
complementary alternative medicines excluded by the study.  All 
medications and procedures a subject receives/undergoes from the date 
that the ICF is signed until 30 days after last dose of study drug will be 
documented. 
All subjects who receive KD025 therapy, that is, all subjects in 
Treatment Group 1 and subjects in Treatment Group 2 who crossover to 
KD025 therapy, are not to take drugs that are sensitive substrates of CYP 
enzymes from first dose until 14 days after last dose of study drug.  
Additionally, use of strong CYP3A4 inducers are prohibited.  Other 
CYP3A4 inhibitors or inducers should be used with caution.  Herbal 
medications (eg, St. John’s Wort) or grapefruit/grapefruit juice should 
not be consumed 14 days prior to first dose of study drug until the end of 
study treatment. 
Safety Evaluation 
The primary safety outcome will be the percent of subjects in each 
treatment group experiencing AEs. 
Safety assessments include AEs, serious AEs (SAEs), PEs, vital sign 
measurements, clinical laboratory evaluations, and ECGs.  Reasons for 


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treatment discontinuation because of toxicity will be documented.  Safety 
assessments will be performed at specified time points and before 
discharge from the clinic. 
The AE reporting period for a subject enrolled in the study begins when 
the subject signs the informed consent and is continued through 30 days 
after their last dose of study drug.  All AEs that occur in enrolled subjects 
during the AE reporting period must be reported to the sponsor (Kadmon 
Corporation), 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 at least possibly related to study drug also 
should be reported to the sponsor. 
Subjects with ongoing AEs/SAEs will be followed until resolution or a 
new treatment for IPF is started. 
Vital sign measurements, including blood pressure, pulse rate, respiratory 
rate, and temperature will be monitored throughout the study. 
Efficacy/Activity 
Evaluation 
Pulmonary function testing (PFT) will be performed at screening, 
baseline, 12 weeks, 24 weeks, and at a 30-day Follow-up visit (for 
subjects continuing, PFTs will be performed every 12 weeks). Pulmonary 
function testing will include FVC, RV, and DLCO. The same equipment 
and tester should be used during the course of the study to the extent 
possible.    The person responsible for conducting the pulmonary 
function tests will be required to comply with the study guidelines and 
the American Thoracic Society/European Respiratory Society joint 
criteria on lung function testing. 
The 6MWD will be assessed at baseline and after 12 weeks and 
24 weeks (for subjects continuing, 6MWD will be performed every 
12 weeks).  The distance traveled during 6 minutes (meters) will be 
measured in accordance with published guidelines.  The total distance 
ambulated in meters during the 6-minute walk test and the number of rest 
stops is recorded.  The 6MWD, weight, heart rate, blood pressure, and 
pulse oximeter oxygen saturation (Sp02) are recorded before and after the 
walk. 
Occurrence of acute exacerbation (frequency and severity) of IPF will 
be assessed throughout the study.  The following clinical deterioration 
symptoms within a month that cannot be explained by other reasons will 
be assessed as acute exacerbation: 
1. Aggravated dyspnea; 
2. Newly discovered chest interstitial lung abnormality by 
radiograph/HRCT, without pneumothorax or pleural effusion; 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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3. SpO2 decreases to < 88% (heart failure or pulmonary embolism 
excluded). 
Acute exacerbation can be diagnosed if Items 1 and 2 are present or if 
Items 1 and 3 are present.  Infection, pulmonary embolism, 
pneumothorax, or heart failure must be ruled out.   
The change in severity of lung fibrosis will be determined using 
measurements from quantitative HRCT. 
Time to progression of IPF is defined as time from the Week 1, Day 1 
visit to any 1 of the following:  
1. First respiratory-related hospitalization. 
2. Respiratory-related death. 
3. Absolute decline in FVC percent of predicted value of ≥ 10% 
versus FVC percent of predicted value recorded at baseline.   
4. Absolute decline in DLCO, adjusted for hemoglobin, percent of 
predicted value of ≥ 15% versus DLCO recorded at baseline. 
Pharmacodynamics 
Serum levels for MMP7, CCL18, and SPD will be assessed at baseline, 
12 weeks, and 24 weeks (For subjects continuing, biomarkers will be 
assessed at End of Week 36, End of Week 48 and EOT).  Serum MMP7 
concentrations in peripheral blood are easily measureable and reflect 
changes in the alveolar microenvironment.  Thus, mean serum MMP7 
concentrations after 24 weeks of KD025 treatment will be studied as a 
potential surrogate biomarker of the effect of KD025 administration on 
disease progression.  
Statistical Analysis 
Study Populations 
Three populations will be employed in the analysis of study data: 
 
The Safety Population will consist of all subjects who are 
randomized and receive at least 1 dose of KD025 (Treatment 
Group 1) or have week 1 assessment for BSC subjects. All safety 
analyses will be performed on the safety population 
 
The Modified Intent-to-Treat (mITT) Population will consist of 
all subjects in the safety population who have evaluable baseline 
and at least 1 evaluable post baseline FVC assessment. Only 
evaluable FVC will be used in efficacy analyses. 
 
The Per Protocol (PP) Population will consist of all subjects in 
the safety population who have evaluable baseline and evaluable 
Week 24 FVC assessment. For any analysis on the per-protocol 
population, for patients assigned to treatment and actually 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
Kadmon Corporation  
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received treatment, re-calculated baseline value should be used 
for cross over patients. 
Primary Endpoints 
 
The primary efficacy/activity endpoint is the change in FVC 
from baseline to 24 weeks.  
 
The primary safety endpoint is a subject experiencing one or 
more AEs during the treatment period.  
Secondary Endpoints: 
 
The change in 6MWD from baseline to 24 weeks  
 
Acute exacerbation of IPF throughout treatment with KD025  
 
The change in severity of lung fibrosis as measured by 
quantitative HRCT at baseline and after 24 weeks of treatment  
 
To evaluate the percentage of subjects with  disease progression 
before or at 24 weeks 
Exploratory Endpoints: 
 
The change in MMP7, CCL18, and SPD serum levels from 
baseline at 24 weeks. 
Data Presentations/Descriptive Statistics 
Demographics, subject disposition, and baseline characteristics will be 
summarized for the safety, mITT and PP, where appropriate. 
The  primary analysis will be conducted with a data cutoff of 
approximately 24 weeks after last patient enrolled has received KD025 or 
when all subjects can be evaluated for primary endpoints. 
AEs will be coded using the MedDRA dictionary (Version 20.0 or 
greater.)  The number and percentages of subjects experiencing 
treatment-emergent AEs will be tabulated by System Organ Class and 
preferred term and will be presented by treatment group.  The number of 
events by preferred term will also be summarized. Tabulation by 
maximum severity and relationship to KD025/BSC treatment will also be 
included by treatment group.  Summary subject listing will be provided 
for SAEs, AEs resulting in study discontinuation, and deaths.  All AEs 
(including SAEs) will be graded using a 5-point scale (mild, moderate, 
severe, life threatening, or death; see Appendix B).  
Adverse events, SAEs, related AEs, related SAEs, ≥ Grade 3 AEs, 
related ≥ Grade 3 AEs, and AEs leading to withdrawal and treatment 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
Kadmon Corporation  
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discontinuation will be summarized according to treatment group; SOC; 
and preferred terms.  AEs 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 classified using the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (see Appendix A) and summarized by treatment 
group.  Incidence of laboratory abnormalities will be summarized by 
treatment group. The worst on-study grade during the treatment period 
after the first dose of KD025 will be summarized (or after Week 1, Day 1 
visit for BSC cohort). 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 by treatment 
group at each scheduled time point using descriptive statistics and 
included in data listings.  
Sample Size  
With 54 subjects in the KD025 Treatment Group and 27 in the BSC 
Treatment Group, the study has over 90% power at the 2-sided 
0.05 significance level to detect a 20% difference between treatment 
groups at 24 weeks in percent change from baseline in FVC assuming a 
standard deviation (SD) in percent change from baseline in FVC of 17%. 
The sample size of 54 subjects receiving KD025 will provide over 
90% probability of 1 or more subjects in the study experiencing an AE 
that has an underlying rate of ≥ 5%.  


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
 
 
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Table 1: 
Study Assessments 
Assessments 
Screening 
Period 
Treatment Period 
 
30-Day 
Follow- 
Upl  
(±3 days) 
UNSm 
 
EOPT 
Visit 
Continuation 
Visits: 
 
(Every 4 Weeks) k 
 
 
 
 
 
EOT 
Screening Visit 
Week 1 
Baseline 
End 
of 
Week 
4 
End of 
Week 8 
End of 
Week 12 
End of 
Week 16 
End of 
Week 20 
End of 
Week 24 
Study Day 
-29 to -1 
1j 
28 
(±3 
days) 
56 
(±3 
days) 
84 
(±3 
days) 
112 
(±3 
days) 
140 
(±3 
days) 
168 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
St. George’s 
Respiratory 
Questionnaire 
 
X 
 
 
X 
 
 
X 
Xo 
 
 
 
X 
Medical historya 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationb 
X 
X 
 
 
X 
 
 
X 
Xo 
 X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
chemistryd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, PTT, INR 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGe, q 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
Pulmonary 
function tests 
(including FVC, 
RV, and DLCO)q 
X 
X 
 
 
X 
 
 
X 
Xo 
Xo 
X 
X 
HRCT 
 
X 
 
 
 
 
 
X 
Xp 
Xp 
 
X 
MMP7, CCL18, 
and SPD 
biomarkers 
 
X 
 
 
X 
 
 
X 
Xn 
Xn 
 
X 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
 
 
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Confidential and Proprietary 
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Table 1: 
Study Assessments 
Assessments 
Screening 
Period 
Treatment Period 
 
30-Day 
Follow- 
Upl  
(±3 days) 
UNSm 
 
EOPT 
Visit 
Continuation 
Visits: 
 
(Every 4 Weeks) k 
 
 
 
 
 
EOT 
Screening Visit 
Week 1 
Baseline 
End 
of 
Week 
4 
End of 
Week 8 
End of 
Week 12 
End of 
Week 16 
End of 
Week 20 
End of 
Week 24 
Study Day 
-29 to -1 
1j 
28 
(±3 
days) 
56 
(±3 
days) 
84 
(±3 
days) 
112 
(±3 
days) 
140 
(±3 
days) 
168 
(±3 days) 
6MWDf 
 
X 
 
 
X 
 
 
X 
Xo 
X 
 
X 
Occurrence of 
exacerbation of 
IPF (frequency 
and severity)  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Study diary 
(dispense/collect)
g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administrationh 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Dispense/Collect 
study drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
           X 
Best supportive 
care i 
 
To be determined by Investigator 
 
 
 
X 
Concomitant 
medications and 
procedures 
 
To be collected from the date that the ICF is signed until 30 days after last dose of KD025.  
For BSC subjects, to be collected through the End-of-Week 24 visit. 
Adverse events 
 
6MWD = 6-minute walk distance;BSC = best supportive care; ECG = electrocardiogram; EOPT = End-of-Primary-Treatment; HRCT = High Resolution Computerized 
Tomography; ICF = informed consent form; INR = international normalized ratio; IPF = idiopathic pulmonary fibrosis; PE = physical examination; PT = prothrombin 
time; PTT = partial thromboplastin time; TSH = thyroid stimulating hormone; UNS = unscheduled. 
a. 
Medical history to include exacerbation of IPF (such as presence of dyspnea, chest interstitial lung abnormalities, or SpO2 < 88%) for 6 months prior. 
b. 
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 (eg, physician’s assistant, nurse practitioner).  


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
 
 
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All PEs will include assessment of cardiac (including heart rate, vital sign, and CPK measurements), musculoskeletal (ie, muscle aches), and neurological (ie, gait) 
systems.  
c. 
Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, and temperature) will be collected after a 5 minute of rest.  See Section 8.2 for 
appropriate blood pressure measuring technique. 
d. 
See Section 8.9 for a complete list of laboratory safety assessments.  If increases in liver enzymes are observed at any time in a subject, refer to Section 12.4. 
e. 
Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an interval of at least 1-2 minutes between ECGs]; perform ECG immediately 
before blood sample collection; see Section 8.10 for additional information).  At the Week 1 Day 1 and End-of-Week 4 visits, ECG to be performed predose and 
4 hours post-dose (Tmax) for subjects in Treatment Group 1. 
f. 
The 6MWD, weight, heart rate, blood pressure, and SpO2 will be recorded before and after the walk.  
g. 
Subjects receiving KD025 will be required to keep study drug diaries in which they will record the date and time of study drug administrations.  These diaries will 
be dispensed, reviewed, and/or collected at each visit. 
h. 
Subjects in Treatment Group 1 will receive their first dose of KD025 in the clinic at Week 1 and at the End of Week 4 visits. KD025 will then be dispensed for 
home administration.  Treatment Group 1:  Subjects should take all 2 KD025 tablets within 5 minutes of finishing a meal.   
i. 
Best supportive care (BSC; Treatment Group 2); as deemed appropriate by the Investigator.  Subjects randomized to BSC will be treated the same as subjects on 
KD025 and undergo all tests in similar fashion.     
j. 
If screening assessments are done within 7 days of the baseline visit, only the PE and vital sign measurements need to be redone.  
k. 
Subjects may continue to receive therapy with KD025 as long as there is no safety signal and clinical progress continues. (Subjects receiving BSC have the option 
of switching to therapy with KD025 after Week 24; see Section 12.1.2). All continuing subjects will return to the clinic every 4 weeks thereafter.  
l. 
Subjects dosed with KD025 will return to the clinic 30 days (± 3 days) after their last dose of study drug.  A Follow-up visit is not required for BSC subjects. 
m. These assessments should be performed if a subject discontinues early from the study and are suggested for any UNS. 
n. 
For those subjects continuing, biomarker sample collection to be performed only at Weeks 36 and 48, and EOT.  
o. 
For those subjects continuing, tests to be completed every 12 weeks. If PFTs were performed within 1 month of the EOT visit, PFTs do not need to be performed 
again. 
p. 
For those subjects continuing HRCT to be performed every 24 weeks. If the HRCT is performed within 1 month of the EOT visit, it does not need to be done again 
at the EOT visit.  
q. 
Every effort should be made to utilize the same ECG and PFT machines and technician to collect data. 
 
 
 
 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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Confidential and Proprietary 
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2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS 5 
2. 
TABLE OF CONTENTS ..........................................................................................20 
3. 
LIST OF ABBREVIATIONS ...................................................................................25 
4. 
BACKGROUND AND RATIONALE .....................................................................27 
4.1. 
Study Rationale ................................................................................................27 
4.2. 
Summary of Known and Potential Risks and Benefits to Human Subjects ....29 
4.3. 
Selection of Doses in this Study ......................................................................29 
4.4. 
Previous Clinical Experience with KD025 ......................................................29 
4.5. 
KD025 Nonclinical Toxicology .......................................................................35 
4.6. 
Compliance Statement .....................................................................................36 
5. 
STUDY OBJECTIVES .............................................................................................37 
5.1. 
Primary Objectives ...........................................................................................37 
5.2. 
Secondary Objectives .......................................................................................37 
5.3. 
Exploratory Objective ......................................................................................37 
6. 
STUDY DESIGN......................................................................................................38 
6.1. 
Study Sites .......................................................................................................38 
6.2. 
Study Endpoints ...............................................................................................38 
6.3. 
Overview of Study Design ...............................................................................38 
6.4. 
Randomization and Blinding ...........................................................................39 
7. 
STUDY POPULATION ...........................................................................................40 
7.1. 
Target Population .............................................................................................40 
7.2. 
Inclusion Criteria .............................................................................................40 
7.3. 
Exclusion Criteria ............................................................................................41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ....................................................43 
8.1. 
Overview ..........................................................................................................43 
8.2. 
Procedures to be Performed .............................................................................43 
8.3. 
Screening Period (Day -29 to -1) .....................................................................46 
8.4. 
Enrollment........................................................................................................47 
8.5. 
Treatment Period ..............................................................................................47 
8.5.1 
Week 1, Day 1 Visit (Baseline) ...........................................................47 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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8.5.2 
End of Week 4, Day 28 (±3 days) and End of Week 8, Day 56 
(±3 days) Visits ....................................................................................48 
8.5.3 
End of Week 12, Day 84 (± 3 days) Visit ............................................49 
8.5.4 
End of Week 16, Day 112 (± 3 days) and End of Week 20, Day 140 
(± 3 days) Visits ...................................................................................49 
8.5.5 
End-of-Primary-Treatment Visit (End of Week 24, Day 168 
[± 3 days]) ............................................................................................50 
8.6. 
Monthly Follow-Up Treatment Period for Those Subjects Continuing Study 
Drug .................................................................................................................51 
8.6.1 
Continuation Visits (Every 4 Weeks [± 3 days]) .................................51 
8.6.2 
End of Treatment Visit [± 3 days]) ......................................................52 
8.7. 
30-Day Follow-Up Visit ..................................................................................53 
8.8. 
Unscheduled Visits ..........................................................................................53 
8.9. 
Laboratory Assessments ..................................................................................54 
8.10.  Electrocardiogram Assessments ......................................................................56 
8.11.  Pulmonary Function Tests (including FVC, RV, and DLCO).........................56 
8.12.  6-Minute Walking Distance .............................................................................56 
8.13.  High Resolution Computed Tomography ........................................................57 
8.14.  Occurrence of Acute Exacerbation ..................................................................57 
8.15.  Time to Progression of IPF ..............................................................................58 
9. 
PHARMACOKINETICS ..........................................................................................59 
10.  PHARMACODYNAMICS ......................................................................................60 
11.  REMOVING SUBJECTS FROM STUDY ..............................................................61 
11.1.  Subjects’ Decision to Withdraw ......................................................................61 
11.1.1 
Treatment Discontinuation ...................................................................61 
11.1.2 
Study Termination ...............................................................................62 
11.2.  Stopping Rules .................................................................................................62 
11.2.1 
Adverse Events Stopping Criteria ........................................................62 
11.2.2 
Blood Pressure Stopping Criteria.........................................................63 
11.3.  Study Discontinuation ......................................................................................63 
11.4.  Replacements ...................................................................................................64 
12.  STUDY DRUG .........................................................................................................65 
12.1.  Dose and Schedule of Study Drug and Comparator ........................................65 
12.1.1 
Primary 24-Week Treatment Period ....................................................65 
12.1.2 
Switching from BSC to KD025 ...........................................................65 
12.1.3 
Continuation of KD025 Dosing ...........................................................66 
12.2.  Missed Doses ...................................................................................................66 


KD025 
IND Number 128024 
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Amendment No. 9 
 
 
 
 
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12.3.  Dose Reduction for KD025 .............................................................................66 
12.4.  Evaluation of Liver-Related Blood Tests ........................................................67 
12.5.  Identity of Investigational Products .................................................................68 
12.6.  Study Drug Packaging and Labeling ...............................................................68 
12.7.  Dispensing of Study Drug and Dosing Compliance ........................................69 
12.8.  Study Drug Storage ..........................................................................................69 
12.9.  Study Drug Accountability ..............................................................................69 
12.10.  Study Drug Handling and Disposal .................................................................70 
12.10.1  Disposition of Used Supplies ...............................................................70 
12.10.2  Inventory of Unused Supplies ..............................................................70 
13.  CONCOMITANT MEDICATION AND PROCEDURES ......................................71 
13.1.  Prohibited Medications for Subjects Receiving KD025 ..................................71 
13.2.  Other Safety Considerations ............................................................................77 
13.2.1 
Laboratory Data ...................................................................................77 
13.2.2 
Medication Errors ................................................................................78 
13.2.3 
Follow-Up of Adverse Events .............................................................78 
14.  STATISTICAL CONSIDERATIONS......................................................................79 
14.1.  General Design.................................................................................................79 
14.2.  Sample Size Justification .................................................................................79 
14.3.  Statistical Considerations .................................................................................80 
14.3.1 
Study Populations ................................................................................80 
14.3.2 
Subject Accountability, Demographics, and Baseline Characteristics 80 
14.3.3 
KD025 Exposure ..................................................................................80 
14.3.4 
Concomitant Medications and Procedures ...........................................80 
14.4.  Activity/Efficacy Analysis ...............................................................................81 
14.5.  Safety Data .......................................................................................................81 
15.  DATA QUALITY ASSURANCE ............................................................................83 
16.  ETHICAL ASPECTS ...............................................................................................84 
16.1.  Local Regulations ............................................................................................84 
16.2.  Informed Consent.............................................................................................84 
16.3.  Institutional Review Board ..............................................................................84 
16.4.  Future Use of Subject Samples ........................................................................85 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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17.  CONDITIONS FOR MODIFYING THE PROTOCOL...........................................86 
18.  CONDITIONS FOR TERMINATING THE STUDY .............................................87 
19.  STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .......................88 
19.1.  Investigator’s Files and Retention of Documents ............................................88 
19.2.  Source Documents and Background Data .......................................................88 
19.3.  Audits and Inspections .....................................................................................89 
19.4.  Electronic Case Report Forms .........................................................................89 
20.  MONITORING THE STUDY ..................................................................................90 
21.  CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...91 
22.  PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............92 
23.  REFERENCES .........................................................................................................93 
24.  APPENDICES ..........................................................................................................95 
APPENDIX A: 
TABLES FOR GRADING LABORATORY ABNORMALITIES ....96 
APPENDIX B: 
CLINICAL SYMPTOM AND ADVERSE EVENT GRADING 
SCALE 
99 
APPENDIX C: 
CLINICAL ADVERSE EVENTS: DETERMINING RELATIONSHIP 
TO STUDY DRUG ................................................................................................100 
APPENDIX D: 
CORRECTION FOR HEART RATE (FRIDERICIA)* ...................102 
APPENDIX E: 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) 
ENGLISH FOR THE U.S.A.22 ...............................................................................103 
APPENDIX F: DRUGS THAT INDUCE AND INHIBIT CYP3A4 ..............................109 
APPENDIX G: DRUGS THAT INDUCE AND INHIBIT CYP1A2 .............................110 
APPENDIX H: DRUGS THAT PROLONG QTC ..........................................................111 
 
 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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LIST OF TABLES 
Table 1: 
Study Assessments .................................................................................... 17 
Table 2: 
Clinical Laboratory Panels ........................................................................ 55 
Table 3: 
Clinical Optimal HRCT Technique for Evaluation of Interstitial Lung 
Disease17 ................................................................................................... 57 
Table 4: 
Dose Reductions for Toxicity Related to Study Drug .............................. 66 
Table 5  Guidelines for Management of Treatment-emergent Toxicities ......................... 67 
Table 6: 
Grading of Liver-Related Laboratory Abnormalities18,19,20 ...................... 68 
Table 7: 
Examples of Clinical Inducers / Inhibitors of CYP3A4 ......................... 109 
Table 8: 
Examples of Clinical Inducers / Inhibitors of CYP1A2 ......................... 110 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Mean (±SD) Concentration-Time Profiles for KD025 following QD or 
BID Oral Dosing of KD025 for 7 Days (KD025-102) ............................. 32 
Figure 2: 
Arithmetic Mean (±SD) Concentration-Time Profiles for KD025, 
KD025m1, and KD025m2 following BID Oral Dosing of KD025 (500 
mg) for 28 Days (KD025-103) ................................................................. 33 
 
 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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3. 
LIST OF ABBREVIATIONS 
6MWD 
6-minute walk distance 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BAL 
bronchoalveolar lavage 
BID 
twice daily 
BSC 
best supportive care 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CCL18 
chemokine ligand 18 
Cmax 
maximum concentration observed  
CPK 
creatinine phosphokinase 
DLCO 
diffusing capacity of carbon monoxide 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOPT 
End-of-Primary-Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HRCT 
high-resolution computed tomography 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IP 
intraperitoneal 
IPF 
idiopathic pulmonary fibrosis 
IRB 
institutional review board 
ITT 
intent-to-treat 
KD025m1 
KD025 Metabolite 1 
KD025m2 
KD025 Metabolite 2 
LFT 
liver function tests 
MAD 
multiple ascending dose 
MCV 
mean corpuscular volume 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MMP7 
matrix metalloproteinase-7 
mITT 
modified Intent-to-Treat 
MMP 
matrix metalloproteinase 
PE 
physical examination 
PK 
pharmacokinetic 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QTc(F) 
corrected QT interval using Fridericia’s formula 
ROCK 
Rho-associated protein kinase 
RPE 
Rating of Perceived Exertion 
RV 
residual volume 
SAD 
single ascending dose 
SAE 
serious adverse event 
SGRQ 
St George’s Respiratory Questionnaire 
SOC 
System Organ Class 
SPD 
surfactant protein-D 
SpO2 
pulse oximeter oxygen saturation  
SUSAR 
suspected unexpected serious adverse event 
t1/2 
half-life 
Tmax 
observed time to reach peak plasma concentration 
TSH 
thyroid stimulating hormone 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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4. 
BACKGROUND AND RATIONALE 
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and often fatal lung disease 
of unknown cause. With a prevalence of 2 to 29 per 100,000 and an incidence of approximately 
10 per 100,000/year, IPF meets the criteria for classification as an orphan disease.1  It affects older 
adults with peak prevalence around 65 years-of-age.1   
The natural history for patients with IPF varies. While most patients progress slowly and gradually 
over many years, others have an accelerated decline often associated with episodes of acute 
respiratory worsening.2,3,4,5  The median survival time is 2 to 4 years from diagnosis and the 5-year 
survival rate ranges between 30% and 50%.1,4,6,7  Its mortality rate is higher than that of most cancers.  
The commonly accepted method of determining disease progression is to identify a decline in forced 
vital capacity (FVC).  Functionally stable patients show a FVC decline of a maximum of 5% of the 
baseline value over 6 to 12 months.1,7,8  A decline in FVC of 5% to 10% in any subject indicates 
prognostically relevant progression, while a decline of ≥ 10% in 6 months is associated with a 4-to 
8-fold increase in the risk of death in the subsequent 12 months.8,9,10  Regular lung function checks to 
measure FVC and diffusing capacity are recommended at intervals of at least 3 to 6 months.1,3 
Acute exacerbations are an important aspect of clinical progression. These are defined by a subacute 
or acute increase in shortness of breath over a period of 30 days and a high-resolution computed 
tomography ([HRCT] slice thickness ≤ 2.0 mm, no contrast media) showing new infiltration of the 
lungs with no identifiable cause. Acute exacerbation frequency is 5% to 15% per year and acute 
exacerbations are associated with high mortality. After an acute exacerbation of IPF, approximately 
50% of patients die within 3 months, and approximately 80% to 90% within 12 months.1,3,4,6,7 
There is no cure for IPF and treatment options are limited. Historically, available pharmacological 
therapies have had limited efficacy/activity and potential serious side effects.  However, recently both 
nintedanib and pirfenidone have been shown to slow decline in FVC in separate Phase 3 clinical 
trials9,10 and both received Food and Drug Administration (FDA) approval in October 2014.  
4.1. 
Study Rationale 
This study is being conducted to evaluate the safety, tolerability, and activity of 400 mg of KD025 
orally administered once-daily (QD) compared to best supportive care (BSC) in subjects with IPF. 
Rho-associated 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.11,12  
Two isoforms of ROCK have been identified, ROCK1 and ROCK2. Early work with nonspecific 


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ROCK inhibitors (eg, fasudil) suggested that both ROCK1 and ROCK2 are involved in 
Rho-mediated changes in the actin/myosin cytoskeletal network.  However, more recent research has 
uncovered additional relevant roles for ROCK signaling, particularly ROCK2, in conditions 
including IPF.  Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of 
chronic fibrosis. The ROCK pathway, which is necessary for contraction and force generation in 
fibroblasts and for downstream actin polymerization, may therefore be a molecular driver for in the 
formation and progression of pulmonary fibrosis. 
The possibility that pulmonary fibrosis could be directly treated by inhibitors of ROCK has been 
investigated in mouse models. In a bleomycin-induced model of lung fibrosis, intratracheal (IT) 
administration of bleomycin in mice induces changes similar to those of diffuse pulmonary fibrosis 
or fibrosing alveolitis in humans, making this a good model of pulmonary fibrosis for testing of new 
IPF therapies. In particular, bleomycin causes increased deposition and net synthesis of collagen in 
the lungs. A study conducted in bleomycin-treated mice, showed that fasudil reduced pulmonary 
fibrosis even when administered 14 days after IT bleomycin when fibrosis was presumably already 
present.13  Treatment with fasudil, an inhibitor of ROCK1 and ROCK2, significantly reduced the 
levels of alpha-smooth muscle actin and collagen content of the lungs.  This study in 
bleomycin-treated mice also demonstrated that ROCK inhibitors may be effective for treating 
pulmonary fibrosis through more than 1 mechanism. Fasudil blocked actin cytoskeletal 
reorganization, fibroblast acquisition of contractile activity, and megakaryoblastic leukemia 
(translocation) 1 MKL1 nuclear translocation, preventing the differentiation of fibroblasts into 
matrix/collagen depositing myofibroblasts in vitro.  
Kadmon Corporation has internally evaluated the efficacy/activity of 13 days of therapy with KD025 
in a bleomycin-induced pulmonary fibrosis model in mice. C57Bl/6 mice were treated with KD025 
or vehicle (0.4% carboxymethyl cellulose) beginning 8 days after IT treatment with 2.25 U/kg of 
bleomycin.  At the initiation of treatment, pulmonary fibrosis was already established. Unlike vehicle 
control therapy, oral QD treatment with 100 mg/kg and 150 mg/kg of KD025 significantly reduced 
pulmonary fibrosis and inflammation.  
Matrix metalloproteinase (MMPs) have been found to be increased in the lung and bronchoalveolar 
lavage (BAL) fluid of patients with IPF.  A matrix metalloproteinase-7 (MMP7) previously 
implicated in the pathogenesis of IPF,14,15 is significantly increased in plasma, serum, BAL fluid, and 
lung tissue of IPF patients, suggesting that MMP7 may be a biomarker for IPF disease progression or 
mortality.  The MMP7 levels will therefore be studied in this clinical trial, in addition to other 


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potential future biomarkers for patient selection and pharmacodynamic response; chemokine 
ligand 18 (CCL18) and surfactant protein-D (SPD).16  
4.2. 
Summary of Known and Potential Risks and Benefits to Human 
Subjects 
All the possible side effects related to KD025 are not known.  The KD025 Investigator’s Brochure 
(IB) contains data on risks associated with KD025.  Other risks to subjects involve side effects from 
study procedures.  There are also other risks associated with taking part in this study, such as the 
risks associated with a loss of privacy or confidentiality because of improper disclosure.   
There may be no direct benefit to subjects enrolled into this study.  Subjects may receive a clinical 
benefit from KD025, and some subjects may progress.  The information from this study may help 
other subjects with IPF and more may be learned about the study drug as a possible new treatment for 
IPF.   
4.3. 
Selection of Doses in this Study  
This study will evaluate KD025 at a dose of 400 mg QD.  Preliminary data from an ongoing study of 
KD025 in patients with moderate to severe psoriasis suggests that the dose of 400 mg QD for 
12 weeks is associated with clinical efficacy/activity and is well-tolerated.  This study will examine 
the safety and clinical efficacy/activity of the 400 mg QD dose compared to BSC in patients with 
IPF.    
The administration of KD025 400 mg QD to subjects with IPF who have disease progression after 
receiving both nintedanib and pirfenidone is supported by the data from a previous KD025 trial in 
subjects with psoriasis as well as by the clinical situation of subjects to be enrolled into this study.  
The safety data from KD025 psoriasis study indicate that the dose of 400 mg daily for 12 weeks was 
tolerable with an acceptable safety.  Finally, subjects with IPF who have disease progression after 
receiving both nintedanib and pirfenidone have a poor clinical prognosis, as poor as some types of 
aggressive cancer.  Thus the risk to benefit ratio in these subjects favors the use of the 400 mg QD 
dose level which has demonstrated tolerability and clinical activity in previous clinical studies. 
The IB includes additional nonclinical and clinical information about KD025.  
4.4. 
Previous Clinical Experience with KD025 
To date, there have been 5 Phase 1 trials conducted with KD025 in normal healthy subjects: a 
single-ascending dose (SAD) trial (Study 2119-09-01), a combined single- and multiple-ascending 
dose (SAD/MAD) trial (Study KD025-101), a MAD trial with QD and BID dosing 


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(Study KD025-102), a placebo-controlled safety and pharmacokinetic (PK) study 
(Study KD025-103), and a food effect study (Study KD025-105).  A Phase 2a, open-label study in 
8 adult subjects with moderately severe psoriasis vulgaris who have failed first-line therapy was 
recently completed (Study KD025-205).  Additionally, a Phase 2 open-label, safety, and tolerability 
study in subjects with psoriasis vulgaris who have disease progression after 1 systemic therapy is 
currently on-going (Study KD025-206).  
The SAD trial (Study SLx-2119-09-01) assessed the safety, tolerability, and PK of KD025.  The dose 
levels of KD025 that were tested included 20, 40, 80, and 160 mg.  Thirty-two subjects were 
randomized in 4 cohorts of 8 subjects with 6 receiving drug and 2 receiving placebo.  No treatment-
emergent adverse events (TEAEs) leading to withdrawal, deaths, or serious adverse events (SAEs) 
were reported in this trial.  There were 14 TEAEs reported, 9 of which were determined by the 
Investigator to be related to study drug and were mild in severity.  One subject at the 160-mg KD025 
dose level experienced joint swelling and arthralgia occurring after the follow-up visit.  No subject 
had laboratory abnormalities during the dosing period or within 1 week after dosing.  There were no 
changes in blood pressure or heart rate and no clinically significant QTcB or corrected QT interval 
using Fridericia’s formula (QTc[F]) parameters.  
KD025 was readily absorbed and was measured out to 24 hours in plasma.  KD025 was the main 
analyte (> 90% parent derived area under the curve [AUC]) and KD025m2 was present at about 5%, 
with KD025m1 < 1%.  The half-life (t1/2) of KD025 was approximately 5–6 hours, supporting 
once- or twice-daily dosing. 
A combined SAD/MAD (Study KD025-101) trial assessed the safety, tolerability, and PK of KD025 
in healthy males with single doses followed by 1 week of rest and then 7 consecutive days of dosing.  
There were 8 cohorts with 8 subjects in each cohort.  For each dosing cohort, 6 subjects received 
KD025 and 2 subjects received placebo.  The dose levels studied were 40, 80, 120, 160, 240, 320, 
400, and 500 mg.  Few TEAEs were reported and of those reported, the majority were determined by 
the Investigator to be mild in severity.  There were no SAEs reported during the study.  One subject 
(Subject No. 50008) was withdrawn because of a TEAE that was considered not related to KD025 
(elevated blood creatinine phosphokinase [CPK] levels of moderate intensity). 
No clinically relevant clinical chemistry (apart from elevated CPK discussed above), hematology, 
coagulation, or urinalysis abnormalities were reported for any of the subjects.  No clinically 
significant abnormalities were reported for any vital signs (systolic or diastolic blood pressure, or 


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heart rate) or 12-lead electrocardiogram (ECG) parameters and no subject had an abnormal physical 
examination (PE) finding of concern. 
A MAD trial (Study KD025-102) was a single-center, placebo-controlled, double-blind, randomized 
(6:2) study to assess the safety, tolerability, and PK of KD025 administered for 7 days in up to 
32 healthy male and postmenopausal female subjects.  This study enrolled 4 cohorts with 8 subjects 
in each cohort (6 subjects received KD025 and 2 subjects received placebo).  The dose regimens 
studied were 500, 800, and 1000 mg administered QD, and 500 mg administered BID.  All 
32 subjects received at least 1 dose of study drug, and 31 subjects completed the study; all 
24 subjects completed all doses of study drug at 500 and 800 mg QD, and 500 mg BID.  Seven of 
8 subjects completed all doses of study drug at 1000 mg QD.  One subject randomized to active study 
drug 1000 mg QD received 6 days of study drug before being discontinued because of a positive 
urine drug test.  
Multiple escalating doses of KD025 ranging from 500 mg to 800 mg to 1000 mg QD and 500 mg 
BID for 7 days were generally well tolerated and no dose-limiting toxicities were reported in this 
study.  Five TEAEs were reported in 4 subjects (16.7%) receiving KD025, including upper 
abdominal pain and diarrhea in 1 subject receiving 500 mg QD, nausea in 2 subjects receiving 
500 mg BID, and diarrhea in 1 subject receiving 1000 mg QD.  There was 1 treatment-related AE of 
diarrhea in 1 subject (12.5%) receiving placebo.  There were no TEAEs in subjects receiving KD025 
800 mg QD.  No subjects discontinued study participation because of AEs.  There were no clinically 
relevant changes and no clinically meaningful trends in hematology, chemistry, and urinalysis 
laboratory results attributable to study drug during this study.  There were no SAEs or deaths. 
The following are PK conclusions from this study: 
 KD025 was rapidly absorbed after QD oral dose administration with median observed time to 
reach peak plasma concentration (Tmax) values ranging from 1.0 to 4.0 hours post-dose. 
 Median Tmax values after BID dosing were more variable and ranged from 4.0 hours after the 
first dose to 12.0 hours after the second dose. 
 Mean half-life (t1/2) values were similar across dose levels for each day, with values ranging 
from 4.55 to 5.76 hours for Day 1 and from 7.68 to 9.73 hours for Day 7. 
 Mean KD025 maximum concentration observed (Cmax) and AUC0-24hr values generally 
increased in a less than dose proportional manner with the increase in QD dose level from 
500 to 1000 mg. 


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 Overall exposure (AUC0-24hr) following BID dose administration of 500 mg of KD025 was 
1.9- to 2-fold higher than the AUC0-24hr after QD dose administration of 1000 mg KD025 and 
2- to 2.3-fold higher than the AUC0-24hr following QD dose administration of 500 mg KD025. 
 Possible accumulation of KD025 was observed after multiple doses. 
Figure 1: 
Mean (±SD) Concentration-Time Profiles for KD025 following QD or BID Oral 
Dosing of KD025 for 7 Days (Study KD025-102) 
 
BID = twice daily; QD = once daily 
Study KD025-103 was a Phase 1, placebo-controlled study examining the safety, tolerability, and PK 
of 500 mg of KD025 administered BID for 28 days in healthy male and postmenopausal female 
subjects.  KD025 500 mg, administered BID for up to 28 days was generally well-tolerated.  A total 
of 6 AEs were reported in 4 of the 6 subjects receiving KD025; there were no AEs reported in the 
2 subjects receiving placebo.  The most common TEAEs were hepatic enzyme elevation reported in 
3 of 6 (50%) subjects receiving KD025 (of which 2 were determined to be possibly related to 
KD025).  The AEs of increased liver enzymes were Grades 1 or 2 in severity (1 was because of 
alcohol ingestion), and all resolved within 15 days of discontinuation with KD025.  Other AEs 
reported in subjects receiving KD025 included nasopharyngitis in 1 subject and upper abdominal 
pain (stomach cramping) in 1 subject.  All AEs, except nasopharyngitis, were considered at least 
possibly related to study drug.  All AEs were mild in intensity, except for the alanine 
aminotransferase (ALT) elevation in 1 subject, which was Grade 2 in intensity.  This subject was 
Linear Scale
Time After Dosing (hours)
0
4
8
12
16
20
24
Concentration (ng/mL)
0
1000
2000
3000
4000
5000
6000
7000
8000
Cohort 1, 500 mg KD025QD
Cohort 2, 800 mg KD025 QD
Cohort 3, 500 mg KD025 BID
Cohort 4, 1000 mg KD025 QD
0
4
8
12
16
20
24
28
32
36
40
44
48
Day 1
Day 7
On both scales:


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discontinued from the study due to the ALT elevation.  There were no SAEs or deaths reported in this 
study.  
The following are PK conclusions from this study: 
 KD025 was rapidly absorbed after oral dose administration with median Tmax values of 
3.0 and 2.0 hours post-dose on Days 1 and 28, respectively. 
 Possible accumulation of KD025 was observed after multiple doses.  
 Two metabolites (KD025m1 [KD025 Metabolite 1] and KD025m2 [KD025 Metabolite 2]) 
rapidly appeared in plasma and were readily eliminated.  No accumulation of KD025m1 was 
observed after multiple doses, while potential accumulation of KD025m2 was observed after 
multiple dosing.  KD025 was metabolized to KD025m2 more extensively than to KD025m1.  
Figure 2: 
Arithmetic Mean (±SD) Concentration-Time Profiles for KD025, KD025m1, and 
KD025m2 following BID Oral Dosing of KD025 (500 mg) for 28 Days 
(Study KD025-103) 
 
BID = twice daily; SD = standard deviation 
The food effect study (Study KD025-105) was a single-dose, 2-period, crossover study to examine 
the safety and PK of KD025 in 12 healthy male subjects in the fed and fasted states.  The dose level 
was 500 mg.  There were no TEAEs, no treatment-related AEs, no SAEs or deaths reported in this 
study. 
The following are PK conclusions from this study:  
Linear Scale
Time After Dosing (hours)
0
4
8
12
Concentration (ng/mL)
0
500
1000
1500
2000
2500
3000
KD025
KD025m1
KD025m2
0
4
8
12
16
20
24
28
32
Day 1
Day 28
On both scales:


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 A high fat meal given 30 minutes prior to KD025 oral administration had a significant effect 
on the PK of KD025.  
 Plasma systemic exposure (Cmax and AUCs) of KD025 was approximately 3–fold higher 
under the fed state compared with the fasted state, and the median Tmax value was delayed by 
2 hours with food. 
 Similar food effects were observed for metabolites KD025m1 and KD025m2 as for the parent 
drug.  
 The high fat meal increased systemic exposure (mean Cmax and AUC0-t values) by 
approximately 1.7- to 2.3-fold for metabolite KD025m1 and approximately 3.1- to 4.4-fold 
for metabolite KD025m2 compared with the fasted treatment. 
Recently completed, Study KD025-205 was a Phase 2a, open-label study in 8 adult subjects with 
moderately severe psoriasis vulgaris who had failed first-line therapy.  The study evaluated the safety 
and tolerability of 200 mg KD025 daily for 28 days.  Efficacy and activity measures included the 
evaluation of any decreases in Psoriasis Area and Severity Index in at least 50% of the subjects after 
4 weeks of dosing with 200 mg of KD025 and improvement in the Physicians Global Assessment for 
psoriasis.  Cytokine levels and expression associated with psoriasis were evaluated in 
pharmacodynamic whole blood samples and punch biopsies of selected lesions, respectively, 
collected at baseline and at the end of treatment.  Eight subjects began treatment with KD025.  Five 
SAEs were reported in this study and all 5 occurred in the same subject:  Subject 001-008 
experienced Grade 2 vomiting (2 events), Grade 2 nausea (2 events), Grade 3 anastomotic ulcer 
(related to the subject’s previous gastric bypass surgery), and Grade 3 kidney stones, none of which 
were assessed to be related to study drug (she was subsequently discontinued after 20 days of 
dosing).  Another subject experienced reversible Grade 1 elevated ALT and aspartate 
aminotransferase (AST) on Day 22 with no known etiology and permanently discontinued treatment 
with KD025.  The ALT/AST returned to normal levels 13 days after the last dose of KD025.  No 
other TEAEs or SAEs were reported. 
Follow-up for efficacy and activity measures in this study has completed.  The following PK 
conclusions can be made for this study: 
 KD025 was rapidly absorbed after oral dose administration with median Tmax values of 2.0 
hours and 4.0 hours post-dose on Days 1 and 28, respectively. 
 Mean t1/2 for KD025 was 6.08 hours and 5.27 hours on Days 1 and 28, respectively. 


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 Two metabolites (KD025m1 and KD025m2) rapidly appeared in plasma and were readily 
eliminated.  No accumulation of either metabolite was apparent after multiple doses.  
Exposure of daily dosing of KD025 at 200 mg for 28 days was comparable to or slightly lower than 
that observed in study KD025-101, for daily dosing at similar dose levels. 
Study KD025-206 is an ongoing Phase 2, open-label, safety and tolerability study of KD025 in 
subjects with psoriasis vulgaris who have disease progression after at least 1 systemic therapy.  The 
primary objective is to evaluate the safety and tolerability of 3 daily dosing regimens (200 mg BID, 
400 mg QD, and 400 mg BID) of KD025 in subjects with psoriasis vulgaris who have progressed 
despite first-line therapy.  To date, preliminary safety data are available on 10 subjects who received 
KD025 at a dose of 200 mg BID, and 10 subjects who received KD025 at a dose of 400 mg QD.  All 
subjects had normal ALT and AST values during screening.  Four subjects (3 subjects receiving 
200 mg BID and 1 subject receiving 400 mg QD) had TEAEs of elevation of ALT or AST.  Bilirubin 
levels remained normal, and all ALT or AST increases were asymptomatic and reversible.  The ALT 
and AST elevations first occurred from study Day 16 to study Day 36.  The ALT/AST elevations 
were mild or moderate in intensity, except in 1 subject who had severe (Grade 3) ALT elevation to a 
maximum of 377 U/L.  KD025 administration was discontinued in 3 subjects, and ALT and AST 
levels decreased.  One subject, who was receiving KD025 400 mg QD, had peak ALT of 121 U/L 
and AST of 127 U/L which then returned to the normal range despite continuing to receive KD025 
400 mg QD.  The data from these subjects suggest that increases in ALT and AST are modest and 
may be reversible despite the continuation of KD025.  
4.5. 
KD025 Nonclinical Toxicology  
To date, Good Laboratory Practice compliant 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 rats and dogs.  In addition, safety pharmacology studies have been completed 
evaluating central nervous system (rat), respiratory (rat), and cardiovascular (dog) function.  
Furthermore, KD025 is not considered genotoxic or mutagenic based on a panel of studies.  Fertility 
(rat [segment 1] and Reproductive toxicology studies (rat and rabbit embryo-fetal [segment 2]) are 
completed. 
Study details and potential clinically-relevant findings from these studies are summarized in the IB.   


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4.6. 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP) E6 (R2), 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 Institutional Review 
Boards/Independent Ethics Committees (IRBs/IECs) must approve the protocol and any 
amendments, and the subject informed consent form (ICF) 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 (eg, loss 
of medical licensure, debarment). 
 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objectives 
The primary objectives of the study are as follows: 
 To evaluate the change in FVC from baseline to 24 weeks after dosing with KD025 400 mg 
QD in subjects with IPF compared with BSC  
 To evaluate the safety and tolerability of KD025 400 mg QD when administered for 24 weeks 
to subjects with IPF compared with BSC 
5.2. 
Secondary Objectives 
The following are the secondary objectives of the study: 
 To evaluate the change in 6-minute walk distance (6MWD) from baseline to 24 weeks  
 To evaluate the occurrence of acute exacerbation of IPF (frequency and severity) throughout 
treatment  
 To evaluate change in severity of lung fibrosis as measured by quantitative HRCT 
 To evaluate the percentage of subjects with disease progression before or at 24 weeks 
5.3. 
Exploratory Objective 
The following is the exploratory objective of the study: 
 To evaluate the change in MMP7, CCL18, and SPD serum levels 
 
 


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6. 
STUDY DESIGN 
6.1. 
Study Sites 
This study will be conducted at approximately 10-15 sites in the United States. 
6.2. 
Study Endpoints 
For Study Endpoints, refer to Section 5.  Further details on the statistical and analytical plan for these 
endpoints are available in Section 14, Statistical Considerations. 
6.3. 
Overview of Study Design 
Approximately 81 eligible subjects will be enrolled and randomized to treatment with KD025 
400 mg QD for 24 weeks (Treatment Group 1) or BSC for 24 weeks (Treatment Group 2) in a 2:1 
ratio (KD025 to BSC). 
Subjects in Treatment Group 1 who complete 24 weeks of treatment with KD025 400 mg QD will 
have the option of continuing therapy with KD025 400 mg QD up to an additional 72 weeks if there 
are no safety signals and if clinical progress continues.  No subject in Treatment Group 1 will be 
permitted to receive therapy with KD025 greater than a total of 96 weeks. 
Subjects in Treatment Group 2 who complete 24 weeks of BSC will have the option of crossing over 
to therapy with KD025 400 mg QD for up to 96 weeks if there are no safety signals and if clinical 
progress continues.  No subject in Treatment Group 2 will be permitted to receive KD025 400 mg 
QD therapy greater than 96 weeks. 
All subjects will receive the same assessments. 
Subjects will undergo medical history evaluations, physical examinations (PEs); vital sign 
measurements; collection of weight; adverse event (AE) assessments; concomitant medication and 
procedures assessments; blood sample collection for hematology (including coagulation), chemistry, 
and thyroid function (TSH); urinalysis; HRCT; and ECG as outlined in the Study Events (Table 1). 
Additionally, FVC, residual volume (RV), diffusing capacity of the lungs for carbon monoxide 
(DLCO), and MMP7, CCL18, and SPD serum levels will be measured as outlined in the Study Events 
(Table 1).  For the 6MWD, weight, heart rate, blood pressure, and pulse oximeter oxygen saturation 
(SPO2) will be recorded before and after the walk. 
The occurrence of acute exacerbation (frequency and severity) of IPF will be assessed throughout the 
study.  


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Note:  If increases in liver enzymes are observed at any time, refer to Section 12.4 for risk 
management of liver function tests (LFTs) changes observed during the study. 
Follow-up visits will occur 30 days (± 3 days) after the last dose of KD025 (Follow-up visit not 
required for BSC subjects).  Subjects will undergo complete PEs, vital signs measurements, 
collection of weight, AE assessments, concomitant medication and procedures assessments, blood 
sample collection for hematology (including coagulation), and chemistry, thyroid function (TSH), 
PFTs, and urinalysis. If another therapy is started within 30 days after the last dose of study drug, the 
Follow-up visit will be conducted before the start of the other therapy. 
6.4. 
Randomization and Blinding 
This is an open-label study.  Subjects who are eligible will be enrolled and randomized into 
Treatment Group 1 or Treatment Group 2 in a 2:1 ratio (KD025 to BSC) and receive KD025 400 mg 
QD orally or BSC for at least 24 weeks.  Study treatment is not blinded. Approximately 81 subjects 
will be randomized in a 2:1 ratio. 
 


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7. 
STUDY POPULATION 
7.1. 
Target Population 
Approximately 81 adult subjects with IPF will be enrolled and randomized into Treatment Group 1 or 
Treatment Group 2 in a 2:1 ratio (KD025 to BSC). Subjects will be eligible for enrollment as defined 
by the following inclusion and exclusion criteria.  
7.2. 
Inclusion Criteria 
The inclusion criteria are detailed below: 
1. Adult male and postmenopausal/surgically sterilized female subjects at least 18 years of age (if 
female, is surgically sterilized [ie, total hysterectomy, or bilateral salpingo-oophorectomy]) 
2. Able to provide written informed consent before the performance of any study specific 
procedures 
3. IPF diagnosis within 5 years before study entry, proven according to the American Thoracic 
Society/European Respiratory Society consensus conference criteria, with surgical lung biopsy.  
In the absence of a surgical lung biopsy, HRCT must be consistent with usual interstitial 
pneumonitis.   
4. Resting state SpO2 ≥ 88% with or without supplemental oxygen, FVC % ≥ 50% normal 
predicted value, and DLCO ≥ 30% normal predicted value at baseline 
5. Men with partners of childbearing potential must be willing to use 2 medically acceptable 
methods of contraception during the trial and for 1 month after the last dose of study drug. 
Effective birth control includes (a) intrauterine device (IUD) plus 1 barrier method; (b) stable 
doses of hormonal contraception for at least 3 months (eg, oral, injectable, implant, 
transdermal) plus 1 barrier method; (c) 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 (d) vasectomy.    
6. Have adequate bone marrow function: 
a. Absolute neutrophil count > 1500/mm3 
b. Hemoglobin > 9.0 g/L 
c. Platelets > 100,000/mm3  
7. Willing to complete all study measurements and assessments in compliance with the protocol 


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8.  Has either received pirfenidone and/or nintedanib or has been offered both treatments (with last 
dose administered at least 1 month before the expected start of study drug dosing). If either or 
both pirfenidone and nintedanib treatment has not been given, then documentation that the 
patient was offered both treatments must be documented. 
7.3. 
Exclusion Criteria 
The exclusion criteria are detailed below: 
1. Interstitial lung disease caused by conditions other than IPF 
2. Severe concomitant illness limiting life expectancy (< 1 year) 
3. Diffusing capacity of the lung for carbon monoxide (DLCO) < 30% predicted 
4. RV ≥ 120% predicted 
5. Obstructive lung disease:  FEV1/ FVC ratio < 0.70 
6. Documented sustained improvement of the subject’s IPF condition up to 12 months before 
study entry with or without IPF-specific therapy 
7. Pulmonary or upper respiratory tract infection within 4 weeks before study entry 
8. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study 
requirements (eg, PFTs) 
9. Chronic heart failure with New York Heart Association Class III/IV or known left ventricular 
ejection fraction < 25% 
10. Moderate to severe hepatic impairment (ie, Child-Pugh Class B or C) 
11. Estimated creatinine clearance < 30 mL/min 
12. AST and/or ALT > 2.0 × upper limit of normal (ULN) 
13. Hemoglobin < 75% of the lower limit of normal 
14. Systolic blood pressure < 100 mmHg 
15. Female subject who is pregnant or breastfeeding 
16. Men whose partner or female subject who is pregnant or breastfeeding  
17. Current drug or alcohol dependence 
18. Chronic treatment with the following drugs (within 4 weeks of study entry and during the 
study): 


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a. Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine 
b. Antifibrotic drugs including pirfenidone, nintedanib, D penicillamine, colchicine, tumor 
necrosis factor α blockers, imatinib and interferon-γ 
c. Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day) 
d. Oral anticoagulants prescribed for IPF 
19. Treatment with endothelin receptor antagonists within 4 weeks before study entry 
20. Systemic treatment within 4 weeks before study entry with cyclosporine A or tacrolimus, 
everolimus, or sirolimus (calcineurin or mammalian target of rapamycin inhibitors) 
21. Previous exposure to KD025 or known allergy/sensitivity to KD025 or any other ROCK2 
inhibitor 
22. Planned treatment, or treatment with another investigational drug within 4 weeks before study 
entry 
23. Subject is taking a medication that has the potential for QTc prolongation 
24. Subject is taking a drug that is a sensitive substrate of CYP enzymes 
25. Subject is taking a strong inducer of CYP3A4 (see Appendix F). 
26. Subject has consumed an herbal medication (eg, St. John’s Wort) or grapefruit/grapefruit juice 
within 14 days prior to the Week 1, Day 1 visit (see Appendix G). 
 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Overview 
The timing for these study assessments is presented in Table 1, while a listing of clinical laboratory 
parameters to be measured in presented in Table 2.   
8.2. 
Procedures to be Performed 
All screening assessments are to be performed within 29 days before the Week 1, Day visit, unless 
otherwise specified. 
Study Day 1 is defined as the date the subject takes the first dose of study drug (or the Week 1, Day 1 
visit for the BSC treatment group), with subsequent study days numbered sequentially thereafter.  
If significant changes from baseline are noted during the course of the study, additional unscheduled 
clinic visits may be undertaken by the Investigator, or requested by the sponsor, in order to 
determine both the relevance of the finding(s) and the duration of the event(s). 
Informed Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed for the 
subject to ask questions and make a voluntary decision.  No protocol-specific procedures, including 
screening procedures are to be performed until the subject has signed and dated an 
IRB/IEC-approved ICF.   
Demographics and Medical History 
A complete medical history will be taken.  Information to be documented includes demographic 
information, prior medical illnesses and conditions, surgical procedures, and smoking history.  
Medical history should include exacerbation of IPF, such as presence of dyspnea, chest interstitial 
lung abnormalities, or SpO2 <88%), within 6 months prior to screening visit. 
IPF history should include: 
 When diagnosis was made  
 Previous treatments with dates and reasons for discontinuation 
 History of PFTs for at least 1 year prior to enrollment 
Physical Examination 
 
Complete PEs will be performed.  All PEs will include assessment of cardiac (including heart rate, 
vital sign, and CPK measurements), musculoskeletal (ie, muscle aches) and neurological (ie, gait) 


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Amendment No. 9 
 
 
 
 
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body systems. 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 (eg, 
physician’s assistant, nurse practitioner).     
Any abnormal or clinically significant findings from the PE must be recorded on the appropriate 
electronic case report form (eCRF) page.   
Vital Sign Measurements 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes.  Vital sign 
assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats per 
minute), respiration rate (breaths per minute), and temperature (Celsius). 
Please note that blood pressure measurements are to be performed using appropriate technique (per 
guidelines of the American Heart Association).  Specifically, subjects should be seated quietly for at 
least 5 minutes in a chair with their backs supported, their feet flat on floor (legs uncrossed), and their 
arms bared on a hard surface, with the arm slightly abducted and bent, with palm up and the midpoint 
of upper arm at heart level.  Correct cuff and bladder size should be utilized.  Two or more readings 
separated by 1 to 2 minutes should be averaged.  If the first 2 readings differ by more than 5 mm Hg, 
an additional 2 readings should be obtained and averaged.  Record cuff size, arm used, and subject’s 
position (if not seated). 
Laboratory Assessments 
Laboratory samples (hematology, chemistry, and urinalysis) are to be collected as outlined in 
Section 8.9. Coagulation parameter assessments are to include measurements of PT, PTT, and INR.  
Thyroid function assessments are to include measurements of TSH 
Safety laboratory analyses will be performed. 
Laboratory results will be classified using the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see Appendix C).  
If significant increases in liver enzymes (ALT, AST, and bilirubin) are observed at any time, study 
drug may be held for that subject at the discretion of the Investigator.  Refer to Section 12.4  
additional information and recommended procedures. 


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IND Number 128024 
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12-Lead Electrocardiogram  
Electrocardiograms will be performed with the subject in a supine position having rested in this 
position for at least 5 minutes before each reading. See Section 8.10 for additional ECG procedure 
information and Table 1 for timing allowances.  At the Week 1 Day 1 and End of Week 4 visits, an 
ECG is to be performed predose and 4 hours post-dose (Tmax) in subjects receiving KD025. 
Blood Sampling for Pharmacodynamics  
All subjects will have serum blood samples drawn for MMP7, CCL18, and SPD at baseline, end of 
Week 12, and end of Week 24.  
St. George’s Respiratory Questionnaire 
The St George’s Respiratory Questionnaire (SGRQ) is a standardized self-completed questionnaire to 
measure and quantify health-related health status in subjects with impaired health and perceived 
well-being (‘quality of life’); see Appendix E.  The SGRQ will be administered prior to all other 
scheduled procedures. Subjects will complete the SGRQ at Weeks 1, 12, 24, and continuation visits 
end of Week 28 and end of Week 48 (and every 12 weeks thereafter).  
The St George’s Respiratory Questionnaire is a standardized self-completed questionnaire for 
measuring impaired health and perceived well-being (‘quality of life’) in airways disease.21  It has 
been designed to allow comparative measurements of health between patient populations and 
quantify changes in health following therapy.  
KD025 Administration 
Subjects in Treatment Group 1 will receive their first dose of study drug in the clinic on Week 1, 
Day 1, and then study drug will be dispensed for home administration.  These subjects also will take 
their dose of study drug at the clinic at the End of Week 4 visit. 
Subjects in Treatment Group 1 will receive 400 mg KD025 QD for 24 weeks. Subjects should take 
two 200-mg tablets within 5 minutes of completing a meal.   
Subjects may continue to receive therapy with KD025 as long as there is no safety signal and clinical 
progress continues.   
See Section 12.1 for dosing schedule and Section 12.2 for missed doses.   
Best Supportive Care 
Subjects in Treatment Group 2 will receive BSC (as deemed appropriate by the Investigator).  
Subjects receiving BSC will have the option of switching to therapy with KD025 after Week 24.  


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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Confidential and Proprietary 
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Subjects who switch to KD025 may receive 24 weeks of dosing with KD025, with the potential to 
continue as long as there is no safety signal and clinical progress continues.  For subjects who switch, 
prior to their first dose of KD025, Investigators should perform the Week 1, Day 1 assessments 
(except for safety labs [hematology and chemistry] if performed within 1 week of this visit and PFTs 
if performed within 4 weeks) and all subsequent visits as outlined Table 1.   
Study Drug Diary 
Subjects will be supplied study drug diaries in which they are to record the amount, date and time of 
each dose of study drug.  In addition, subjects are to bring their diary to each study visit. 
Prior and Concomitant Medications and Procedures 
All concomitant medications and procedures will be collected from time the subject signs the ICF 
until 30 days after last dose of KD025.  For BSC subjects, concomitant medications and procedures 
will be recorded through the end of Week 24 visit.   
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the ICF 
throughout their participation in the study, including a period of 30 days after last dose of KD025. 
For BSC subjects, AE information will be recorded through the end of Week 24 visit. Subjects with 
ongoing AE/SAE(s) will be followed until resolution of the AE/SAE(s) or until a new treatment for 
IPF is started.  
Note:   Adverse events resulting in a subject’s permanent discontinuation from the 
study, regardless of seriousness or relationship to study drug, MUST be 
promptly reported to the sponsor. 
See Section 11.2  for stopping rules for this study.  Also, if significant increases in liver enzymes are 
observed at any time, the Investigator should refer to Section 12.4 for additional information. 
8.3. 
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 of the study inclusion and exclusion criteria.   


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
 Informed consent 
 Medical history, including documentation of previous exacerbations of IPF (such as 
presence of dyspnea, chest interstitial lung abnormalities, or SpO2 <88%) during past 
6 months and demographic data 
 Complete PE, including height and weight 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
 Pulmonary function tests (including FVC, RV, and DLCO) 
 Screening concomitant medications and procedures assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Screening AE assessment 
8.4. 
Enrollment 
After completion of screening procedures and confirmation of subject eligibility, the subject will be 
enrolled and randomized into Treatment Group 1 or Treatment Group 2 in a 2:1 ratio (KD025 to 
BSC). Subjects who are enrolled and randomized into the study are to undergo all subsequent 
evaluations required by the protocol. 
8.5. 
Treatment Period 
8.5.1 
Week 1, Day 1 Visit (Baseline) 
At the Week 1, Day 1 visit, subjects will come to the clinic to have the following procedures 
completed (if screening was completed within 7 days of baseline, only the complete PE and vital sign 
measurements need to be repeated): 
 St. George’s Respiratory Questionnaire 
 Complete PE, including weight 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, and INR 
 TSH 
 Urinalysis 
 Supine 12-Lead ECG; perform predose and 4 hours post-dose (for subjects receiving 
KD025) (repeat 3 times consecutively within 30 minutes [must have an interval of at least 
1-2 minutes between ECGs]; perform ECG immediately before blood sample collection) 
 MMP7, CCL18, and SPD serum biomarkers  
 Occurrence of exacerbation of IPF (frequency and severity) 
 Study diary (dispense/collect) (for subjects receiving KD025) 
 Pulmonary function tests (including FVC, RV, and DLCO) 
 HRCT 
 6MWD 
 Randomization 
 Study drug administration (for subjects receiving KD025), only to be performed at 
Week 4. 
 Dispense/collect study drug (for subjects receiving KD025) 
 Concomitant medications and procedures assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
8.5.2 
End of Week 4, Day 28 (±3 days) and End of Week 8, Day 56 (±3 days) Visits 
Subjects will come to the clinic to have the following procedures completed: 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, INR 
 TSH 
 Urinalysis 
 Supine 12-Lead ECG; End of Week 4 visit only; perform predose and 4 hours post-dose 
(for subjects receiving KD025) (repeat 3 times consecutively within 30 minutes [must 
have an interval of at least 1-2 minutes between ECGs]; perform ECG immediately before 
blood sample collection) 


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IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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 Occurrence of exacerbation of IPF (frequency and severity) 
 Study drug administration (for subjects receiving KD025) 
 Study diary (dispense/collect) (for subjects receiving KD025) 
 Dispense/collect study drug (for subjects receiving KD025) 
 Concomitant medications assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
8.5.3 
End of Week 12, Day 84 (± 3 days) Visit 
Subjects will come to the clinic to have the following procedures completed: 
 St. George’s Respiratory Questionnaire 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Complete PE, including weight 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, INR 
 TSH 
 Urinalysis 
 Pulmonary function tests (including FVC, RV, and DLCO)  
 MMP7, CCL18, and SPD biomarkers 
 Occurrence of exacerbation of IPF (frequency and severity) 
 6MWD  
 Study diary (dispense/collect) (for subjects receiving KD025) 
 Dispense/collect study drug (for subjects receiving KD025) 
 Concomitant medications assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.) 
 Adverse event assessment 
8.5.4 
End of Week 16, Day 112 (± 3 days) and End of Week 20, Day 140 (± 3 days) Visits 
Subjects will come to the clinic to have the following procedures completed: 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, INR 
 TSH 
 Urinalysis 
 Occurrence of exacerbation of IPF (frequency and severity) 
 Study diary (dispense/collect) (for subjects receiving KD025) 
 Dispense/collect study drug (for subjects receiving KD025) 
 Concomitant medications assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
8.5.5 
End-of-Primary-Treatment Visit (End of Week 24, Day 168 [± 3 days]) 
Subjects will come to the clinic to have the following procedures completed:  St. George’s 
Respiratory Questionnaire 
 Complete PE, including weight 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, and INR 
 TSH 
 Urinalysis 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
 Pulmonary function tests (including FVC, RV, and DLCO) 
 HRCT 
 MMP7, CCL18, and SPD biomarkers 
 6MWD 
 Study diary (dispense/collect) (for subjects receiving KD025) 
 Occurrence of exacerbation of IPF (frequency and severity) 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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Confidential and Proprietary 
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 Collect/Dispense study drug (for subjects receiving KD025; if continuing) 
 Concomitant medications assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
8.6. 
Monthly Follow-Up Treatment Period for Those Subjects Continuing 
Study Drug  
8.6.1 
Continuation Visits (Every 4 Weeks [± 3 days]) 
After 24 weeks, subjects in Treatment Group 1 with a stable FVC from baseline may continue to 
receive therapy with KD025 as long as there is no safety signal and clinical progress continues.  
Subjects receiving BSC have the option of switching to therapy with KD025 after Week 24. Subjects 
who switch may receive 24 weeks of dosing with KD025, with the potential to continue on the trial 
as long as there is no safety signal and clinical progress continues. These subjects will start over at 
Week 1 and follow the same schedule as outlined in Section 8.5. All subjects will return to the clinic 
every 4 weeks to have the following procedures completed as per below: 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature), to be completed every 4 weeks. 
 Clinical laboratory tests (hematology and serum chemistry panel), to be completed every 
4 weeks. 
 PT, PTT, and INR, to be completed every 4 weeks. 
 TSH, to be completed every 4 weeks. 
 Urinalysis, to be completed every 4 weeks. 
 Occurrence of exacerbation of IPF (frequency and severity), to be completed every 
4 weeks. 
 Collect/dispense study drug (for subjects receiving KD025), to be completed every 
4 weeks. 
 Concomitant medications and procedures assessment, to be completed every 4 weeks. 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment, to be completed every 4 weeks. 
 St. George’s Respiratory Questionnaire, to be completed every 12 weeks. 
 Complete PE, including weight, to be completed every 12 weeks. 


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Amendment No. 9 
 
 
 
 
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 Pulmonary function tests (including FVC, RV, and DLCO), to be completed every 
12 weeks.  
 MMP7, CCL18, and SPD biomarkers (at End of Week 36 and End of Week 48 visits 
only), to be completed every 12 weeks. 
 6MWD (at End of Week 36 and End of Week 48 visits only), to be completed every 
12 weeks. 
 HRCT, to be completed every 24 weeks. 
8.6.2 
End of Treatment Visit [± 3 days]) 
Subjects who discontinue from the study will have the following tests completed: 
 Complete PE, including weight 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, and INR 
 TSH 
 Urinalysis 
 12 Lead ECG 
 Pulmonary function tests. Not to be performed if PFTs were done within 1 month of the 
EOT visit. 
 HRCT. Not to be performed if HRCT was done within 1 month of the EOT visit. 
 MMP7, CCL18, and SPD biomarkers 6MWD (to be performed at End of Week 48 and 
every 12 weeks thereafter) 
 Study diary (dispense/collect) (for subjects receiving KD025) 
 Occurrence of exacerbation of IPF (frequency and severity) 
 Collect/dispense study drug (for subjects receiving KD025) 
 Concomitant medications and procedures assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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8.7. 
30-Day Follow-Up Visit 
Subjects will return to the clinic 30 days (± 3) after their last dose of KD025 (Follow-up visit not 
required for BSC subjects).  At this visit, the following procedures will be completed: 
 Complete PE, including weight 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, and INR 
 TSH 
 Urinalysis 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
 Pulmonary function tests (including FVC, RV, and DLCO) 
 Occurrence of exacerbation of IPF (frequency and severity) 
 Collect study diary (for subjects receiving KD025) 
 Concomitant medications and procedures assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
8.8. 
Unscheduled Visits 
For subjects requiring an unscheduled visit, the following assessments may be performed at the 
Investigator’s discretion: 
 St. George’s Respiratory Questionnaire 
 Complete PE, including weight 
 Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel) 
 PT, PTT, INR 
 TSH 
 Urinalysis 


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IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
 MMP7, CCL18, and SPD biomarkers 
 Pulmonary function tests (including FVC, RV, and DLCO) 
 6MWD 
 Occurrence of exacerbation of IPF (frequency and severity) 
 Dispense /collect study drug (for subjects receiving KD025) 
 Dispense /collect study drug diary (for subjects receiving KD025) 
 Concomitant medications and procedures assessment 
 Urine pregnancy test (for females of childbearing potential. Positive results are to be 
confirmed with serum testing.)  
 Adverse event assessment 
8.9. 
Laboratory Assessments 
 A Central laboratory will perform hematology, serum chemistry, coagulation, thyroid, and urinalysis 
tests and results will be provided to the Investigator (Table 2).  Blood and urine samples for 
hematology, serum chemistry, coagulation, TSH, and urinalysis will be prepared using standard 
procedures.   


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Table 2: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
 
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 
 
carbon dioxide 
 
chloride 
 
cholesterol 
 
creatinine 
 
CPK 
 
direct bilirubin 
 
GGT 
 
globulin 
 
glucose 
 
lactate dehydrogenase 
 
magnesium 
 
phosphorus 
 
potassium 
 
sodium 
 
total bilirubin 
 
total protein 
 
uric acid
 
appearance 
 
color 
 
pH 
 
specific gravity 
 
ketones 
 
protein 
 
glucose 
 
bilirubin 
 
nitrite 
 
urobilinogen 
 
occult blood (microscopic examination 
of sediment will be performed only if 
the results of the urinalysis dipstick 
evaluation are positive) 
Coagulation 
Thyroid 
 
 
INR 
 
PT 
 
PTT 
 
TSH 
 
Biomarkers  
 
 
 
MMP7 
 
CCL18  
 
Serum SPD 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CCL18 = chemokine ligand 18; 
CPK = creatine phosphokinase; GGT = gamma glutamyl transferase; INR = international normalized ratio; MCV =  mean 
corpuscular volume; MMP7 = matrix metalloproteinase; PT = prothrombin time; PTT = partial thromboplastin time; SPD = 
surfactant protein-D; TSH = thyroid stimulating hormone 
 
Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, 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 Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (see Appendix C).  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 13.1). 


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8.10. 
Electrocardiogram Assessments 
Digital 12-lead ECGs will be obtained during the study (see Table 1 for timing of ECG assessments).  
Note that at the Week 1 Day 1 and End of Week 4 visits, an ECG is to be performed predose and 4 
hours post-dose (Tmax) for subjects in Treatment Group 1. 
Digital 12-lead ECG recordings are to be made with the subject in a supine position having rested in 
this position for at least 5 minutes before each reading.  The ECG is to be repeated 3 times 
consecutively within 30 minutes (must have an interval of at least 1–2 minutes between ECGs).  At 
each visit, the ECG is to be performed immediately before any blood sample collection. 
The following ECG parameters will be collected:  PR interval, QRS interval, and QTc or QTc(F); 
Fridericia’s correction (see Appendix D for formula).  The ECG findings will be evaluated by a 
qualified physician for the 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 (eg, dose reduction or delay, 
requirement for additional medication or monitoring) 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 (see 
Section 13.1). 
8.11. 
Pulmonary Function Tests (including FVC, RV, and DLCO) 
Pulmonary function testing will be performed during the study (see Table 1 for timing of 
assessments). Pulmonary function testing will include FVC, RV, and DLCO. The same equipment and 
tester should be used during the course of the study. For each subject, PFT should be done at 
approximately the same time of the day. The test will be conducted while the subject is in a seated 
position and will be done in triplicate. 
8.12. 
6-Minute Walking Distance 
The 6MWD will be measured during the study (see Table 1 for timing of assessment).  The distance 
travelled during 6 minutes (meters) will be measured in accordance with published guidelines.  The 
total distance ambulated in meters during the 6MWD test and the number of rest stops is recorded. 
The 6MWD, weight, heart rate, blood pressure, and Sp02 will be recorded before and after the walk. 


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IND Number 128024 
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8.13. 
High Resolution Computed Tomography 
The change in severity of lung fibrosis as measured by Quantitative HRCT during the study (see 
Table 1 for timing of assessment) will be read via a central reader.  Optimal HRCT technique for 
evaluation is listed in Table 3 below.  
Table 3: 
Clinical Optimal HRCT Technique for Evaluation of Interstitial Lung Disease17 
The scans should be without contrast and include at a minimum: 
 
1. Scans obtained on full inspiration without respiratory motion 
2. Contiguous or noncontiguous axial scans with thin sections, reconstructed at ≤ 2 cm 
intervals 
3. Reconstructed slice collimation ≤ 2 mm 
4. High-resolution reconstruction algorithm 
5. Field of view to include lungs only 
6. Expiratory scans are helpful to exclude lobular air trapping suggestive of hypersensitivity 
pneumonitis 
7. Prone scans if dependent density obscures detail on supine images 
8. Optional coronal and sagittal reconstructions if volumetric images are obtained 
8.14. 
Occurrence of Acute Exacerbation  
Occurrence of acute exacerbation (frequency and severity) of IPF will be assessed throughout 
treatment (see Table 1 for timing of assessment).  The following clinical deterioration symptoms 
within a month that cannot be explained by other reasons will be assessed as acute exacerbation. 
1. Aggravated dyspnea; 
2. Newly discovered chest interstitial lung abnormality by radiograph/HRCT, without 
pneumothorax or pleural effusion; 
3. SpO2 decreases to < 88% (heart failure or pulmonary embolism excluded). 
Acute exacerbation can be diagnosed if items 1 and 2 are present or if items 1 and 3 are present. Per 
the 2011 IPF Diagnosis Management and Guidelines,1 criteria for acute exacerbations should include 
an absence of an alternative explanation such as infection, pulmonary embolism, pneumothorax, or 
heart failure.    


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IND Number 128024 
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8.15. 
Time to Progression of IPF 
Time to progression of IPF will be determined and is defined as time from Week 1, Day 1 to any 1 of 
the following:  
1. First respiratory-related hospitalization. 
2. Respiratory-related death. 
3. Absolute decline in FVC percent of predicted value of ≥ 10% versus FVC percent of 
predicted value recorded at baseline.  
4. Absolute decline in DLCO, adjusted for hemoglobin, percent of predicted value of 
≥ 15% versus DLCO recorded at baseline. 
 


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9. 
PHARMACOKINETICS  
Not applicable.  


KD025 
IND Number 128024 
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10. 
PHARMACODYNAMICS 
The MMP7, CCL18, and SPD serum levels will be assessed during the study (see Table 1 for 
sampling times).  Serum MMP7 concentrations in peripheral blood are easily measurable and reflect 
changes in the alveolar microenvironment.  Thus, mean serum MMP7 concentrations after 24 weeks 
of KD025 treatment will be studied as a potential surrogate biomarker of the effect of KD025 
administration on disease progression.  
Detailed instructions for sample collection and preparation will be provided in a separate manual. 
 


KD025 
IND Number 128024 
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11. 
REMOVING SUBJECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, in the event that a 
subject is withdrawn from the study, every effort will be made by the Investigator to complete and 
report the reasons for withdrawal as thoroughly as possible.  This evaluation should include final 
observations, as required by the protocol at the time of the subject’s withdrawal.  The reason(s) for 
termination must be clearly documented on the appropriate eCRF.  A termination eCRF page must be 
completed for any subject who is enrolled in the study.  
11.1. 
Subjects’ Decision to Withdraw  
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. 
Subjects can decline to continue receiving study drug and/or other protocol-required therapies or 
procedures at any time during the study.  If this occurs, the Investigator is to discuss with the subject 
the appropriate processes for discontinuation from study drug or other protocol-required therapies 
and must discuss with the subject the options for continuation of the Schedule of Assessments 
(Table 1) and collection of data, including endpoints and AEs.   
Withdrawal of consent for a study means that the subject does not wish to receive further 
protocol-required therapies or procedures, and the subject does not wish to or is unable to continue 
further study participation.  Subject data up to withdrawal of consent will be included in the analysis 
of the study, and where permitted, publically available data can be included after withdrawal of 
consent.  The Investigator is to discuss with the subject appropriate procedures for withdrawal from 
the study.   
11.1.1 
Treatment Discontinuation   
Treatment discontinuation reasons include any of the following: 
 An AE requires permanent discontinuation of study drug or BSC 
 Investigator decision 
 Voluntary withdrawal by subject 
 Noncompliance to protocol 
 Subject lost to follow-up 
 Termination of the study by sponsor 
 Subject death 
 Disease progression 


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IND Number 128024 
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11.1.2 
Study Termination 
Reasons for study termination include:  
 Completion of Follow-up Period 
 Voluntary withdrawal by subject 
 Subject lost to follow-up 
 Termination of the study by sponsor 
 Subject death 
In the event of premature discontinuation, every effort should be made to have the subject come to 
the clinic for an End of Treatment visit in order for the Investigator to perform study follow-up 
procedures.  Refer to Table 1, Study Assessments for a complete list of procedures to be performed at 
the End of Treatment visit.    
Subjects who are withdrawn from this study because of toxicity are to be followed until there is 
either: 
 Resolution or stabilization of toxicity 
 The subject is lost to follow-up 
 The event is otherwise explained 
If there is an ongoing toxicity because of KD025, subjects must be followed with appropriate medical 
management until resolution or stabilization. 
A reasonable effort should be made to contact any subject lost to follow-up during the course of the 
study in order to complete assessments and retrieve any outstanding data.  If the subjects are 
unreachable by telephone after 3 attempts, a certified registered return receipt letter should be sent 
requesting that contact be made with the Investigator to report survival information. 
Once a subject discontinues from the study for any reason, every effort will be made to collect all 
clinical and laboratory data as scheduled for the follow-up. 
11.2. 
Stopping Rules 
Stopping criteria will be assessed using the Clinical Symptom Adverse Event Grading scale (see 
Appendix B) and will include clinically significant changes with respect to blood pressure, dyspepsia, 
nausea or vomiting, or other TEAEs that are Grade 2 (moderate) or higher.   
11.2.1 
Adverse Events Stopping Criteria 
AEs that require consideration of study drug discontinuation include the following: 


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 AEs of clinical concern 
 Grade 2 (moderate) or higher TEAEs that are determined by the Investigator to be 
possibly, probably or definitely related to study drug and last at least 5 days.  
 Clinically significant elevation of ALT or AST.  See Section 12.4 for risk management of 
LFT changes observed during the study.   
11.2.2 
Blood Pressure Stopping Criteria 
Blood pressure is to be measured with the subject in a sitting position.  Blood pressure measurements 
meeting stopping criteria should be repeated once, to confirm the measurement.  The repeat 
measurement will be used to determine whether the subject meets the stopping criteria. 
Clinically significant blood pressure decreases will be defined as follows: 
 An absolute systolic blood pressure < 85 mm Hg at any time point, or a decrease > 30 mm 
Hg in systolic blood pressure from baseline with accompanying symptoms of hypotension 
at any time point, or an asymptomatic decrease > 30 mm Hg from baseline on any 
2 consecutive time points; or 
 An absolute diastolic blood pressure < 45 mm Hg at any time point, or a decrease 
> 20 mm Hg in diastolic blood pressure from baseline with accompanying symptoms of 
hypotension at any time point, or an asymptomatic decrease > 20 mm Hg in diastolic 
blood pressure from baseline on 2 consecutive time points. 
Clinically significant blood pressure increases are defined as: 
 An absolute systolic blood pressure > 180 mm Hg at any time point, or an increase 
> 30 mm Hg in systolic blood pressure from baseline with accompanying symptoms 
of hypertension at any time point, or an asymptomatic increase > 30 mm Hg from baseline 
on any 2 consecutive time points; or 
 An absolute diastolic blood pressure > 110 mm Hg at any time point, or an increase 
> 20 mm Hg in diastolic blood pressure from baseline with accompanying symptoms of 
hypertension at any time point or an asymptomatic increase > 20 mm Hg in diastolic 
blood pressure from baseline on 2 consecutive time points. 
11.3. 
Study Discontinuation 
Kadmon Corporation has the right to terminate or to stop the study at any time.  Reasons for study 
discontinuation may include, but are not limited to the following:  
 The incidence or severity of AEs in this or other related studies indicates a potential health 
hazard to subjects  
 Subject enrollment is unsatisfactory 


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IND Number 128024 
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 Drug supply issues 
 Excessive subject self-withdrawal 
 Significant protocol violations (eg, violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
11.4. 
Replacements 
Subjects withdrawn from the study before receiving any study drug or BSC drugs/treatment will be 
replaced by enrolling additional subjects into the study.   
 
 


KD025 
IND Number 128024 
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12. 
STUDY DRUG 
12.1. 
Dose and Schedule of Study Drug and Comparator 
12.1.1 
Primary 24-Week Treatment Period 
Eligible subjects will be treated with 400 mg KD025 QD orally administered for 24 weeks or BSC 
(as determined by the Investigator).  
Treatment Group 1 
400 mg KD025 QD  
Treatment Group 2 
BSC 
Treatment Group 1: Subjects should take 2 tablets within 5 minutes of finishing a meal. Subjects 
will be dispensed study drug to self-administer while on an outpatient basis.  Subjects will take their 
first dose of study drug at the clinic on Day 1 and also take their dose of study drug at the clinic at the 
End of Week 4 visit.  Additionally, subjects will be asked to bring their study drug diary to each visit. 
Study drug will be dispensed by the site pharmacist.  After the completion and review of all 
screening and baseline procedures, qualified subjects will receive study drug.  KD025 will be 
supplied as 200-mg tablets.    
Product 
Strength 
Dosage Form 
Route 
KD025 
200 mg 
Pale yellow tablet  
Oral 
 
 
 
 
Product 
Dose 
Number of 200-mg tablets to be 
administered per dose 
KD025 
400 mg QD 
2 
 
Treatment Group 2:  Subjects will receive BSC (as deemed appropriate by the Investigator). 
Subjects randomized to BSC will be treated exactly the same as subjects on KD025 and undergo all 
tests in a similar fashion.   
12.1.2 
Switching from BSC to KD025 
Subjects receiving BSC have the option of switching to therapy with KD025 after Week 24.  Subjects 
who switch may receive 24 weeks of dosing with KD025, with the potential to continue on the trial 
as long as there is no safety signal and clinical progress continues.  For subjects who switch to 
KD025, prior to their first dose of KD025, Investigators should perform the Week 1, Day 1 
assessments (except for safety labs [hematology and chemistry] if performed within 1 week of this 


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visit and PFTs if performed within 4 weeks) and all subsequent visits as outlined in Table 1, Study 
Assessments.   
12.1.3 
Continuation of KD025 Dosing  
Subjects in Treatment Group 1 may receive additional therapy with KD025 as long as there is no 
safety signal and clinical progress continues.    
No subject will receive more than 96 weeks of study drug treatment in this study. 
12.2. 
Missed Doses 
Subjects should make every effort to take the study drug at the same scheduled time daily.  In the 
event that the subject misses the planned dose of study drug, the following protocol should be 
followed: 
 If less than 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 more than 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. 
If the subject skips more than 7 consecutive days of drug, the subject should be discontinued from the 
study. 
12.3. 
Dose Reduction for KD025 
Every effort should be made to keep the subject on the full dose of drug.  However, in the event that 
the Investigator feels that an AE requires dose modification, the drug may be decreased as shown in 
Table 4 and Table 5.  Once a subject has their dose decreased, an increase back to 400 mg QD is not 
allowed. 
Table 4: 
Dose Reductions for Toxicity Related to Study Drug 
Study Drug 
Starting Dose 
Dose Reduction 
KD025 
400 mg KD025 QD 
200 mg QD 
No more than 1 dose reduction is permitted.  Subjects who require more than 1 dose reduction will 
have study drug discontinued and enter the Follow-up Period.  Liver function test risk management is 
treated separately; see Section 12.4, below. 


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IND Number 128024 
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Table 5  Guidelines for Management of Treatment-emergent Toxicities 
Toxicity 
Recommended Action 
Grade 4 organ 
toxicities considered at 
least possibly related to 
KD025 
 
Discontinue KD025 
Grade ≥3 LFTs (AST, 
ALT or total bilirubin) 
regardless of 
attribution to KD025 
 
Hold KD025 dosing until resolution to Grade 1 or below levels 
 
Consider resuming KD025.  If resuming, then resume at one dose 
decrement 
 
If toxicity recurs, discontinue KD025 permanently 
Other Grade ≥3 
clinically significant 
toxicities considered at 
least possibly related to 
KD025  
 
Hold KD025 dosing until toxicity has resolved to Grade 1 or below 
then consider resuming KD025. If resuming, then resume at one dose 
decrement 
 
If toxicity recurs, hold dose as above then consider resuming KD025 at 
one dose decrement 
ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; LFT = liver function test 
12.4. 
Evaluation of Liver-Related Blood Tests 
If ALT or AST > 2.0 × ULN subject should remain on study drug with close observation which 
includes: 
1. Immediately contacting the medical monitor. 
2. Repeating liver enzyme, serum bilirubin, and PT/INR once a week.  
(Frequency of retesting can decrease if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic.)  
3.  Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
4.  Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets.  
5. Ruling out acute viral hepatitis types A, B, C; autoimmune or alcoholic hepatitis; nonalcoholic 
steatohepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease.  
6. Obtaining a history of exposure to environmental chemical agents.  
If close observation is not possible, the subject should be discontinued from the study at the 
Investigators discretion. 


KD025 
IND Number 128024 
Protocol Number KD025-207
Amendment No. 9 
 
 
 
 
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Subjects with ALT or AST > 3 × ULN, who do not have clinically significant elevations of 
liver-related blood tests as described below, should have KD025 administration halted for 2 to 
3 weeks with weekly evaluation of ALT and AST.  If ALT and AST return to normal within 3 weeks, 
then KD025 can be restarted at a lower dose.  If ALT and AST do not return to normal within 
3 weeks, then KD025 administration should be terminated (Table 6). 
Clinically significant elevations of liver-related blood tests as defined below require immediate drug 
termination. 
1. ALT or AST > 5 × ULN  
2. ALT or AST > 3 × ULN and total bilirubin > 2 ×ULN or INR > 1.5  
3. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
4. If the total bilirubin is > 2 × ULN then discontinue KD025 and obtain direct bilirubin 
Table 6: 
Grading of Liver-Related Laboratory Abnormalities18,19,20  
Feature 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT 
> ULN-3.0 × ULN 
> 3.0-5.0 × ULN 
> 5.0-20 × ULN 
> 20 × ULN 
AST 
> ULN-3.0 × ULN 
> 3.0-5.0 × ULN 
> 5.0-20 × ULN 
> 20 × ULN 
Alkaline 
Phosphatase 
> ULN-2.5 × ULN 
> 2.5-5.0 × ULN 
> 5.0-20.0 × ULN 
> 20 × ULN 
GGT 
> ULN-2.5 × ULN 
> 2.5-5.0 × ULN 
> 5.0-20.0 × ULN 
> 20 × ULN 
Bilirubin 
> ULN-1.5 × ULN 
> 1.5-3.0 × ULN 
> 3.0-10.0 × ULN 
> 10.0 × ULN 
ALT = Alanine aminotransferase; AST = aspartate aminotransferase; GGT = Gamma-glutamyl transferase; ULN = upper limit 
of normal 
12.5. 
Identity of Investigational Products 
KD025 will be supplied by Kadmon Corporation.   
12.6. 
Study Drug Packaging and Labeling 
KD025 will be packaged and labeled by the sponsor.  The label attached to each bottle will provide 
the following information: 
 Description of contents (number and strength of tablet) and route of administration 
 Directions for use 
 Storage conditions 
 Product identification code 


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 Lot Number identification  
 Bottle number 
 Name of protocol sponsor 
 The statement, “Caution: New Drug – Limited by Federal Law to Investigational Use.”  
 The statement, “Keep out of the reach of children and pets.”  
12.7. 
Dispensing of Study Drug and Dosing Compliance 
Subjects will be dispensed study drug to self-administer while on an outpatient basis.  Subjects will 
return to the clinic as outlined in the Study Assessments table (Table 1), and will receive that day’s 
dose of study drug while at the clinic. 
The amount of study drug dispensed to the subject at the beginning of each dosing month should be 
sufficient to allow for 1 month of dosing with KD025. 
The Investigator (or designee) will be responsible for recording this information on the appropriate 
study drug inventory.  This inventory will be maintained throughout the duration of the trial and will 
be periodically reviewed by a representative of the sponsor. 
The Investigator (or designee) will instruct the subject that all dispensed bottles must be returned at 
each follow-up visit, at which time a capsule or tablet count will be conducted to assure subject 
dosing compliance. 
Additionally, subjects will be required to keep study drug diaries in which they will record the 
amount, date and time of study drug administrations.  These diaries will be dispensed and/or 
reviewed/collected at each visit. 
12.8. 
Study Drug Storage 
All supplies of study drug are to be stored at USP controlled room temperature of 25°C (77°F) with 
excursions permitted between 15°C and 30°C (59°F and 86°F).  At the clinic, the study drugs are to 
be stored in a securely locked area, accessible to authorized persons only, until needed for dosing. 
12.9. 
Study Drug Accountability 
The US FDA and other regulatory agencies require accounting for the disposition of all 
investigational drugs received by each clinical site.  Information on drug disposition required by law 
consists of the date received, date administered, quantity administered, and the subject to whom the 
drug was administered.  The principal Investigator is responsible for the accounting for all unused 


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study drugs and all used study drug containers.  The Investigator must maintain a complete and 
current dispensing and inventory record that has been supplied by the sponsor. 
12.10. 
Study Drug Handling and Disposal 
At the termination of the study, a final drug accountability review and reconciliation must be 
completed and any discrepancies must be investigated and their resolution documented. 
12.10.1 
Disposition of Used Supplies 
At the completion of a subject’s participation in the trial, all partially used and empty pill bottles 
must be returned to the Investigator (or designee) so that a final subject-dosing inventory may be 
conducted.  This information will be recorded on the Drug Dispensing Log.  
12.10.2 
Inventory of Unused Supplies 
Periodically throughout and at the conclusion of the study, an inventory of unused bottles of study 
drug will be conducted by a representative of the sponsor.   
 


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13. 
CONCOMITANT MEDICATION AND PROCEDURES 
If the subject must use a concomitant medication or concomitant procedures during the study, it is the 
responsibility of the Investigator to ensure that details regarding the medication or procedures are 
recorded on the eCRF. 
A reasonable effort is to be made to document any medications or procedures the subject receives 
from the date that the ICF is signed until 30 days after last dose of KD025.  For BSC subjects, 
concomitant medications and procedures will be recorded through the End-of-Week 24 visit.  
The concomitant medication names will be coded by the sponsor according to the World Health 
Organization Drug Dictionary (WHO-DD) and classified by anatomical therapeutic chemical 
categories. 
13.1. 
Prohibited Medications for Subjects Receiving KD025 
All subjects who receive KD025 therapy, that is, all subjects in Treatment Group 1 and subjects in 
Treatment Group 2 who crossover to KD025 therapy are not to take drugs that are sensitive 
substrates of CYP enzymes from first dose until 14 days after last dose of study drug.  Additionally, 
use of strong CYP3A4 inducers are prohibited.  Other CYP3A4 inhibitors or inducers should be used 
with caution.  Herbal medications (eg, St. John’s Wort) or grapefruit/grapefruit juice should not be 
consumed 14 days prior to first dose of study drug until the end of treatment.  Please refer to 
Appendix F for drugs that induce and inhibit CYP3A4 and Appendix G for drug that induce and 
inhibit CYP1A2. 
 
SAFETY 
Safety Parameters 
The Clinical Symptom and Adverse Event Grading Scale will be used for grading toxicities (see 
Appendix B).  Laboratory results will be classified using the Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see Appendix A).  
Subjects will be monitored throughout the treatment and follow-up period for occurrence of AEs 
(acute, delayed, and/or cumulative), as well as for changes in clinical status, vital sign measurements, 
and laboratory data.  Safety parameters to be measured/assessed include vital sign measurements, PE 
findings, hematology, serum chemistries, coagulation, and urinalysis results, and ECG recordings. 
Adverse Event Definition 


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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 (eg, 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 (eg, 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 
 Exacerbation of a pre-existing condition 
For the purpose of data collection, all untoward events that occur after informed consent through 
30 days after last dose of KD025 are to be recorded on eCRFs by the investigational site.   For BSC 
subjects, AEs will be recorded through the End-of-Week 24 visit. 
Evaluating Adverse Events 
The Investigator will determine the seriousness, intensity, and causality of an AE associated with the 
use of the study drug (ie, events where there is a reasonable possibility that the event may have been 
caused by the study drug) based on the definitions that follow. 
Serious Adverse Events 
(Notify sponsor or designee within 24 hours; document on eCRF) 
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 Studies. 
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 30 days after study drug administration.  


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Note: Death is an outcome of an AE, and not an AE in itself.  The event(s) that caused death (eg, 
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.  
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 1 of the outcomes 
listed in this definition.   
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
(Notify sponsor or designee within 24 hours of first awareness) 
A suspected unexpected serious adverse reaction is any adverse drug event, the specificity or severity 
of which is not consistent with those noted in the current protocol and/or IB.  This refers to any AE 
that has not been previously observed (eg, included in the Investigator Brochure), rather than from 
the perspective of such an event not being anticipated from the pharmacological properties of the 
product.  


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Unexpected Adverse Events  
(Notify sponsor or designee by the next business day) 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the specificity or 
severity that has been observed; or, if an IB is not required or available, is not consistent with the risk 
information described in the General Investigational Plan or elsewhere in the current application. 
Also refers to AEs that are mentioned in the IB as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation. 
Non-Serious Adverse Events  
All other AEs, not fulfilling the previous definitions, are classified as nonserious. 
Protocol-Related Adverse Events 
AEs 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. 
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; see 
Appendix C). 
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 a 
5-point scale (mild, moderate, severe, life threatening, or death; see Appendix B).  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.  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.    
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: 


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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 that has 
not worsened does not count as an SAE. 
Serious Adverse Event Reporting 
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: 
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 IRBs 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. 
13.1.1.1. Time-Frame for Reporting 
Any death, SAE, pregnancy (including pregnancy of a partner), or unexpected (and severe) AE 
experienced by a subject while receiving or within 30 days of receiving study drug, regardless of 
relationship to study drug, or any death that occurs more than 30 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/SUSAR reporting: 
APCER Life Sciences, LLC 
Fax: 646-430-9549


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In the event of an issue with the fax line, forward 
SAE/SUSAR via email to: 
ClinicalSAEReporting@kadmon.com 
 
 
Additionally, the Investigator will be able to contact the medical monitor at all times: 
Sanjay Aggarwal, M.D. Kadmon Corporation 
55 Cambridge Parkway, Suite 300E 
New York, NY  10016 
Telephone:     
Direct: 724-778-6129 
Cell: 857-253-8642 
E-mail: Sanjay.Aggarwal@kadmon.com 
   
 
13.1.1.2. Information to be Provided by the Investigator 
SAEs for all enrolled subjects must be recorded on both the SAE form and the AE eCRF page 
(during study participation).  This requirement includes all SAEs that occur after informed consent 
and through 30 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 30 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 (ie, 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.  Forms for reporting SAE 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 SAE, 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 


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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:  
o Elective or previously scheduled surgery (eg, 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 (eg, an emergency room visit for hematuria that results in a diagnosis of 
cystitis and discharge to home on oral antibiotics) 
 SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 
13.1.1.3. Regulatory Reporting 
Kadmon Corporation Drug Safety (or designee) will process and evaluate all SAEs as soon as the 
reports are received.  For each SAE received, Kadmon Corporation will make a determination as to 
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 will be done in accordance with the standard 
operating procedures and policies of the IRB.  Adequate documentation must be maintained showing 
that the IRB was properly notified. 
13.2. 
Other Safety Considerations 
13.2.1 
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 (eg, dose reduction or delay, requirement for additional 
medication or monitoring) or is considered to be of clinical significance by the Investigator should be 


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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 Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (see Appendix A). 
13.2.2 
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. 
13.2.3 
Follow-Up of Adverse Events 
Any SAE or AE assessed as possibly related that led to treatment discontinuation (including 
clinically significant abnormal laboratory values that meet these criteria) and is ongoing 30 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 30 days after last dose of study drug.  The status of all 
other continuing AEs will be documented as of 30 days after last dose of study drug.   


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14. 
STATISTICAL CONSIDERATIONS  
All statistical analyses will be performed using SAS® (SAS Institute, Cary, North Carolina) statistical 
software Version 9.3 or higher, unless otherwise noted.   
The primary  analysis will be conducted with a data cutoff of approximately 24 weeks after last 
patient enrolled has received KD025 or when all subjects can be evaluated for primary endpoints.  
Ongoing monitoring of safety data will be conducted in accordance with study stopping rules. 
14.1. 
General Design  
All data for randomized subjects will be presented in data listings by subject number.  For those 
summary tables in which baseline and change from baseline measurements will be presented, the last 
observed measurement prior to the initial dose of KD025 will be considered the baseline 
measurement.   
Continuous data will be described using descriptive statistics: number of observations (n), mean, 
standard deviation, median, minimum and maximum.  Frequencies and percentages will be used for 
summarizing discrete (categorical) data.  When categorical data are presented, the percent will be 
suppressed when the count is zero in order to draw attention to the nonzero counts.  The denominator 
for all percentages, unless otherwise specified, will be the number of subjects in the specified 
analysis population.   
Hypothesis testing, if appropriate, will be carried out at the 5% (2-sided) significance level.  Because 
of the exploratory nature of the study, no adjustments will be made for the multiplicity of endpoints.  
Nonparametric tests may be used in preference to parametric tests if parametric assumptions are 
notably violated.  Missing values will not be imputed.  If a subject does not have sufficient data for a 
particular analysis, they will be excluded from that analysis.  Endpoints defined as an average of 
multiple measurements will be used those data points that are non-missing, and the denominator was 
adjusted accordingly. 
14.2. 
Sample Size Justification  
With 54 subjects in the KD025 Treatment Group and 27 in the BSC Treatment Group, the study has 
over 90% power at the two-sided 0.05 significance level to detect a 20% difference between 
treatment groups at 24 weeks in percent change from baseline in FVC assuming a standard deviation 
in percent change from baseline in FVC of 17%. 
The sample size of 54 subjects receiving KD025 will provide over 90% probability of 1 or more 
subjects in the study experiencing an AE that has an underlying rate of ≥ 5%.    


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14.3. 
Statistical Considerations  
The statistical methodology will be further described in a Statistical Analysis Plan which will be 
finalized prior to database lock. 
14.3.1 
Study Populations  
Three populations will be employed in the analysis of study data: 
 The Safety Population will consist of all subjects who are randomized and receive at least 
1 dose of KD025 (Treatment Group 1) or have Week 1 assessment for BSC subjects. All 
safety analyses will be performed on the safety population 
 The Modified Intent-to-Treat (mITT) Population will consist of all subjects in the Safety 
Population who have evaluable baseline and at least one evaluable post baseline FVC 
assessment. Only evaluable FVC will be used in efficacy. 
 The Per Protocol (PP) Population will consist of all subjects in the safety population who 
have evaluable baseline and evaluable Week 24 FVC assessment. For any analysis on the PP 
Population, for subjects assigned to treatment and actually received treatment, re-calculated 
baseline value should be used for cross over patients. 
The primary and secondary efficacy/activity endpoints will be analyzed using both the mITT and PP 
Populations.  
14.3.2 
Subject Accountability, Demographics, and Baseline Characteristics  
Demographics, subject disposition, and screening and baseline characteristics will be summarized for 
the mITT Population, where appropriate.    
14.3.3 
KD025 Exposure  
For the KD025 Treatment Group, the amount of KD025 administered by visit and overall will be 
tabulated and presented by subject in data listings.  In addition, delays and all other alterations in 
KD025 administration will be presented.  
14.3.4 
Concomitant Medications and Procedures 
Concomitant medications will be coded using WHO Drug Dictionary and the data will be 
summarized by treatment group and presented in tables and listings. Concomitant procedures 
performed during the study will also be collected and presented in listings.  


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14.4. 
Activity/Efficacy Analysis 
The primary efficacy/activity endpoint is the change in FVC from baseline to 24 weeks. A mixed 
model (if numeric stable) or analysis of covariance (ANCOVA) model will be used for the between 
treatment groups comparison of the Week 24 change from baseline in FVC with treatment group as a 
fixed effect and baseline FVC as a covariate.  
The primary safety endpoint is a subject experiencing one or more AEs during the treatment period.  
The percentage of subjects experiencing an AE will be summarized for the KD025 and BSC 
treatment groups (descriptive statistics only). Primary safety analyses will be performed on the safety 
population.    
Secondary Endpoints  
 The change in 6MWD from baseline to 24 weeks  
 Acute exacerbation of IPF throughout the treatment period  
 The change in occurrence, frequency and severity of lung fibrosis as measured by 
quantitative HRCT at baseline and after 24 weeks of treatment  
 To evaluate the percentage of subjects with disease progression before or at 24 weeks 
Treatment group differences in the Week 24 change from baseline to 24 weeks in 6MWD and 
Week 24 change from baseline in severity of lung fibrosis as measured by quantitative HRCT will be 
analyzed by a mixed or ANCOVA model with treatment group as a fixed effect and the 
corresponding baseline value as a covariate.   
The percentage of subjects in each treatment group who experience acute exacerbation of IPF 
throughout the treatment period will be compared by a Fisher’s Exact test.  
Exploratory Endpoints 
 The change in MMP7, CCL18 and SPD serum levels from baseline to 24 weeks  
For each of these exploratory endpoints, a mixed or ANCOVA model will be used to assess treatment 
differences with treatment as a fixed effect and the corresponding baseline value as a covariate. 
14.5. 
Safety Data  
Safety assessments include AEs, SAEs, PEs, vital sign measurements, clinical laboratory evaluations, 
ECGs, and reasons for treatment discontinuation due to toxicity.  
AEs will be coded using the MedDRA dictionary (Version 20.0 or greater.)  The number and 
percentages of subjects experiencing treatment-emergent AEs will be tabulated by SOC and preferred 
term and will be presented by treatment group.  The number of events by preferred term will also be 


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summarized. Tabulation by maximum severity and relationship to KD025 will also be included by 
treatment group.  Summary subject listing will be provided for SAEs, AEs resulting in study 
discontinuation and deaths.  All AEs (including SAEs will be graded using a 5-point scale (mild, 
moderate, severe, life threatening, or death; see Appendix B).  
AEs, SAEs, related AEs, related SAEs, ≥ Grade 3 AEs, related ≥ Grade 3 AEs, and AEs leading to 
withdrawal and treatment discontinuation will be summarized according to treatment group, SOC, 
and preferred terms.  AEs 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 classified using the Toxicity Grading Scale for Healthy Adult and 
summarized by treatment group.  Incidence of laboratory abnormalities will be summarized by 
treatment group. The worst on-study grade after the first dose of study drug will be summarized (or 
after Week 1, Day 1 visit for BSC cohort). 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 by treatment group at each scheduled time 
point using descriptive statistics and included in data listings.  


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15. 
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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16. 
ETHICAL ASPECTS 
16.1. 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH 
E6 Tripartite Guideline (January 1997), 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” or applicable local equivalent. 
16.2. 
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.  The final IRB-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 consent form was accurately explained and understood.  A copy 
of the ICF must be provided to the subject or to the subject’s legally authorized representative.  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. 
16.3. 
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.  This 
board must operate in accordance with the current federal or local regulations.  The Investigator will 


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send a letter or certificate of IRB approval to Kadmon Corporation (or designee) before subject 
enrollment and whenever subsequent modifications to the protocol are made. 
16.4. 
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 25 April 25 2006) and 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. Samples will be held no longer than 10 years from time 
of collection.  No genomic research will be conducted. 


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17. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between a Kadmon 
Corporation representative and the Investigator.  Protocol modifications will be reviewed, and 
approved by Kadmon Corporation representatives. 
All protocol modifications must be submitted to the IRB 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 
(eg, change in monitor, change of telephone number). 


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18. 
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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19. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
19.1. 
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, and governmental approval with correspondence, sample informed consent, 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/activity 
and safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s 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.  
When source documents are required for the continued care of the subject, appropriate copies should 
be made for storing outside of the study site. 
19.2. 
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 problems or governmental queries 
or requests for audit inspections, it is also necessary to have access to the complete study records, 
provided that subject confidentiality is protected. 


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19.3. 
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. 
19.4. 
Electronic Case Report Forms 
Clinical trial data for this study will be captured on 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.  
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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20. 
MONITORING THE STUDY 
It is understood that the responsible Kadmon Corporation 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 that 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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21. 
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 number and not by their names.  The 
subjects’ personal information should be redacted on all source documents prior to submission to 
Kadmon Corporation. The Investigator should keep a subject enrollment log showing subject 
numbers, names, and addresses.  The Investigator should maintain documents not for submission to 
Kadmon Corporation (eg, subjects’ written consent forms) in strict confidence. 


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22. 
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. 


KD025 
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03 March 2020 
 
23. 
REFERENCES 
 
1. Raghu G, Collard HR, Egan JJ, et al.  Committee on Idiopathic Pulmonary Fibrosis:  An 
Official Ats/Ers/Jrs/Alat Statement: Idiopathic Pulmonary Fibrosis: Evidence Based 
Guidelines for Diagnosis and Management. Am J Respir Crit Care Med. 2011; 183(6):788–
824. 
 
2. Selman M, Carrillo G, Estrada A, et al. Accelerated Variant of Idiopathic Pulmonary Fibrosis: 
Clinical Behavior and Gene Expression Pattern. Plos One 2007, 2:E482. 
 
3. Song JW, Hong S-B, Lim C-M, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis: 
Incidence, Risk Factors and Outcome. Eur Respir J 2011; 37(2):356–363. 
 
4. Collard HR, Moore BB, Flaherty KR, et al. Idiopathic Pulmonary Fibrosis Clinical Research 
Network Investigators: Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir 
Crit Care Med. 2007; 176(7):636–643. 
 
5. Renzoni E, Srihari V, Sestini P. Pathogenesis of idiopathic pulmonary fibrosis: review of 
recent findings. F1000Prime Rep. 2014 Aug 1;6:69. doi: 10.12703/P6-69. eCollection 2014. 
Review. 
 
6. Colby T. Pulmonary Pathology: Lc22-1 Diagnosis Of Idiopathic Pulmonary Fibrosis (IPF): 
Histologic and HRCT Diagnosis. Pathology. 2014 Oct;46 Suppl 2:S36. 
 
7. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in 
idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care 
Med 2001;164:1171–1181. 
 
8. American Thoracic Society; European Respiratory Society. Idiopathic pulmonary fibrosis: 
diagnosis and treatment: international consensus statement. Am J Respir Crit Care Med 
2000;161:646–664. 
 
9. Luca Richeldi, M.D., Ph.D. et al.  Efficacy and Safety of Nintedanib in Idiopathic Pulmonary 
Fibrosis. N Engl J Med 2014;370:2071-82. 
 
10. King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial 
of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 
29;370(22):2083-92. 
 
11. Leung 1995, Leung T, Manser E, Tan L, and Lim L.  A novel serine/threonine kinase binding 
the ras-related rhoA GTPase which translocates the kinase to peripheral membranes.  J Biol 
Chem. 49:29051-29054, 1995. 
 
12. Nakagawa 1996 Nakagawa O, Fujisawa K, Ishizaki, et al. ROCK-I and ROCK-II, two 
isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice.  FEBS 
Lett, 2:189-193, 1996. 
 
13. Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H, Jin TH, Desai L, Bernard 
K, Thannickal VJ. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates 


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experimental pulmonary fibrosis. J Clin Invest. 2013 Mar 1;123(3):1096-108. doi: 
10.1172/JCI66700. Epub 2013 Feb 22. 
 
14. De Lauretis A, Renzoni EA. Molecular biomarkers in interstitial lung diseases. Mol Diagn 
Ther. 2014 Oct;18(5):505-22. 
 
15. Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, et al. (2008) MMP1 and MMP7 as 
potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med 5(4): e93. 
 
16. Vii R and Noth, I. Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis. Transl Res. 
2012 April 159(4):218-277. 
 
17. Abstracted from Table E6 online Supplement. 
http://ajrccm.atsjournals.org/content/183/6/788.long 
 
18. CDER-PHRMA-AASLD Conference. Clinical White Paper. Drug-Induced Liver Injury: A 
National and Global Problem.  2000. 
http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm091457.pdf. 
 
19. Dufour, DR, Lott JA, Nolte FS, et al. Diagnosis and Monitoring of Hepatic Injury I, 
Performance Characteristics of Laboratory Tests. Clin Chem. 2000a; 46(12):2027-49. 
 
20. Dufour, DR, Lott JA, Nolte FS, et al. Diagnosis and Monitoring of Hepatic Injury II, 
Recommendations for Use of Laboratory Tests in Screening, Diagnosis, and Monitoring. Clin 
Chem. 2000b;46(12):2050-68. 
 
21. Jones, PW, Quirk FH, Baveystock CM, et al. A self-complete measure of health status for 
chronic airflow limitation.  The St. George's Respiratory Questionnaire.  Am Rev Respir Dis. 
1992;145(6):1321-1327. 
 
 
 
 
 
 
 
 
 


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24. 
APPENDICES  


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Amendment No. 9 
 
 
 
 
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APPENDIX A: 
TABLES FOR GRADING LABORATORY 
ABNORMALITIES 
 
The laboratory values provided in the tables below serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
Note:  For LFT and bilirubin abnormalities, see Section 12.4. 
 
Chemistry* 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Potentially 
Life 
Threatening
Sodium – Hyponatremia 
mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia 
mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia 
mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia 
mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – 
Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
 
100 – 110 
110 – 125 
 
111 – 125 
126 – 200 
 
>125 
>200 
Insulin 
requirements 
or 
hyperosmolar 
coma
Blood Urea 
Nitrogen 
BUN 
mg/dL 
23 – 26 
27 – 31 
> 31 
Requires 
dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or 
requires 
dialysis
Calcium – hypocalcemia 
mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia 
mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – 
hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – 
hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 × 
ULN***
1.6 – 3.0 × ULN 
3.1 –10 × ULN 
> 10 × ULN 
Albumin – Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – 
Hypoproteinemia g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, 
lipase 
1.1 – 1.5 × ULN 
1.6 – 2.0 × ULN 
2.1 – 5.0 × ULN 
> 5.0 × ULN 


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The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters.  Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls 
within a Grade 3 parameter (125-129 mEq/L) should be recorded as a Grade 4 hyponatremia event if the 
subject had a new seizure associated with the low sodium value. 
***ULN” is the upper limit of the normal range. 
 
 
Hematology * 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially 
Life 
Threatening
Hemoglobin (Female) - 
gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from Baseline 
value - gm/dL 
Any decrease – 1.5
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - 
gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from Baseline 
value – gm/dL 
Any decrease – 1.5
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 15,000
15,001 – 20,000
20,001 – 25, 000 
> 25,000
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm3 
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - 
cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 
1501 - 5000 
> 5000 
Hypereosinophilic
Platelets Decreased - 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000
25,000 – 99,000 
< 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 × 
ULN**
1.11 – 1.20 × ULN
1.21 – 1.25 × ULN 
> 1.25 ULN 
PTT – increase by 
factor (partial 
thromboplastin time) 
1.0 – 1.2 × ULN 
1.21 – 1.4 × ULN 
1.41 – 1.5 × ULN 
> 1.5 × ULN 
Fibrinogen increase - 
mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - 
mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or 
associated with 
gross bleeding or 
disseminated 
intravascular 
coagulation (DIC)
* 
 The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters.  Institutional normal reference ranges should be provided to demonstrate that 
they are appropriate. 
**   “ULN” is the upper limit of the normal range. 
 
 
Urine * 
Mild (Grade 1) 
Modera
te 
(Grade 
Severe  
(Grade 3) 
Potentially 
Life 
Threatening
Protein 
Trace 
1+ 
2+ 
Hospitalization 
or dialysis
Glucose 
Trace 
1+ 
2+ 
Hospitalization 
for


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Blood 
(microscopic) – 
red blood cells 
per 
high power field (rbc/hpf) 
1 - 10 
11 – 50 
> 50 and/or 
gross blood 
Hospitalization 
or packed red 
blood cells 
(PRBC) 
transfusion
* 
 The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters.  Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate. 
 
 
 
 
 
 
Abstracted from: 
Food and Drug Administration (FDA). Guidance for Industry.  Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials.  US Department of Health and Human Services, Center 
for Biologics Evaluation and Research. September 2007.  


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APPENDIX B: 
CLINICAL SYMPTOM AND ADVERSE EVENT GRADING 
SCALE 
 
CLINICAL ADVERSE EVENT GRADING 
Severity 
Grade 
Definition 
Mild 
1 
Awareness of symptom, but easily tolerated.  Usually transient 
requiring no special treatment; does not interfere with usual status or 
activities 
 
Moderate 
2 
May be ameliorated by simple therapeutic measures; may interfere 
with usual activities 
 
Severe 
3 
Incapacitating; unable to perform usual activities 
 
Life-threatening 
4 
Requires immediate intervention; need for emergency treatment 
 
Death 
5 
Resulting in the subsequent death of the subject 
 
 
 
 


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APPENDIX C: 
CLINICAL ADVERSE EVENTS: DETERMINING 
RELATIONSHIP TO STUDY DRUG 
 
1 
NOT RELATED 
This category applies to those AEs which, after careful medical consideration, are clearly felt to be 
due to extraneous causes (eg, 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. 
 
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. 


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 
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. 
 
 
Adapted from:  Cobert, B. (2012).  Cobert’s Manual of Drug Safety and Pharmacovigilance (2nd ed.).  
Massachusetts:  Jones & Bartlett Learning, LLC. 
 
 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug relatedness 
clearly exists. 
 


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APPENDIX D: 
CORRECTION FOR HEART RATE (FRIDERICIA)* 
 
The following formula will be used to correct to QT interval: 
 
 
 
Where QTF is the QT interval corrected for heart rate, and RR is the cube root of the interval from 
the onset of 1 QRS complex to the onset of the next QRS complex.  
*Adapted from:  Fridericia LS (1920). "The duration of systole in the electrocardiogram of normal subjects and of 
patients with heart disease." Acta Medica Scandinavica. (53): 469–486. 
 


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APPENDIX E: 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) 
ENGLISH FOR THE U.S.A.22 
 
 
 
 
 
 
 
 
Continued…… 
 
UK/ English (original) version  
 
f:\institut\cultadap\project\gsk1881\question\final versions\sgrqoriq.doc 14/03/03 
 


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Continued…… 
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Continued…… 
 
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Continued…… 
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f:\institut\cultadap\project\gsk1881\question\final versions\sgrqoriq.doc 14/03/03 
 


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Continued… 
 
 
 
 
 
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APPENDIX F: DRUGS THAT INDUCE AND INHIBIT CYP3A4 
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with KD025. 
Table 7: 
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 
Source: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/
ucm093664.htm 
Accessed 5-Apr-18 


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APPENDIX G: DRUGS THAT INDUCE AND INHIBIT CYP1A2 
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with KD025. 
Table 8: 
Examples of Clinical Inducers / Inhibitors of CYP1A2 
 
Strong 
Moderate 
Weak 
Inducers 
- 
Phenytoin 
Rifampin 
Ritonavir 
Smoking 
Teriflunomide 
- 
Inhibitors 
Ciprofloxacin 
Enoxacin 
Fluvoxamine 
Zafirlukast 
Methoxsalen 
Mexiletine 
Oral contraceptives 
 
Acyclovir 
Allopurinol 
Cimetidine 
Peginterferon α-2a 
Piperine 
Zileuton 
Source: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/
ucm093664.htm 
Accessed 5-Apr-18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX H: DRUGS THAT PROLONG QTC 
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with KD025. 
Table 8: 
Examples of Drugs that Prolong QTc 
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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Source: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf  Accessed 4-Jun-18
 
 
 
 

SAP_001.pdf: 
 
Kadmon Corporation 
 
 
KD025-207                                                                                            Statistical Analysis Plan 
 
SAP Version 2, 10-March-2020  
 
 
 
       Page 1 of 29 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the 
Safety, Tolerability, and Activity of KD025 in Subjects with Idiopathic 
Pulmonary Fibrosis (IPF) 
 
Protocol Number: KD025-207 
 
 
 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
 
 
Version 1 
 
29-Jun-2018 
 
Version 2 
 
10-Mar-2020 
 
 
 
 
 
 




 
Kadmon Corporation 
 
 
KD025-207                                                                                            Statistical Analysis Plan 
 
SAP Version 2, 10-March-2020  
 
 
 
       Page 3 of 29 
 
DOCUMENT HISTORY 
 
Version 
Author 
Description 
1.0 
Zhongming Yang 
New Document 
2.0 
Zhongming Yang 
Revision 
The primary reasons for this new version include: 
 Add St. George's Respiratory Questionnaire as 
secondary efficacy endpoint 
 Add options to accommodate the following issues 
for mixed/ANCOVA models: 
o Nonconvergence 
o Validity of linear model assumptions 
 Format and clean list of TLFs 
 Other minor formatting or organization changes 
 
 


 
Kadmon Corporation 
 
 
KD025-207                                                                                            Statistical Analysis Plan 
 
SAP Version 2, 10-March-2020  
 
 
 
       Page 4 of 29 
 
Table of Contents 
1 
INTRODUCTION ................................................................................................ 7 
2 
STUDY SUMMARY ........................................................................................... 7 
2.1 
STUDY OBJECTIVES .................................................................................. 7 
2.2 
STUDY DESIGN ........................................................................................... 8 
2.2.1 
Number of Subjects................................................................................. 8 
2.2.2 
Efficacy Assessments.............................................................................. 8 
2.2.3 
Safety Assessments ............................................................................... 10 
2.2.4 
Pharmacodynamic Assessments ........................................................... 10 
2.2.5 
Study Assessment Summary ................................................................. 10 
3 
STATISTICAL METHODS ............................................................................... 11 
3.1 
General Methods .......................................................................................... 11 
3.1.1 
Computing Environment ....................................................................... 11 
3.1.2 
Reporting of Numerical Values ............................................................ 11 
3.1.3 
Efficacy Analysis Methods ................................................................... 11 
3.1.4 
Hypothesis Testing and Multiplicity Adjustment ................................. 13 
3.1.5 
Baseline Value and Change from Baseline (if applicable) ................... 13 
3.1.6 
Handling of Missing/Incomplete Values .............................................. 13 
3.2 
Analysis Populations .................................................................................... 14 
3.3 
Patients Disposition and Evaluability .......................................................... 14 
3.3.1 
Protocol Deviations ............................................................................... 14 
3.4 
Demographics and Baseline Characteristics ................................................ 15 


 
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3.4.1 
Demographics ....................................................................................... 15 
3.4.2 
Medical History .................................................................................... 15 
3.4.3 
IPF History ............................................................................................ 15 
3.5 
Prior and Concomitant Medications/Procedures .......................................... 15 
3.6 
Treatment Compliance and Exposure .......................................................... 16 
3.6.1 
Exposure to KD025............................................................................... 16 
3.6.2 
Compliance to Study Treatment ........................................................... 16 
3.6.3 
Dose Modifications ............................................................................... 16 
3.7 
Efficacy Analysis ......................................................................................... 16 
3.7.1 
Primary Efficacy Endpoints and Analyses ........................................... 16 
3.7.2 
Secondary Efficacy Endpoints and Analyses ....................................... 17 
3.7.3 
Exploratory Endpoints .......................................................................... 19 
3.8 
Safety Analysis ............................................................................................. 20 
3.8.1 
Adverse Events ..................................................................................... 20 
3.8.2 
Clinical Laboratory Evaluation ............................................................. 20 
3.8.3 
Vital Signs and Other Physical Findings .............................................. 21 
3.8.4 
ECG....................................................................................................... 21 
3.8.5 
Physical Examination............................................................................ 22 
4 
List of Tables, Figures and Listings .................................................................... 22 
Appendix A: Tables for Grading Laboratory Abnormalities ...................................... 26 
Appendix B: References ............................................................................................. 29 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
6MWD 
6- minute walking distance 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
BSC  
standard of care 
CCL-18 
chemokine ligand 18 
CRF  
case report form 
CSR 
clinical study report 
DLCO 
diffusing capacity of carbon monoxide 
FVC 
forced vital capacity 
HLGT 
high level group term 
HRCT 
high-resolution computed tomography  
ICH 
International Conference on Harmonisation  
IPF 
idiopathic pulmonary fibrosis 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
mL 
Milliliter 
MMP7 
matrix metalloproteinase-7 
Msec 
Millisecond 
PE 
physical exam 
PFTs 
pulmonary function tests 
PT 
prothrombin time 
PT 
preferred term 
PTT 
partial thromboplastin time 
QD 
once-daily 
QTcF 
corrected QT interval using Fridericia's formula 
RV 
residual volume 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGRQ 
St. George's respiratory questionnaire 
SOC  
system organ class 
SPD 
surfactant protein-D 
SpO2 
pulse oximeter oxygen saturation  
TEAE 
treatment emergent adverse event 
WHO 
World Health Organization 
 


 
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1 INTRODUCTION 
This study, KD025-207, is being conducted to evaluate the safety, tolerability, and 
activity of 400 mg of KD025 once-daily (QD) compared to best supportive care 
(BSC) in subjects with Idiopathic Pulmonary Fibrosis (IPF) previously treated with or 
offered pirfenidone and/or nintedanib. 
This Statistical Analysis Plan (SAP) describes data-handling and statistical 
procedures to be used for the analysis and reporting of efficacy and safety data 
collected under Study KD025-207 (Amendment 8 20-Sep-2019) and presented in the 
clinical study report (CSR). This SAP has been developed and finalized prior to 
locking the clinical database.  
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 
Primary objectives: 
 To evaluate the change in forced vital capacity (FVC) from baseline to 24 weeks 
after dosing with KD025 400 mg QD in subjects with IPF compared with BSC. 
 
 To evaluate the safety and tolerability of KD025 400 mg QD when administered 
for 24 weeks to subjects with IPF compared to BSC. 
Secondary objectives: 
 To evaluate the change in 6-minute walk distance (6MWD) from baseline to 24 
weeks 
 
 To evaluate the occurrence of acute exacerbation of IPF (frequency and severity) 
throughout treatment 
 
 To evaluate change in severity of lung fibrosis as measured by quantitative high-
resolution computed tomography (HRCT) 
 
 To evaluate the percentage of subjects with disease progression before or at 24 
weeks 
 


 
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 To evaluate the change in score of St. George's Respiratory Questionnaire 
(SGRQ) from baseline to 24 weeks 
Exploratory Objective 
 To evaluate the change in matrix metalloproteinase-7 (MMP7), chemokine ligand 
18 (CCL-18), and surfactant protein-D (SPD) serum levels 
2.2 STUDY DESIGN 
This is a Phase 2, randomized (2:1), open-label, multicenter study in subjects with 
IPF. Eighty-one (81) subjects with IPF who are eligible will be randomly enrolled in 
a 2:1 ratio (KD025 to BSC) to one of two treatment groups. Subjects randomized to 
Treatment Group 1 will receive KD025 400 mg QD orally for 24 weeks. Subjects 
randomized to Treatment Group 2 will receive BSC (as deemed appropriate by the 
investigator).  
Subjects may continue to receive therapy with KD025 beyond week 24, for total 
treatment duration of up to 96 weeks. Subjects receiving BSC (Treatment Group 2) 
have the option of switching to therapy with KD025 at any time during the first 6 
months of the study (up to and including Amendment 5).  Starting from Amendment 
6, subjects receiving BSC have the option to switch to therapy with KD025 after 
week 24. 
2.2.1 Number of Subjects 
Approximately eighty one subjects with IPF. 
2.2.2 Efficacy Assessments 
2.2.2.1 Pulmonary function testing 
Pulmonary function testing will be performed at screening, baseline, then every 12 
weeks on study (12 weeks, 24 weeks, 36 weeks etc.) and at a 30-day Follow-up visit. 
Pulmonary function testing will include FVC, residual volume (RV), and diffusing 
capacity of carbon monoxide (DLCO). 
2.2.2.2 Six minute walking distance (6MWD) 
Six minute walking distance (6MWD) will be assessed at the same times as pulmonary 
function tests (PFTs), in accordance with published guidelines. The total distance 
ambulated in meters during the 6-minute walk is recorded. The 6MWD, heart rate, 
blood pressure, pulse oximeter oxygen saturation (SpO2) are recorded before and after 
the walk. 


 
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2.2.2.3 Occurrence of acute exacerbation of IPF 
Occurrence of acute exacerbation of IPF (frequency and severity) will be assessed 
throughout the study. The following clinical deterioration symptoms within a month 
that cannot be explained by other reasons will be assessed as acute exacerbation: 
1. Aggravated dyspnea; 
2. Newly discovered chest interstitial lung abnormality by radiograph/HRCT, 
without pneumothorax or pleural effusion; 
3. SpO2 decreases to < 88% (heart failure or pulmonary embolism excluded). 
Acute exacerbation can be diagnosed if Items 1 and 2 are present or if Items 1 and 3 
are present and the following AEs have not occurred: 
 Any AE with the Preferred term containing the word “infection”  
 Pulmonary embolism (Preferred Term) 
 Pneumothorax (Preferred Term) 
 Any AE with the Preferred Term containing the word “Cardiac failure”  
If any of these AEs occurred with a start date in the period between the date of the 
IPF assessment and the previous scheduled visit (+ 1 day so as to not include the day 
of the previous visit), the event will not be considered an acute exacerbation of IPF.  
2.2.2.4 The change in severity of lung fibrosis 
The change in severity of lung fibrosis will be determined using measurements from 
quantitative HRCT. 
2.2.2.5 Time to progression of IPF 
Time to progression of IPF is defined as time from the Week 1 Day 1 visit to the first 
occurrence of any of the following:  
1. First respiratory-related hospitalization. 
2. Respiratory-related death. 
3. Absolute decline in FVC percent of predicted value of ≥ 10% versus FVC percent 
of predicted value recorded at baseline. 
4. Absolute decline in DLCO, adjusted for hemoglobin, percent of predicted value of 
≥15% versus DLCO recorded at baseline. 
Note: the following conventions will be used for assessing these criteria: 
First respiratory-related hospitalization 
 Any AE where the High Level Group Term (HLGT) contains the terms 
“respiratory” (case insensitive) and the AE resulted in a hospitalization (as 
determined by the AE Serious Check box “Result in initial or prolonged 
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Respiratory-related death 
 Any AE where the High Level Group Term (HLGT) contains the terms 
“respiratory” (case insensitive) and the AE resulted in a “death”.  
2.2.2.6 St. George’s respiratory questionnaire (SGRQ) 1 
SGRQ is a disease-specific instrument designed to measure impact on overall health, 
daily life, and perceived well-being in patients with obstructive airways disease. 
There are following two parts: a) symptoms component (frequency & severity) with a 
3-month recall; b) activities that cause or are limited by breathlessness; Impact 
components (social functioning, psychological disturbances resulting from airways 
disease) refer to current state as the recall. SGRQ score will be calculated by an 
Excel-based scoring Calculator licensed from St George’s University of London.  
SGRQ scores range from 0 to 100, with higher scores indicating more limitations. 
Based on empirical data and interviews with patients, a mean change score of 4 units 
is associated with slightly efficacious treatment, 8 units for moderately efficacious 
change and 12 units for very efficacious treatment2,3. 
2.2.3 Safety Assessments 
The primary safety outcome will be the percent of subjects in each treatment group 
experiencing AEs. 
Safety assessments include AEs, serious AEs (SAEs), physical exams (PEs), vital sign 
measurements, clinical laboratory evaluations, and ECGs. Reasons for treatment 
discontinuation because of toxicity will be documented. Safety assessments will be 
performed at specified time points and before discharge from the clinic. 
The AE reporting period for a subject enrolled in the study begins when the subject 
signs the informed consent and is continued through 28 days after their last dose of 
KD025. For BSC subjects, AEs will be reported through the End-of-Week 24 visit.  
Vital sign measurements, including blood pressure, pulse rate, respiratory rate, and 
temperature will be monitored throughout the study. 
2.2.4 Pharmacodynamic Assessments 
Serum levels for MMP7, CCL18, and SPD will be assessed at baseline and every 12 
weeks in study.  
2.2.5 Study Assessment Summary 
Detailed study assessments and schedule are listed in Table 1 “Study Assessments” in 
study protocol. 


 
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3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS Version 9.3 or higher for 
Windows. 
3.1.2 Reporting of Numerical Values 
All clinical study data will be presented in patient data listings  
Continuous data will be described using descriptive statistics: number of observations 
(n), mean, standard deviation, median, minimum and maximum. Frequencies and 
percentages will be used for summarizing categorical data. When categorical data are 
presented, the percent will be suppressed when the count is zero in order to draw 
attention to the nonzero counts. The denominator for all percentages, unless otherwise 
specified, will be the number of subjects in the specified analysis population or group. 
Means, medians, standard deviations, and confidence intervals 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. P-values will be 
reported to 4 decimal places. 
3.1.3 Efficacy Analysis Methods 
3.1.3.1 Subgroup analyses 
The following subgroup analyses will be conducted for major efficacy and safety 
endpoints: 
 Prior treatment of either Nintedanib or Pirfenidone   
 Baseline GAP stage  
The GAP model4 consists of four baseline variables: gender (G), age (A) and two 
lung physiology variables (P) (FVC and DLCO). GAP index is the summation of 
individual points from Table 1. Three stages, I, II and III, were identified based on 
the GAP index as defined in the same table. 
 
 


 
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Table 1 Definition of GAP stage 
  
Predictor 
Points 
G 
Gender 
  
  
 
Female 
0 
  
Male 
1 
A 
Age years 
  
  
 
≤60 
0 
 
61-65 
1 
  
>65 
2 
P 
Physiology 
  
  
     FVC % predicted 
 
 
 
>75 
0 
 
50-75 
1 
 
≤50 
2 
     DLCO % predicted 
 
 
 
>55 
0 
 
36-55 
1 
 
≤35 
2 
  
Cannot perform 
3 
Maximum possible index = 8.  Stage is defined according to 
index as I (0-3), II (4-5), III (6-8). 
 
3.1.3.2 Mixed model 
The following mixed model will be used to estimate and compare rate of change from 
baseline for FVC percent of predicted value, FVC (mL), 6MWD and other applicable 
endpoints 
𝑦𝑖(𝑡) = 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝛼∙𝑦𝑖(0) + ∆𝑦𝐵𝑆𝐶∙𝐵𝑆𝐶∙𝑡+ ∆𝑦𝐾𝐷∙𝐾𝐷∙𝑡+ ∆𝑦𝑠𝑓∙𝑠𝑓∙𝑡+
𝑎𝑖+ 𝑏𝑖∙𝑡+ 𝜀𝑖(𝑡)  
where,  
 t is weeks since baseline or cross over 
 ∆𝑦𝑥  is the change rate of efficacy endpoint y caused by factor x 
 BSC and KD is treatment indicator 
 i is the patient id 
 sf is the categorical variable for subgroup factor  
 a and b are random effects dual to individual patient 
 𝜀𝑖(𝑡) is the random error  


 
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Treatment effect will be calculated by point estimate, 95% confidence interval and p 
value of ∆𝑦𝐾𝐷, ∆𝑦𝐵𝑆𝐶 𝑎𝑛𝑑  ∆𝑦𝐾𝐷−∆𝑦𝐵𝑆𝐶.  
 
If there is a convergent issue due to small sample size, following approaches should be 
tried sequentially: 
 Use ANCOVA model 
 
𝑦𝑖(𝑡) = 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝛼∙𝑦𝑖(0) + ∆𝑦𝐵𝑆𝐶∙𝐵𝑆𝐶∙𝑡+ ∆𝑦𝐾𝐷∙𝐾𝐷∙𝑡+ ∆𝑦𝑠𝑓∙𝑠𝑓∙𝑡 
 
 Use ANCOVA model 
 
𝑦𝑖(𝑡) = 𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡+ 𝛼∙𝑦𝑖(0) + ∆𝑦𝐵𝑆𝐶∙𝐵𝑆𝐶∙𝑡+ ∆𝑦𝐾𝐷∙𝐾𝐷∙𝑡 
 
If the linear model assumptions are not satisfied through residual analyses, only 
descriptive statistics will be provided.  
 
3.1.3.3 Proportion Difference 
Proportion difference and its confidence interval will be calculated with Wilson 
(score) method.   
3.1.4 Hypothesis Testing and Multiplicity Adjustment   
This study is designed as an exploratory, proof-of-concept study, and p values serve as 
tools for exploration rather than strict criteria for accepting or rejecting various 
hypotheses. There will be no multiplicity adjustment.   
3.1.5 Baseline Value and Change from Baseline (if applicable)  
Baseline value is defined as the average of screening and week 1 most recent non-
missing value obtained immediately prior to randomization (i.e., generally the study 
day 1 assessment which occurs pre-randomization) if their visit dates are 28 or fewer 
days apart, otherwise is defined as the week 1 most recent non-missing value. The 
crossover baseline value is defined as the average of the last BSC value and cross over 
W1D1 value if their visit dates are 28 or fewer days apart, otherwise is defined as the 
cross over W1D1 value.  
3.1.6 Handling of Missing/Incomplete Values 
Unless otherwise explicitly specified, missing data will not be imputed; observed cases 
will be used in the analyses. 


 
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3.2 Analysis Populations 
Three populations will be employed in the analysis of study data: 
 The safety population will consist of all subjects who are randomized and receive 
at least 1 dose of KD025 (Treatment Group 1) or have week 1 assessment for BSC 
subjects. All safety analyses will be performed on the safety population. 
 
 The modified intent-to-treat (mITT) population will consist of all subjects in the 
safety population who have evaluable baseline and at least one evaluable post 
baseline FVC assessment. Only evaluable FVC will be used in efficacy.  
 
 The per-protocol (PP) population will consist of all subjects in the safety 
population who have evaluable baseline and evaluable week 24 FVC assessment. 
For any analysis on per-protocol population, patient should assigned to treatment 
actually received, and re-calculated baseline value should be used for cross over 
patients.    
 
There will be following four treatment groups in all descriptive efficacy and safety 
tables except otherwise specified. 
1. KD025 as randomized 
2. BSC as randomized 
3. ALL KD025 treated: KD025 as randomized and KD025 data for crossed over 
subjects after cross over 
4. BSC without cross over: data for those randomized to BSC up to the point of 
cross over 
3.3 Patients Disposition and Evaluability 
A disposition of all enrolled subjects will be provided. This will include the number 
and percentage of patients evaluated for each of the analysis populations (Section 3.2) 
by treatment group and overall.  The number of patients discontinuing from the study 
and the primary reason for discontinuation will also be summarized.  
3.3.1 Protocol Deviations 
A listing of protocol deviations will be presented by treatment group.  


 
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3.4 Demographics and Baseline Characteristics 
3.4.1 Demographics 
Patient demographics and baseline characteristics will be summarized for the safety 
Populations.  
Descriptive statistics will be provided for age, height, weight, and body mass index 
Frequencies and percentages will be tabulated for sex, race, and ethnicity.  
Age will be calculated as (informed consent date – date of birth + 1)/365.25, truncated 
and displayed as years. BMI will be calculated as weight (kg)/height2 (m2), using the 
weight and height measurements obtained at baseline (or screening if missing at 
baseline).  
3.4.2 Medical History 
Medical history will be collected and summarized by treatment group and overall for 
mITT population. 
3.4.3 IPF History 
The following IPF history will be summarized by treatment group and overall for 
safety population: 
 Smoking history 
 Time since diagnosis 
 Prior pirfenidone 
 Prior nintedanib 
 FVC decline in 1 year prior to randomization (by mixed model and descriptive 
statistics) 
 Presence of aggravated dyspnea within the previous 6 months prior to signing 
of informed consent? (yes/no) 
 
3.5 Prior and Concomitant Medications/Procedures 
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary and the data will be summarized by treatment group and presented in tables 
and listings. Incidence of prior and concomitant medication will be presented by 
preferred (generic) drug name for each treatment group and overall. 
 
Prior medications are those that started and stopped before randomization; 
concomitant medications are all medications taken after randomization, during the 
study period, including those started before but ongoing at randomization. Where a 


 
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medication start date is partially or fully missing, and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that it is concomitant. 
3.6 Treatment Compliance and Exposure 
3.6.1 Exposure to KD025 
The number of days on study will be calculated as last visit date – first visit date + 1. 
The exposure to KD025will be calculated by the number of days on study treatment 
(last dose date – first dose date + 1). Descriptive statistics of days on study and overall 
exposure will be tabulated and presented by subject in data listings.  
3.6.2 Compliance to Study Treatment 
Compliance with study drug will presented for the KD025 treatment group and cross 
over patients.  
Compliance rates will be derived with the following formula:  
100* ((Total days in study  – days missed dose)/ (Total days in study)).  
Descriptive statistics of compliance rates will be tabulated and presented by subject in 
data listings. 
3.6.3 Dose Modifications 
The incidence of dose modifications for the KD025 treatment group will be 
summarized, including the percentage of dose reductions, drug holds, and reasons for 
dose modifications.  
3.7 Efficacy Analysis 
3.7.1 Primary Efficacy Endpoints and Analyses 
3.7.1.1 W24 FVC (Volume, mL) 
 The change from baseline to W24, using data up to and including W24 and 
using the mixed model described in section 3.1.3.2, will be reported for each 
group defined in section 3.2 
 The difference in the change from baseline at W24 will be analyzed for the 
following: 
 Groups 3 (All KD025 treated) and Group 4 (BSC without crossover) 
 Groups 1 (KD025 as randomized) and Group 4 


 
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3.7.1.2 W24 FVC (% predicted) 
The analyses described in section 3.7.1.1 for FVC (Volume, mL) will be repeated for 
FVC (% predicted) 
3.7.2 Secondary Efficacy Endpoints and Analyses 
3.7.2.1 FVC (Volume, mL) 
 The change from baseline to W48 and W96, using data up to and including 
W48 and W96 respectively and using the mixed model described in section 
3.1.3.2, will be reported for groups 1 and 3. 
3.7.2.2 FVC (% predicted) 
 The analyses described in section 3.7.2.1 for FVC (Volume, mL) will be 
repeated for FVC (% predicted) 
 The proportion of subjects with ≥5% and ≥10% declines in FVC %predicted 
from baseline to week 24 will be reported for each group defined in section 
3.2.  
 The differences in the proportions will be analyzed for the following: 
i. Group 3 and Group 4  
ii. Group 1 and Group 4 
 The proportion of subjects with ≥5% and ≥10% declines in FVC %predicted 
from baseline to W48 and W96 will be reported for groups 1 and 3 
3.7.2.3 6MWD 
 The change from baseline to W24, using data up to and including W24 and 
using the mixed model described in section 3.1.3.2, will be reported for each 
group defined in section 3.2 
 The difference in the change from baseline at W24 will be analyzed for 
the following: 
i. Group 3 and Group 4  
ii. Group 1 and Group 4 
 The proportion of subjects with ≥50m declines in 6MWD from baseline to 
week 24 will be reported for each group defined in section 3.2.  
 The differences in the proportions will be analyzed for the following: 
i. Group 3 and Group 4  
ii. Group 1 and Group 4 
 The change from baseline to W48 and W96, using data up to and including 
W48 and W96 respectively and using the mixed model described in section 
3.1.3.2, will be reported for groups 1 and 3. 
 The proportion of subjects with ≥50m declines in 6MWD from baseline to 
W48 and W96 will be reported for groups 1 and 3. 


 
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3.7.2.4 DLco (Corrected for Hemoglobin) 
The analyses described in section 3.7.2.3 for 6MWD will be repeated for hemoglobin 
corrected  DLco  
DLCO Predicted Corrected = DLCO Predicted * (1.7 * Hgb /(Age-Sex-Factor + Hgb)) 
where, Age-Sex-Factor is 
 9.38 for females of any age, and children less than 15 years old 
 10.22 for males 15 years old or older 
The cutoff criterion for proportion calculation uses 15% decline instead of 50m 
decline.   
 
3.7.2.5 Lung Fibrosis as Measured by Quantitative HRCT 
 The change from baseline to W24, using data up to and including W24 and 
using the mixed model described in section 3.1.3.2, will be reported for each 
group defined in section 3.2 
 The difference in the change from baseline at W24 will be analyzed for 
the following: 
i. Group 3 and Group 4  
ii. Group 1 and Group 4 
 The change from baseline to W48 and W96, using data up to and including 
W48 and W96 respectively and using the mixed model described in section 
3.1.3.2, will be reported for groups 1 and 3. 
 
3.7.2.6 Descriptive statistics for FVC, 6MWD, DLco 
Descriptive statistics (n, mean, std, median, min, max) of FVC, 6MWD and DLco, and 
their change from baseline will be tabulated by treatment group and study visits  
For proportions, descriptive statistics (n, %) will also be tabulated by treatment groups 
and total.   
 
3.7.2.7 Descriptive statistics for lung fibrosis throughout the treatment 
period 
 
Descriptive statistics (n, mean, std, median, min, max) in severity of lung fibrosis as 
measured by quantitative HRCT (total fibrosis, reticular abnormality, honeycombing 
scores) on baseline, week 24, 48 and 96 and change from baseline will be summarized 
by treatment group. 
 


 
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3.7.2.8 Acute exacerbation of IPF throughout the treatment period 
The incidence of patients who had an acute exacerbation of IPF throughout the 
treatment period by study visit will be presented by treatment group and will be 
compared by means of a Fisher’s exact test on week 24.  
 
Kaplan Meier curves and descriptive statistics will also be used to summarize time to 
IPF exacerbation.     
 
3.7.2.9 Time to IPF progression 
Kaplan-Meier curves and descriptive statistics will be used to summarize time to 
disease progression. Log-rank test will be used for comparing treatment difference. 
BSC patients will be censored on cross over.   
 
3.7.2.10 Time to first respiratory-related hospitalization 
Kaplan-Meier curves and descriptive statistics will be used to summarize first 
respiratory-related hospitalization. Log-rank test will be used for comparing treatment 
difference. BSC patients will be censored on cross over. 
 
3.7.2.11 Time to respiratory-related death 
Kaplan-Meier curves and descriptive statistics will be used to summarize respiratory-
related death. Log-rank test will be used for comparing treatment difference. BSC 
patients will be censored on cross over. 
 
3.7.2.12 SGRQ 
Descriptive statistics (n, mean, std, median, min, max) of SGRQ scores on 
baseline, week 12, 24, 48 and 96 and change from baseline will be summarized by 
treatment group. 
 
3.7.3 Exploratory Endpoints 
Descriptive statistics (n, mean, std, median, min, max) of MMP7, CCL18 and SPD 
will be tabulated by treatment group and study visit.  


 
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3.8 Safety Analysis 
Safety assessments include AEs, serious adverse events (SAEs), PEs, vital sign 
measurements, clinical laboratory evaluations, ECGs, and reasons for treatment 
discontinuation due to toxicity.  
3.8.1 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (Version 20.0 or greater). The number and percentages of subjects 
experiencing treatment-emergent AEs will be tabulated by system-organ class and 
preferred term and will be presented by treatment group. The number of events by 
preferred term will also be summarized. Tabulation by maximum severity and 
relationship to KD025 will also be included by treatment group. Summary subject 
listing will be provided for SAEs, AEs resulting in study discontinuation and deaths. 
All AEs (including SAEs will be graded using a 5-point scale (mild, moderate, severe, 
life threatening, or death). 
Treatment emergent adverse events (TEAEs) are any adverse events occurring or 
worsening in severity after the first administration of study medication or 
randomization (for BSC patients).  The TEAE incidence will be presented by 
treatment group.   
The number and percentage of patients who experienced at least one TEAE as well as 
the number and percentage of patients who experienced each specific system organ class 
(SOC) and preferred term (PT) will be presented.  For the presentation of AE 
incidences, the SOCs will be sorted alphabetically, and within SOC, the PT will be 
used and presented by decreasing total frequency. Separate tables will be provided for 
patients with adverse events occurring with an incidence in preferred term greater than 
5% (in at least one treatment arm) and presented by decreasing total frequency, 
TEAEs, SAEs, related TEAEs, related SAEs, ≥ Grade 3 TEAEs, related ≥ Grade 3 
TEAEs, and TEAEs leading to withdrawal and treatment discontinuation will be 
summarized according to treatment group, system-organ-class, and preferred terms.  
AEs will also be presented in listings. Duration of AEs will be determined and 
included in listings, along with action taken and outcome. 
The AE summaries will be presented for the 24 week Treatment Period as well as the 
entire treatment duration. 
3.8.2 Clinical Laboratory Evaluation 
The summary statistics (including number, mean, standard deviation, median, 
minimum and maximum) of all laboratory variables and changes from baseline will be 
calculated for each visit or study assessment by treatment group. For parameters of 
white blood cell counts, neutrophils (absolute count), lymphocytes (absolute count), 


 
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monocytes (absolute count), hemoglobin, platelets, ALP, ALT, aspartate 
aminotransaminase, gamma glutamyl transferase, total bilirubin, glomerular filtration 
rate, plots of mean/mean changes from baseline with the corresponding standard error 
will be displayed. 
 
Laboratory results will be classified using the Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (as 
described in study Appendix A) and summarized by treatment group. Incidence of 
laboratory abnormalities will be summarized by treatment group. The worst on-study 
grade after the first dose of study drug will be summarized (or after Week 1, Day 1 
visit for BSC cohort).  
 
The incidence of ≥ Grade 3 laboratory abnormalities under treatment and shifts in 
toxicity grading from baseline to highest grade post-baseline will be displayed for both 
the 24 week Treatment Period and the entire study duration. 
  
Summaries of the observed and change from baseline values at each scheduled 
assessment time-point will also be presented.  
 
3.8.3 Vital Signs and Other Physical Findings 
Descriptive statistics for vital signs (i.e. heart rate, body temperature, and blood 
pressure) values and the change from baseline will be presented by treatment group 
and overall for each scheduled assessment time point. 
3.8.4 ECG 
Descriptive statistics for ECG parameters (i.e., heart rate (HR), PR interval, RR 
interval, QRS interval, QT interval, and QTcF interval) at each scheduled assessment 
time point will be presented for the values and change from baseline scores (note: 
Fridericia’s correction:  QTcF = QT/RR(1/3)).  
The number and percentage of subjects having observed QTcF values that satisfy the 
following conditions will be presented by treatment group and study visit: 
 < 450 msec  
 450 to 500 msec 
 > 500 msec. 
The number and percentage of subjects having change from baseline QTcF values that 
satisfy the following conditions will be presented by treatment group and study visit: 


 
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 ≤ 0 msec 
 >0 to ≤ 30 msec 
 >30 to ≤ 60 msec 
 > 60 msec. 
The 2 analyses will also be repeated using QT instead of QTcF.  
3.8.5 Physical Examination 
The complete set physical examination findings will be provided in listings. Clinically 
significant physical examination abnormalities will be included and summarized as 
AEs if appropriate.  
4 List of Tables, Figures and Listings 
 
Table 2 lists demographic and baseline characteristics TLFs; Table 3 lists treatment 
exposure and concomitant medication TLFs; Table 4 lists efficacy TLFs; and Table 5 
lists safety TLFs. 
Table 2.  Demographics and Baseline Characteristics TLFs 
T/F/L 
Title 
Population 
T 
Patient disposition and analysis population 
All randomized 
patients 
L 
Patient disposition  
mITT 
L 
Protocol deviations 
All randomized 
patients 
T 
Demographics 
mITT 
L 
Demographics and baseline characteristics  
mITT 
T 
Medical history  
mITT 
L 
Medical history 
mITT 
T 
IPF history 
mITT 
L 
IPF history 
mITT 
T 
Prior medications  
mITT 
 
Table 3.  Treatment Exposure and Concomitant Medication TLFs 
T/F/L Title 
Population 
T 
Concomitant medications 
mITT 
L 
Concomitant medications  
mITT 
T 
Treatment exposure and compliance - 24 week treatment period 
mITT 
L 
Treatment exposure and compliance  
mITT 


 
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T/F/L Title 
Population 
T 
Dose modifications - 24 week treatment period 
mITT 
L 
Dose modifications  
mITT 
T 
Treatment exposure and compliance - entire treatment duration 
mITT 
T 
Dose modifications - entire treatment duration 
mITT 
 
Table 4.  Efficacy TLFs 
T/F/L 
Title 
Population 
T 
24 week change from baseline on FVC (ml)   
mITT 
T 
24 week change from baseline on FVC % of predicted value  
mITT 
T 
48, 72, 96 week change from baseline on FVC (ml)   
mITT 
T 
48, 72, 96 week change from baseline on FVC % of predicted value  
mITT 
T 
FVC % predicted value decrease from baseline >=5% within 24 weeks  mITT 
T 
FVC % predicted value decrease from baseline >=10% within 24 
weeks 
mITT 
T 
FVC % predicted value decrease from baseline >=5% within 48, 72, 
96 weeks  
mITT 
T 
FVC % predicted value decrease from baseline >=10% within 48, 72, 
96 weeks 
mITT 
T 
Change from baseline on FVC (ml)  
mITT 
F 
Mean (SD) Profiles for FVC (ml) change from baseline by group - 
Linear scale 
mITT 
T 
Change from baseline on FVC % of predicted value  
mITT 
F 
Mean (SD) Profiles for FVC % of predicted value change from 
baseline by group - Linear scale 
mITT 
T 
24 week change from baseline on 6MWD 
mITT 
T 
48, 72, 96 week change from baseline on 6MWD  
mITT 
T 
6MWD decrease >=50 meters within 24 weeks  
mITT 
T 
6MWD decrease >=50 meters within 48, 72, 96 weeks  
mITT 
T 
Change from baseline on 6MWD  
mITT 
F 
Mean (SD) Profiles for 6MWD change from baseline by group - 
Linear scale 
mITT 
T 
24 week change from baseline on Dlco (%)  
mITT 
T 
48, 72, 96 week change from baseline on Dlco (%)  
mITT 
T 
24 week change from baseline on Dlco (%) <= -15%  
mITT 
T 
48, 72, 96 week change from baseline on Dlco (%) <= -15%  
mITT 
T 
Change from baseline on Dlco (%)   
mITT 
F 
Mean (SD) Profiles for DLco (%) change from baseline by group - 
Linear scale 
mITT 
L 
Efficacy measurements  
mITT  
T 
Time to acute exacerbation of IPF 
mITT 
F 
Kaplan Meier Plot of Time to acute exacerbation of IPF 
mITT 
T 
Time to IPF progression 
mITT 


 
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T/F/L 
Title 
Population 
T 
Time to first respiratory-related hospitalization 
mITT 
F 
Kaplan Meier Plot of Time to first respiratory-related hospitalization 
mITT 
T 
Time to respiratory-related death 
mITT 
F 
Kaplan Meier Plot of Time to respiratory-related death 
mITT 
L 
Time to event endpoints 
mITT 
T 
Change from baseline on lung fibrosis (HRCT)  
mITT 
F 
Mean (SD) Profiles for lung fibrosis (HRCT) change from baseline by 
group - Linear scale 
mITT 
T 
Change from baseline on SGRQ score   
mITT 
F 
Mean (SD) Profiles for SGRQ score change from baseline by group - 
Linear scale 
mITT 
T 
Change from baseline on MMP7 (ug/L)    
mITT 
F 
Mean (SD) Concentration Profiles for MMP7 (ug/L) change from 
baseline by group - Linear scale 
mITT 
T 
Change from baseline on CCL18 (ng/L)   
mITT 
F 
Mean (SD) Concentration Profiles for CCL18 (ng/L) change from 
baseline by group - Linear scale 
mITT 
T 
Change from baseline on SPD (ug/L) 
mITT 
F 
Mean (SD) Concentration Profiles for SPD (ug/L) change from 
baseline by group - Linear scale 
mITT 
 
Table 5.  Safety TLFs 
T/F/L 
Title 
Population 
T 
Overall summary of TEAEs - 24 week treatment period   
Safety 
T 
TEAEs by SOC and PT - 24 week treatment period  
Safety 
T 
Serious TEAEs by SOC and PT - 24 week treatment period 
Safety 
T 
Related TEAEs by SOC and PT - 24 week treatment period  
Safety 
T 
Related Serious TEAEs by SOC and PT - 24 week treatment period 
Safety 
T 
Grade 3 and 4 TEAEs by SOC and PT - 24 week treatment period  
Safety 
T 
Related Grade 3 and 4 TEAEs by SOC and PT - 24 week treatment 
period 
Safety 
T 
TEAEs leading to treatment discontinuation by SOC and PT - 24 week 
treatment period  
Safety 
T 
Related TEAEs leading to treatment discontinuation by SOC and PT - 
24 week treatment period 
Safety 
T 
Related TEAEs occuring in >=1% patients by PT - 24 week treatment 
period 
Safety 
T 
TEAEs occuring in >=5% patients by PT - 24 week treatment period 
Safety 
T 
TEAEs by PT and maximum severity - 24 week treatment period 
Safety 
L 
Overall summary of TEAEs - entire treatment duration 
Safety 
T 
TEAEs by SOC and PT - entire treatment duration 
Safety 
T 
Serious TEAEs by SOC and PT - entire treatment duration 
Safety 


 
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T/F/L 
Title 
Population 
T 
Related TEAEs by SOC and PT - entire treatment duration 
Safety 
T 
Related Serious TEAEs by SOC and PT - entire treatment duration 
Safety 
T 
Grade 3 and 4 TEAEs by SOC and PT - entire treatment duration 
Safety 
T 
Related Grade 3 and 4 TEAEs by SOC and PT - entire treatment 
duration 
Safety 
T 
TEAEs leading to treatment discontinuation by SOC and PT - entire 
treatment duration 
Safety 
T 
Related TEAEs leading to treatment discontinuation by SOC and PT - 
entire treatment duration 
Safety 
T 
Related TEAEs occuring in >=1% patients by PT - entire treatment 
duration 
Safety 
T 
TEAEs occuring in >=5% patients by PT - entire treatment duration 
Safety 
T 
TEAEs by PT and maximum severity - entire treatment duration 
Safety 
L 
Adverse events 
Safety 
L 
Serious Adverse events 
Safety 
L 
Grade 3 and 4 Adverse events 
Safety 
L 
Death 
Safety 
T 
Change from baseline on lab values 
Safety 
T 
Shifts in toxicity grading from baseline to highest grade post-baseline 
of laboratory abnormalities - 24 week treatment perio 
Safety 
T 
Shifts in toxicity grading from baseline to highest grade post-baseline 
of laboratory abnormalities - entire treatment duration 
Safety 
L 
Lab values with CTC grade >= 3 
Safety 
T 
Change from baseline on vital signs 
Safety 
L 
Vital signs 
Safety 
T 
Change from baseline on ECG parameters 
Safety 
T 
QTcF abnormalities 
Safety 
L 
ECG values 
Safety 
 
 


 
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Appendix A: Tables for Grading Laboratory Abnormalities  
The laboratory values provided in the tables below serve as guidelines and are 
dependent upon institutional normal parameters. Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate. 
 
Grading of Liver-Related Laboratory Abnormalities 
FEATURE 
Grade  1 
Grade 2 
Grade 3 
Grade 4 
ALT 
> ULN-3.0 ULN 
> 3.0-5.0 ULN 
> 5.0-20 ULN 
> 20 ULN 
AST 
> ULN-3.0 ULN 
> 3.0-5.0 ULN 
> 3.0-10 ULN 
> 10 ULN 
Alkaline 
Phosphatase 
> ULN - 2.5 × ULN 
> 2.5 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20 ULN 
GGT 
> ULN - 2.5 × ULN 
> 2.5 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20 × ULN 
Bilirubin 
> ULN - 1.5 × ULN 
> 1.5 - 3.0 × ULN 
> 3.0 - 10.0 × ULN 
> 10.0 × ULN 
ALT = Alanine aminotransferase; AST = aspartate aminotransferase; GGT = Gamma-glutamyl 
transferase; ULN = upper limit of normal 
 
Chemistry* 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening (Grade 4)** 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia 
mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
 
100 – 110 
110 – 125 
 
111 – 125 
126 – 200 
 
>125 
>200 
Insulin requirements or 
hyperosmolar coma 


 
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Chemistry* 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening (Grade 4)** 
Blood Urea Nitrogen BUN 
mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – 
hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 × 
ULN*** 
1.6 – 3.0 × 
ULN 
3.1 –10 × 
ULN 
> 10 × ULN 
Albumin – Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, 
lipase 
1.1 – 1.5 × 
ULN 
1.6 – 2.0 × 
ULN 
2.1 – 5.0 × 
ULN 
> 5.0 × ULN 
The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters.  Institutional normal reference ranges should be provided 
to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in 
characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). 
For example, a low sodium value that falls within a Grade 3 parameter (125-129 mEq/L) 
should be recorded as a Grade 4 hyponatremia event if the subject had a new seizure 
associated with the low sodium value. 
***”ULN” is the upper limit of the normal range. 
 
 


 
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Hematology * 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially 
Life 
Threatening 
Hemoglobin (Female) - 
gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from Baseline 
value - gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - 
gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from Baseline 
value – gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25, 000 
> 25,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm3 
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - 
cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 
1501 - 5000 
> 5000 
Hypereosinophilic 
Platelets Decreased - 
cell/mm3 
125,000 – 140,000 
100,000 – 
124,000 
25,000 – 99,000 
< 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 × 
ULN** 
1.11 – 1.20 × 
ULN 
1.21 – 1.25 × 
ULN 
> 1.25 ULN 
PTT – increase by 
factor (partial 
thromboplastin time) 
1.0 – 1.2 × ULN 
1.21 – 1.4 × ULN 1.41 – 1.5 × ULN 
> 1.5 × ULN 
Fibrinogen increase - 
mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - 
mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or 
associated with 
gross bleeding 
or disseminated 
intravascular 
coagulation 
(DIC) 
* 
 The laboratory values provided in the tables serve as guidelines and are dependent 
upon institutional normal parameters.  Institutional normal reference ranges 
should be provided to demonstrate that they are appropriate. 
**   “ULN” is the upper limit of the normal range. 
 
 


 
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Urine * 
Mild  
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic) – red blood 
cells per high power field 
1 – 10 
11 – 50 
> 50 and/or 
gross blood 
Hospitalization or packed 
red blood cells (PRBC) 
transfusion 
* 
 The laboratory values provided in the tables serve as guidelines and are 
dependent upon institutional normal parameters.  Institutional normal reference 
ranges should be provided to demonstrate that they are appropriate. 
 
 
Abstracted from: Food and Drug Administration (FDA). Guidance for 
Industry.  Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials.  US Department of Health and Human 
Services, Center for Biologics Evaluation and Research. 
September 2007.  
Appendix B: References 
 
1. American Thoracic Society, St. George's Respiratory Questionnaire (SGRQ) 
(https://www.thoracic.org/members/assemblies/assemblies/srn/questionaires/sg
rq.php) 
2. Jones PW and the Nedocromil Sodium Quality of Life Study Group. Quality of 
life, symptoms, and pulmonary function in asthma: long-term treatment with 
nedocromil sodium examined in a controlled multicentre trial. Eur Respir J 
1994, 7:55-62. 
3. Jones PW. Interpreting thresholds for a clinically significant change in health 
status in asthma and COPD. Eur Respir J. 2002 Mar, 19(3):398-404. 
4. Kolb M, Collard HR, Staging of idiopathic pulmonary fibrosis: past, present 
and future. European Respiratory Review, 2014, 23:220-224.