Open-label, 2-part Study Designated to Assess the Absolute Bioavailability of KD025 and to Determine the Mass Balance Recovery, Metabolite Profile and Identification of Metabolite Structures for [14C]-KD025 in Healthy Male Subjects
Phase: PHASE1
Conditions: Autoimmune Diseases, Fibrosis
Sponsor: Kadmon Corporation, LLC

 
 
Protocol Number:  KD025-108 
 
Document Title:  An Open-label, Two-part Study Designed to Assess the Absolute 
Bioavailability of KD025 and to Determine the Mass Balance Recovery, 
Metabolite Profile and Identification of Metabolite Structures for [14C]-KD025 in 
Healthy Male Subjects 
 
Version Number:  1.0 
 
Date of Document:  17 Jan 2019 
 
NCT Number:  NCT03907540 

Quotient Sciences 
CLINICAL STUDY PROTOCOL 
An open-label, two-part study designed to assess the absolute 
bioavailability of KD025 and to determine the mass balance 
recovery, metabolite profile and identification of metabolite 
structures for [14q-KD025 in healthy male subjects 
Quotient Study Number: 
Sponsor Study Number: 
EudraCT Number: 
Clinical Study Site: 
QSC200323 
KDO25-108 
2018-004773-28 
Quotient Sciences Limited 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 
Sponsor: 
Kadmon Corporation LLC 
450 East 29th Street 
New York 
NY 10016 
Tel. +1(212) 308-6000 
Date of Protocol: 
Status of Protocol: 
17 JAN 2019 
Version 1.0 
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL 
This clinical protocol may not be reproduced or communicated to a third party 
without the written permission of Kadmon Corporation LLC. 
PRS005 Ti v17.0 26 Nov 2018 

Sponsor/Quotient Sciences Confidential 
Study Contacts 
Principal Investigator: 
Sub-Investigators: 
Programme Manager: 
Project Manager: 
Study Monitor: 
Medical Monitor: 
Pharmacovigilance 
Provider: 
ARSAC Practitioner 
Nand Singh BSc, MD, DPM, MFPM 
Quotient Sciences Limited 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Sharan Sidhu MBChB, BAO, MRCS, MFPM 
Philip Evans MBChB, MRCS (Ed) 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Litza McKenzie MBChB, BScMedSci 
Martina Fieldingova MD 
Dan Hamzea MD 
Elizabeth Maria van Niekerk MBChB, DipPalMed 
Somasekhara Menakuru MBBS, MS, MRCS 
Jonathan Whitton BMBS, BSc, MRCS, PGcert 
Naila Aslam BSc, MBBS, MRCPCH 
Quotient Sciences Limited 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Sue Melbourne PGCert, DipNurs 
Quotient Sciences Limited 
+44 (0)115 931 5120 
Samantha Gott BSc (Hons) 
Quotient Sciences Limited 
Tel: +44 (0)115 974 9000 
Mat Dawson 
Stoneygate Clinical Research Ltd 
260 Kimberley Road 
Leicester 
LE2 1LJ 
Sanjay K Aggarwal, MB BChir (Cantab) MRCP (UK) 
Kadmon Corporation, LLC 
55 Cambridge Parkway 
Cambridge, MA 02142, USA 
Tel: +1-724-778-6129 
Tel (mobile): +1-857-253-8642 
Kadmon Corporation, LLC 
450 East 29th Street 
New York 
NY 10016 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Tel: +44 (0)115 974 9000 
Email: stuart.mair@quotientsciences.com  
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Central Laboratory: 
Metabolism 
Laboratory: 
AMS Laboratory: 
The Doctors Laboratory 
The Halo Building 
1 Mabledon Place 
London WC1H 9AX 
Covance Laboratories Ltd 
FAO Sample Management 
Otley Road 
Harrogate, North Yorkshire 
HG3 1PY 
UK 
Tel: +44 (0)142 350 0011 
Pharmaron 
Pegasus Way 
Crown Business Park 
Rushden 
Northamptonshire 
NN10 6ER 
UK 
Tel:+44 (0)1933 319 970 
Xceleron Inc., A Pharmaron Company 
20340 Seneca Meadows Parkway 
Germantown, MD 20876 
USA 
Tel: +1 240 361 1901 
Bioanalytical 
Laboratory: 
7 
1 
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Sponsor/Quotient Sciences Confidential  
Signatures for Quotient 
CONFIDENTIALITY AND GCP COMPLIANCE STATEMENT  
I confirm that I have read and that I understand this protocol, the Investigator's Brochure, 
and any other product information provided by the sponsor. I agree to conduct this study 
in accordance with the requirements of this protocol and also protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation E6 (R2) Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws 
and regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 16.3 
of this protocol. 
Information taken from the study protocol may not be disseminated or discussed with a 
third party without the express consent of the sponsor. 
Nand Singh BSc, MD, DPM, MFPM 
Principal Investigator 
Senior Clinical Research Physician 
Signature 
fa??
:
Mi0I9 
 
Date 
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Sponsor/Quotient Sciences Confidential 
Signatures for Sponsor 
Sanjay K Aggarwal, MB BChir (Cantab) 
MRCP (UK) 
Vice President, Clinical Development 
IF - 	
- 2- 2I1 
Date 
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Sponsor/Quotient Sciences Confidential 
'1 	
Table of Contents 
1 	
Table of Contents 	
6 
2 	
List of Tables and Figures 	
• 10 
2.1 	
Table of In-Text Tables 	
10 
2.2 	
Table of In-Text Figures 	
10 
3 	
Synopsis 	
11 
4 	
List of Abbreviations 	
17 
5 	
Background Information 	
19 
5.1 	
Introduction 	
19 
5.2 	
Investigational Medicinal Product(s) 	
19 
5.3 	
Previous Study Findings 	
20 
5.3.1 	
Non-clinical Data Summary 	
20 
5.3.2 Clinical Data Summary 	
21 
6 	
Rationale 	
22 
6.1 	
Study Rationale 	
22 
6.2 	
Dose Rationale 	
23 
6.3 	
Population Rationale 	
24 
6.4 	
Risks and Benefits 	
25 
6.4.1 	
Potential Risks associated with KD025 	
25 
6.4.2 Risks associated with Radiation Exposure 	
25 
6.4.3 Risks associated with exposure to Radiation Microdose 	25 
6.4.4 	
Other considerations 	
26 
7 	
Objectives and Endpoints 	
26 
7.1 	
Objectives 	
26 
7.1.1 	
Primary Objectives 	
26 
7.1.2 Secondary Objectives 	
26 
7.2 	
Endpoints 	
26 
7.2.1 	
Primary Endpoints 	
26 
7.2.2 Secondary Endpoints 	
27 
8 	
Study Design 	
27 
8.1 	
Study Plan 	
27 
8.1.1 	
Study Plan Part 1 	
27 
8.1.2 Study Plan Part 2 	
28 
8.2 	
Criteria for In-Study Decisions 	
29 
8.3 	
Subject Withdrawal 	
29 
8.4 	
Subject Replacement 	
30 
8.5 	
Stopping Criteria 	
30 
8.6 	
Study Termination 	
31 
8.7 	
Lost to Follow-up 	
31 
8.8 	
Treatment Allocation 	
32 
8.8.1 	
Subject Numbers 	
32 
8.8.2 	
Blinding 	
32 
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9 	
Selection of Subjects 	
32 
9.1 	
Informed Consent 	
32 
9.2 	
Inclusion Criteria 	
32 
9.3 	
Exclusion Criteria 	
33 
9.4 	
Contraception 	
34 
9.4.1 	
Exposure to Partners During the Study 	
34 
9.4.2 Sperm Donation 	
35 
9.5 	
Pregnancy 	
35 
9.6 	
Additional Study Restrictions 	
35 
10 	
Study Procedures 	
35 
10.1 	
Screening 	
35 
10.1.1 Subject Re-Screening 	
36 
10.2 	
Admission and Pre-dose Procedures 	
36 
10.3 	
Study Day Procedures 	
36 
10.3.1 Blood Volume 	
36 
10.3.2 Timing of Procedures 	
36 
10.3.3 Discharge from the Clinical Unit 	
37 
10.3.4 Medical Supervision 	
37 
10.3.5 Follow-up 	
38 
11 	
Dosing of Subjects 	
38 
11.1 	
Food and Fluid Intake 	
38 
11.2 	
Administration of Test Preparations 	
38 
11.1 	
Dosing Compliance 	
39 
11.2 	
Prior and Concomitant Medications 	
39 
12 	
Assessment of Efficacy 	
39 
13 	
Assessment of Mass Balance, Pharmacokinetics, Metabolic Profiling 
and Identification and Pharmacodynamics 	
40 
13.1 	
Assessment of Mass Balance, Pharmacokinetics and 
Metabolic Profiling and Identification 	
40 
13.1.1 Blood Sampling 	
40 
13.1.2 Urine Sampling (Part 2 only) 	
40 
13.1.3 Faecal Sampling (Part 2 Only) 	
41 
13.1.4 Unexpected Sources of Elimination 	
41 
13.2 	
Assessment of Pharmacodynamics 	
41 
14 	
Assessment of Safety 	
41 
14.1 	
Definition and Classification of Adverse Events 	
41 
14.2 	
Assessment of Causality 	
42 
14.3 	
Recording Adverse Events 	
42 
14.4 	
Serious Adverse Events 	
43 
14.4.1 Definition of Serious Adverse Events 	
43 
14.4.2 Definition of Suspected Unexpected Serious Adverse 
Reactions 	
43 
14.5 	
Laboratory Measurements 	
43 
14.5.1 Haematology and Clinical Chemistry 	
43 
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14.5.2 Urinalysis 	
44 
14.5.3 Drug Screen 	
44 
14.5.4 Alcohol Breath Test 	
44 
14.5.5 Carbon Monoxide Breath Test 	
44 
14.5.6 Abnormal Laboratory Findings 	
44 
14.6 	
Vital Signs Measurements 	
45 
14.7 ECG Measurements 	
45 
14.8 	
Body Weight and Height 	
45 
14.9 	
Physical Examination 	
45 
14.10 Additional Safety Procedures 	
46 
15 	
Statistics and Data Analysis 	
46 
15.1 	
Sample Size Justification 	
46 
15.2 	
Data Management 	
46 
15.3 	
Mass Balance and Pharmacokinetic Data Analysis 	
46 
15.3.1 Mass Balance Data Analysis 	
46 
15.3.2 Pharmacokinetic Data Analysis 	
47 
15.3.3 Metabolite Profiling and Identification 	
49 
15.4 	
Statistical Data Analysis 	
49 
15.5 	
Interim Analysis 	
49 
16 	
Safety Reporting to Ethics Committees and Regulatory Authorities 	
50 
16.1 	
Events Requiring Expedited Reporting 	
50 
16.2 	
Urgent Safety Measures 	
50 
16.3 	
Reporting 	
50 
16.3.1 Reporting Serious Adverse Events 	
50 
16.3.2 Reporting of Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 	
51 
16.3.3 Expedited Reporting of Events 	
51 
16.3.4 Reporting of Urgent Safety Issues 	
52 
16.4 	
Serious Breaches 	
52 
17 	
Protocol Amendments and Deviations 	
52 
17.1 	
Amendments 	
52 
17.2 	
Protocol Deviations 	
52 
18 	
Regulatory 	
53 
18.1 	
Compliance 	
53 
18.2 	
Ethics Approval 	
53 
18.3 	
MHRA Approval 	
53 
18.4 	
Administration of Radiation 	
53 
18.5 	
Source Data 	
54 
18.6 	
Declaration of the End of the Study 	
54 
18.7 	
Document Storage and Archiving 	
54 
18.8 	
Protection of Personal Data and Confidentiality 	
54 
18.9 	
Data Security Breach 	
55 
19 	
Quality Control and Quality Assurance 	
55 
19.1 	
Monitoring 	
56 
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1 
Sponsor/Quotient Sciences Confidential 
20 	
Finance and Insurance 	
56 
21 	
Publication 	
56 
22 	
References 	
56 
Appendix 1 	
Clinical Laboratory Parameters 	
59 
Appendix 2 	
Part 1 Study Flow Chart 	
60 
Appendix 2 	
Part 1 Study Flow Chart (Continued) 	
61 
Appendix 3 	
Part 2 Study Flow Chart 	
63 
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2 	
List of Tables and Figures 
2.1 	
Table of In-Text Tables 
Table 1 	
Investigational Medicinal Products 	
20 
2.2 	
Table of In-Text Figures 
Figure 1 Study Sequence 	
29 
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Sponsor/Quotient Sciences Confidential 
3 Synopsis 
Sponsor: 
Kadmon Corporation LLC 
Drug Substance: 
KD025 and [14C1-KD025 
EudraCT No.: 
2018-004773-28 
Title of Study: 
An open-label, two-part study designed to assess the absolute bioavailability of KD025 and 
to determine the mass balance recovery, metabolite profile and identification of metabolite 
structures for [14q-KD025 in healthy male subjects 
Principal Investigator: Nand Singh BSc, MD, DPM, MFPM 
Study Centre: 
Quotient Sciences Limited, Mere Way, Ruddington Fields, Nottingham, NG11 6JS, UK 
Objectives: 
Primary Objectives: 
• To determine the absolute oral bioavailability of KD025 (Part 1) 
• To determine the mass balance recovery after a single oral dose of carbon-14 [14q-KD025 
(Part 2) 
• To provide plasma, urine and faecal samples for metabolite profiling and structural 
identification (Part 2) 
Secondary Objectives: 
• To obtain information regarding the oral pharmacokinetics (PK) of total radioactivity, 
KD025 and its metabolites KDO25m1 and KD025m2, in plasma 
• To obtain information regarding the intravenous (IV) PK of [14q-KD025 in plasma (Part 1) 
• To determine the routes and rates of elimination of r4q-KD025 and associated total 
radioactivity (Part 2) 
• To evaluate the extent of distribution of total radioactivity into blood cells (Part 2) 
• To assess the qualitative and quantitative metabolic profile of [14q-KD025 and carry out 
the structural elucidation of the main metabolites in plasma (accounting for 	
10% of 
circulating total radioactivity) and in urine and faecal samples (accounting for 	
10% of 
administered dose; Part 2) 
• To provide additional safety and tolerability information for KD025 
Methodology: 
This is a single centre, non-randomised, open-label, two-part study in healthy male subjects. 
Part 1 Methodology: 
Part 1 is an open-label, non-randomised single oral dose followed by an IV microtracer 
assessment in 6 healthy male subjects. On Day 1 subjects will receive a single dose of KD025 
(Treatment A), in the fed state. Subjects will then receive an IV dose of [14q-KD025 (100 pg, 
a `microdose') containing not more than (NMT) 37 kBq (1000 nCi) [14C], as a 15 min IV infusion 
(Treatment B), 1.75 h after the oral dose administration (Treatment A) ie, 15 min before the 
expected Tmax (2 h) for the oral dose. 
Treatment 
Investigational Medicinal Product (IMP) 
A 
B 
KD025 Tablet, 200 mg 
[14C1-KD025 solution for infusion, 20 pg/mL (100 pg in 5mL), 
containing NMT 37 kBq (1000 nCi) [14C], as a 15 min IV infusion, 
100 pg 
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14C: carbon-14, kBq: Kilobecquerel, IV: Intravenous, pCi: Microcurie, nCi: Nanocurie, NMT: Not more than. All 
IMPs are described as free base equivalent. 
Part 1 Study Design 
All subjects will undergo preliminary screening procedures to determine their eligibility for 
Parts 1 and 2 of the study at the screening visit (Day -28 to Day -2 of Part 1). Subjects will be 
admitted to the clinical unit on the evening prior to investigational medicinal products (IMPs) 
administration (Day -1) for confirmation of eligibility and baseline procedures. Subjects will be 
dosed on the morning following admission (Day 1). Following an overnight fast (approximately 
10 h), subjects will consume a standard breakfast and will receive a single dose of KD025 
(Treatment A) 30 min after the start of breakfast. One hour and 45 min post Treatment A 
administration, subjects will receive an IV infusion of [14C]-KD025 solution (Treatment B). 
Subjects will remain resident in the clinic until up to 48 h post-oral dose (up to Day 3). The 
minimum washout period between dose administrations in Part 1 and 2 will be 7 days. 
Part 2 Methodology: 
Part 2 is an open-label, non-randomised absorption, distribution, metabolism, excretion 
(ADME) assessment in 6 healthy male subjects. Following a minimum washout period of 7 
days, subjects who participated in Part 1 of the study will be admitted to the clinical unit for 
participation in Part 2 of the study. On Day 1 each subject will receive a single oral 
administration of 200 mg [14C]-KD025 capsule containing (NMT 9.8 MBq) (215 pCi) [140] 
(Treatment C) on the morning of Day 1 after a standard breakfast. 
Treatment 	
IMP Dose 
[14q-KD025 capsule, containing NMT 9.8 MBq (215 pCi) 14C, 
200 mg 
14C:carbon-14, MBq: megabecquerel, pCi: Microcurie, NMT: not more than. IMP is described as free base 
equivalent. 
Part 2 Study Design 
Approximately 7 days after subjects have been discharged from Part 1 of the study, subjects 
will be admitted to the clinical unit on the evening of the day prior to IMP administration 
(Day -1) for the confirmation of eligibility and baseline procedures. Subjects will be dosed on 
the morning following admission (Day 1). Following an overnight fast (approximately 10 h), 
subjects will consume a standard breakfast and will receive a single dose of [14C]-KD025 
capsule (Treatment C) 30 min after the start of breakfast. Subjects will remain resident in the 
clinic until up to 168 h after dosing (up to Day 8). It is planned that subjects will be released 
as a group when all subjects have achieved a mass balance cumulative recovery of >90% or 
if <1% of the dose administered has been collected in urine and faeces within 2 separate, 
consecutive 24 h periods. This may result in the subjects being discharged as a group prior 
to completion of the planned residency period. Once the discharge criteria or the planned 
residency period has been achieved, the subjects will undergo discharge assessments and 
collection of all samples (blood, urine and faeces) will be stopped. 
If mass balance criteria have not been met by all subjects on Day 8, the residency period for 
the subjects not achieving the release criteria may be extended up to a maximum of 216 h 
post-dose (Day 10). During the additional residency period only urine and/or faeces will be 
collected. If the criterion is still not met by Day 10, or if additional residency is not considered 
appropriate or necessary, then home collections of urine and/or faeces may be requestOd at 
the discretion of the investigator for individual subjects. To ensure ongoing wellbeing of the 
subjects, a follow-up phone call will take place 5 to 7 days post-discharge from the study or 
after the end of the last collection period. 
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An overview of the study is presented below: 
Part 1 
Day -28 to Day -2 
Screening 
1,  
Day -1 
Admission (evening) 
Day 1 
KD025 Tablet, 200 mg 
+ [14q-KD025 
20 pg/mL solution for 
IV infusion 
Day 3 
Discharge (morning)a 
Part 2 
Day -113 
Admission (evening) 
Day 
[14q-KD025 capsule, 
200 mg 
Day 8c 
Discharge (morning) 
Follow-Up Call 
(5 to 7 days post- 
discharge/after the end 
of the final collection 
period) 
Minimum 7 day 
washout period 
a Discharge time relative to oral dose, 48 h post-dose. 
b Subjects who participated in Part 1 will be admitted to the clinical unit on Day -1 of Part 2 after a minimum washout 
period of 7 days. 
If mass balance criteria have not been met by all subjects on Day 8, the residency period for the subjects not 
achieving the release criteria may be extended up to a maximum of 216 h post-dose (Day 10). During the additional 
residency period only urine and/or faeces will be collected. If the criterion is still not met by Day 10, or if additional 
residency is not considered appropriate or necessary, then home collections of urine and/or faeces may be 
requested at the discretion of the investigator for individual subjects. 
Number of Subjects Planned: 
It is planned to enrol 6 healthy male subjects to ensure data in 4 evaluable subjects. Subjects 
must have participated in Part 1 in order to be eligible for Part 2. No replacement subjects are 
planned for this study. 
Duration of Study: 
Subjects will receive a single oral dose of KD025 followed by an IV infusion of [14q-KD025 
administered 1.75 h after the oral dose on one occasion in Part 1 and a single oral dose of 
[14C1_ KDO25 capsule on one dosing occasion in Part 2. 
The estimated time from screening until the follow-up phone call is approximately 8 weeks. 
Main Inclusion Criteria: 
Healthy males aged 30 to 65 years 
Body mass index (BMI) 18.0 to 35.0 kg/m2  
Sponsor/Quotient Sciences Confidential 
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Investigational Medicinal Product, Dose and Mode of Administration: 
The following IMPs will be used in this clinical study: 
Investigational Medicinal 
Product 
Part 
Dose and Route of Administration 
KD025 Tablet, 200 mg 
200 mg (as 1 x 200 mg tablet), Oral 
100 pg, containing NMT 37 kBq 
(1000 nCi), IV infusion  
200 mg, containing NMT 9.8 MBq 
(215 pCi) 14C, Oral 
14c = carbon-14, IV = intravenous, kBq = kilobecquerel, MBq: megabecquerel, pCi: microcurie, nCi = nanocurie, 
NMT = Not more than. All IMPs are described as free base equivalent. 
A total of 240 mL of water will be given immediately following oral administration. 
Pharmacokinetic Assessments: 
Part 1 
Plasma samples will be collected from pre-dose until 48 h post-dose for the analysis of KD025 
and [14C]-KD025. Blood samples will be collected at regular time intervals. 
The concentration-time data will be analysed by Quotient Sciences using industry standard 
software (Phoenix WinNonlin version 8.0 or a more recent version, [Certara, Princeton, New 
Jersey]) using appropriate non-compartmental techniques to obtain estimates of the following 
parameters where possible and appropriate: 
For Plasma [14C]-KD025 following IV administration 
• Tmax: Time of maximum observed concentration 
• Cmax: The maximum observed plasma concentration 
• AUC(0-last): Area under the curve from 0 time to the last measurable concentration 
• AUC(0-inf): The area under the concentration-time curve from dosing extrapolated to 
infinity 
• AUC%extrap: Percentage of AUC(0—inf) extrapolated beyond last measured time point 
• lambda-z: The first order rate constant associated with the terminal (log-linear) portion of 
the curve 
• 
T112: The apparent terminal elimination half-life 
• CL: Total clearance 
• Vz: Volume of distribution based on area 
• Vss: Volume of distribution at steady state 
• MRT: Mean residence time 
For Plasma KD025 following oral administration 
• Tlag: Time prior to the first measurable (non-zero) concentration 
• Tmax: Time of maximum observed concentration 
• Cmax: The maximum observed plasma concentration 
• AUC(0-last): Area under the curve from 0 time to the last measurable concentration 
• AUC(0-inf): The area under the concentration-time curve from dosing extrapolated to 
infinity 
• AUC%extrap: Percentage of AUC(0—inf) extrapolated beyond last measured time point 
• lambda-z: The first order rate constant associated with the terminal (log-linear) portion of 
the curve 
• T1/2: The apparent terminal elimination half-life 
• F: Bioavailability of oral formulation compared to IV 
• CL/F: Apparent clearance 
2 
[14q-KD025 solution for 
infusion, 20 pg/mL 
[14q-KD025 capsule, 200 mg 
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-r 
• Vz/F: Apparent volume of distribution 
• MRT: Mean residence time 
Part 2: 
Plasma samples will be collected from pre-dose until 168 h post-dose for the analysis of total 
radioactivity, KD025, KDO25m1, KDO25m2 and [14C]-KD025. 
The concentration-time data will be analysed by Quotient Sciences using industry standard 
software (Phoenix WinNonlin version 8.0 or a more recent version, [Certara, Princeton, New 
Jersey]) using appropriate non-compartmental techniques to obtain estimates of the 
following parameters where possible and appropriate: 
For Total Radioactivity, KD025, KDO25m1 and KDO25m2 in plasma: 
• Tlag: Estimated time from dosing at which the analyte was first quantifiable in a 
concentration versus time profile 
• Tmax: Time of maximum observed concentration 
• Cmax: The maximum observed plasma concentration 
• AUC(0-last): Area under the curve from 0 time to the last measurable concentration 
• AUC(0-inf): The area under the concentration-time curve from dosing extrapolated to 
infinity 
• AUC%extrap: Percentage of AUC(0—inf) extrapolated beyond last measured time point 
• lambda-z: The first order rate constant associated with the terminal (log-linear) portion of 
the curve 
• 11/2: The apparent terminal elimination half-life 
• Cl/F: Apparent clearance KD025 only 
• Vd/F: Apparent volume of distribution KD025 only 
• MRT: Mean residence time 
• Metabolite:Parent ratio for KD025m1 and KDO25m2 
• whole blood/plasma total radioactivity concentration at selected time points. 
Mass Balance Assessments: 
For Urine: 
• Ae: Total radioactivity 
• %Ae: Total radioactivity expressed as a percentage of the dose 
• Cum Ae: Cumulative recovery of total radioactivity 
• Cum %Ae: Cumulative recovery expressed as a percentage of the dose 
For Faeces: 
• Ae: Total radioactivity 
• %Ae: Total radioactivity expressed as a percentage of the dose 
• Cum Ae: Cumulative recovery of total radioactivity 
• Cum %Ae: Cumulative recovery expressed as a percentage of the dose 
For Mass Balance Recovery of Total Radioactivity from all excreta: 
• Ae: Total radioactivity 
• %Ae: Total radioactivity expressed as a percentage of the dose 
• Cum Ae (Total): Cumulative recovery of total radioactivity 
• Cum %Ae (Total): Cumulative recovery expressed as a percentage of the dose 
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Metabolite Profiling and Identification 
Metabolite 	
profiling 	
of 	
plasma, 	
urine 	
and 	
faeces 	
will 	
be 	
performed 	
using 	
liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate. 
Identification of the chemical structure of each metabolite accounting for greater than 10% of 
circulating radioactivity in plasma ("AUC pool") and accounting for greater than 10% of the 
dose in the urine and faeces (from urine pools and faeces homogenate pools) will be 
performed. These aspects will be reported separately from the clinical study report as a 
standalone document. 
Safety Assessments: 
The following safety assessments will be performed at appropriate time points during the 
study: 
• Physical examinations 
• Safety laboratory tests (clinical chemistry, haematology and urinalysis) 
• Electrocardiograms (ECGs) 
• Vital signs 
• Adverse Events (AEs) 
Statistical Methodology: 
No formal statistical analysis will be performed for the safety, pharmacokinetics (PK), or mass 
balance data. 
Sample Size and Power: 
The study is exploratory and no formal sample size calculation has been made. Based on 
experience from previous studies of a similar design, a total of 6 subjects are to be enrolled 
and a minimum of 4 evaluable subjects are considered sufficient. 
An evaluable subject for Part 1 is defined as a subject who has sufficient data for evaluation 
of the primary bioavailability objective of the study. 
A subject in Part 2 will be considered evaluable if they have provided biological samples for 
up to 168 h after drug administration or have demonstrated >90% mass balance recovery, or 
have <1% of the administered dose eliminated in excreta for two consecutive days, whichever 
is the sooner. 
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4 	
List of Abbreviations 
.1 
Abbreviation 
14c 
ADR 
ADME 
AE 
ALP 
ALT 
ARSAC 
AST 
BID 
BMI 
cGVHD 
CLcr 
CTGF 
CYP 
DMP 
EC 
ECG 
EMA 
GCP 
GI 
GP 
HBsAg 
HCV Ab 
HIV 
IB 
ICF 
ICH 
IMP 
IL 
IPF 
IV 
MBq 
MedDRA 
Definition 
carbon-14 
adverse drug reaction 
absorption, distribution, metabolism and elimination 
adverse event 
alkaline phosphatase 
alanine aminotransferase 
Administration of Radioactive Substances Advisory 
Committee 
aspartate aminotransferase 
twice daily 
body mass index 
Chronic graft versus host disease 
creatinine clearance 
connective tissue growth factor 
Cytochrome P450 
Data management plan 
ethics committee 
electrocardiogram 
European Medicines Agency 
good clinical practice 
gastrointestinal 
general practitioner 
hepatitis B surface antigen 
hepatitis C virus antibody 
human immunodeficiency virus 
Investigator's Brochure 
informed consent form 
International Council for Harmonisation 
investigational medicinal product 
interleukin 
idiopathic pulmonary fibrosis 
intravenous 
megabecquerel 
Medical Dictionary for Regulatory Activities 
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MHRA 
pCi 
mSv 
nCi 
NMT 
PHE 
PI 
PIS 
PK 
QA 
QD 
QTc 
QTcF 
RAP 
ROCK 
SAE 
SOP 
SUSAR 
Th 
Treg 
UGT 
ULN 
WHO 
Medicines and Healthcare products Regulatory Agency 
microcurie 
millisievert 
nanocurie 
not more than 
Public Health England 
Principal Investigator 
Participant Information Sheet 
pharmacokinetic(s) 
quality assurance 
once daily 
correct QT interval 
correct QT interval by Fredericia's formula 
Reporting and Analysis Plan 
Rho-associated coiled-coil protein kinase 
serious adverse event 
standard operating procedure 
suspected unexpected serious adverse reaction 
T-helper 
regulatory T cells 
Uridine 5'-diphospho-g lucuronosyltransferase 
Upper limit of normal 
World Health Organisation 
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5 	
Background Information 
5.1 	
Introduction 
Rho-associated coiled-coil protein kinases (ROCKs) are members of the 
serine/threonine kinase family, often studied for their role in cell morphology, motility and 
shape through effects on the cytoskeleton [1][2]. Two ROCK isoforms have been 
identified, ROCK1 and ROCK2. Both are involved in Rho-mediated changes in the 
actin/myosin cytoskeletal network. ROCK1 and ROCK2 are not redundant signalling 
molecules and may serve different functions within cells [3][4][5]. Recent research has 
uncovered additional roles for ROCK signalling, particularly ROCK2, in conditions 
including autoimmune disease aggravated or caused by a 1-helper (Th)17-polarised 
T cell response [6] and pulmonary fibrosis [7]. 
Rho GTPase-mediated signalling pathways play a central role in coordinating and 
balancing T cell mediated immune responses, including T cell receptor-mediated 
signalling, cytoskeletal reorganisation, and the acquisition of the appropriate T cell 
effector program [8]. Recent studies have demonstrated that aberrant activation of 
ROCK2 leads to induction of interleukin (IL)-17 and IL-21 via interferon regulatory factor 
4-dependent mechanism [9]. 
In addition, ROCK activity was found to be up-regulated in patients with rheumatoid 
arthritis (RA) and systemic lupus erythematosus (SLE) [10] and inhibition of ROCK2 
effectively decreased IL-17 production in vivo and demonstrated efficacy in arthritis and 
lupus mouse models. Autoimmunity also involves alterations to regulatory T cells (Tregs) 
that suppress activation of the immune system and play a critical role in maintaining 
immunological tolerance to self-antigens and inhibiting autoimmune responses [11]. 
ROCK2 inhibition may increase the suppressive function of Tregs. 
ROCK is also downstream of several major pro-fibrotic mediators, including: 
transforming growth factor beta (TGF-(3), connective tissue growth factor (CTGF), and 
lysophosphatidic acid (LPA). A defining feature of pathologic fibrosis is the differentiation 
of fibroblasts to myofibroblasts, a process mediated by ROCK. In addition, ROCK 
mediates stress fibre formation and regulates the transcription of pro-fibrotic genes, 
including CTGF and alpha-smooth muscle actin (a-SMA). Further, ROCK inhibition has 
demonstrated anti-fibrotic activity in murine models [12]. 
KD025 (formerly called SLx-2119), (2-(3-(4-(1H-indazol-5-ylamino) quinazolin-2-y1) 
phenoxy)-N-isopropylacetamide-methane sulfonic acid salt) is an orally available 
ROCK2 selective inhibitor that is currently in Phase II clinical development for treating 
autoimmune and fibrotic disorders. 
Pre-clinical investigations have identified that KD025 is metabolised via first pass 
metabolism to 2 main metabolites KD025m1 and KD025m2 in the species dosed. 
6.2 Investigational Medicinal Product(s) 
The following investigational medicinal products (IMPs) will be used in this clinical study 
(Table 1). 
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1 
Table 1 	
Investigational Medicinal Products 
Part 
Investigational Medicinal 
Product 
Dose and Route of Administration 
KD025 Tablet, 200 mg 
200 mg (as 1 x 200 mg tablet), Oral 
100 pg, containing NMT 37 kBq 
(1000 nCi), IV infusion 
2 	
114q-KD0 
200 mg, containing NMT 9.8 MBq 
(215 pCi) 14C, Oral 
[14q-KD025 solution for 
infusion, 20 pg/mL 
25 capsule, 200 mg 
lac = carbon-14, IV = intravenous, kBq = kilobecquerel, MBq: megabecquerel pCI: microcurie, nCi = 
nanocurie, NMT = not more than. All IMPs are described as free base equivalent. 
Only subjects enrolled in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatments will be stored in a 
secure, environmentally-controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions. Access will be limited to the investigator 
and authorised site staff. 
Where Quotient Sciences is manufacturing the IMP(s), suitability of the manufacturing 
process will be documented in a Pharmaceutical Development and Control Strategy 
Report. 
All IMPs will be reconciled and destroyed in accordance with the study-specific quality 
agreement and technical addendum. 
5.3 	
Previous Study Findings 
5.3.1 	
Non-clinical Data Summary 
Nonclinical pharmacology studies demonstrate the potential of KD025 to have a 
therapeutic benefit in a number of indications, particularly in autoimmune disease 
through effects on Th17-type immune responses, and idiopathic pulmonary fibrosis (IPF) 
through anti-fibrotic mechanisms [12]. 
Solubility of KD025 is pH dependent ie, it is 100 pg/mL at pH 2.7, -4 pg/mL at pH 6.5 
and -3 pg/mL at pH 7.4. The lower solubility at higher pH could potentially impact 
absorption of KD025 under physiological conditions. 
KD025 plasma exposure generally increased with dose, was dose proportional or greater 
than dose proportional, and showed some accumulation. The elimination half-life of 
KD025 was variable in nonclinical studies with calculated values of approximately 2 h in 
mice, 1 to 7 h in rat and rabbit, and 1 to 3 h in dog. 
KD025 undergoes first pass metabolism in all evaluated species after oral administration 
to form a ROCK2 active metabolite, KDO25m1 and a metabolite that is relatively less 
active against ROCK2, KD025m2. 
Distribution studies performed in rats with oral administration of carbon-14 [14q-KD025 
demonstrated distribution primarily into tissues associated with elimination 
(gastrointestinal [GI], liver, kidney, urinary bladder), adrenal gland, and exocrine 
glandular tissue. All tissues demonstrated clearance and no appreciable radioactivity 
was observed in the brain. Melanin-containing tissues (uveal tract and pigmented skin) 
demonstrated higher tissue retention, indicating some affinity of KD025 for melanin. 
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[14C]-KD025 excretion was similar in male and female rats and was predominantly via 
the faecal route (-90%), while urine accounted for a smaller proportion of excretion 
(<1%). 
Based on in-vitro assessment, cytochrome P450 (CYP)3A4 and CYP1A2 were the 
predominant CYP isoforms responsible for the metabolism of KD025, although CYP2C8, 
CYP2D6 and Uridine 5'-diphospho-glucuronosyltransferase (UGT)1A9 may also 
contribute to a lesser extent. Metabolism of KD025 to KDO25m1 was CYP3A4 and 
CYP2C8 dependent. Metabolism of KD025 to KD025m2 was CYP3A4 dependent with 
further metabolism of KD025m2 dependent on UGT1A1 with no to little contribution from 
CYP enzymes. 
KD025 and the active metabolite KDO25m1 is > 99% bound to human, dog and rat 
plasma proteins. KD025m2 is > 99% bound to human plasma protein. 
Good laboratory practice (GLP)-compliant rat and dog general toxicology/toxicokinetic 
studies of acute, sub-chronic (1 and 3 month), and chronic (6-month rat and 9-month 
dog) duration have been completed. In addition, safety pharmacology studies evaluating 
human ether-a-go-go related gene (hERG) (in-vitro), central nervous system (rat), 
respiratory (rat), and cardiovascular (dog) organ systems have been completed. 
Embryo-foetal toxicology (rat and rabbit) and fertility (rat) studies have also been 
completed. Furthermore, KD025 has been evaluated in a panel of studies evaluating 
drug genotoxicity and phototoxicity potential. The primary non-clinical toxicology finding 
at/near clinically relevant exposures were limited to changes in the cardiovascular (blood 
pressure lowering), hepatic (transaminitis, hypertrophy/increased organ weight, and 
cholestasis/inflammation), renal (increased blood urea nitrogen [BUN], tubular changes, 
pigmentation and intracellular protein droplets in the epithelium), GI (decreased 
appetite), and hematopoietic/immunologic (anemia with regeneration and thymic/splenic 
lymphoid depletion) systems. In addition, KD025 demonstrated embryo-foetal 
toxicity/teratogenicity as well as reduced male fertility (reduced fertility index/sperm 
concentration/motility and increased abnormal sperm percentage; testes/epididymis 
[decreased organ weights and degenerative histopathology]). Male fertility findings were 
generally at higher than clinically relevant exposures. 
Data from these nonclinical studies support a thorough understanding of the potential for 
safety-related effects of KD025 and have facilitated the development of the current 
clinical trial monitoring plan. Further details of non-clinical studies can be found in the 
Investigator's Brochure (IB) [12]. 
5.3.2 	
Clinical Data Summary 
To date, 7 clinical studies have been completed, consisting of 6 Phase I clinical studies 
(SLx-2119-09-01, KDO25-101, KDO25-102, KDO25-103, KDO25-105, and KDO25-106) in 
healthy subjects, and 1 Phase Ila study (KD025-205) in subjects with psoriasis vulgaris. 
Additionally, a Phase II study (KD025-206) in subjects with psoriasis vulgaris has been 
clinically completed; however, the clinical study report is pending. In addition to the 
completed studies, 5 Phase II studies are ongoing in subjects with chronic graft versus 
host disease (cGVHD) (KD025-208 and KD025-213), IPF (KD025-207), psoriasis 
(KDO25-211) and systemic sclerosis (KD025-209). A drug-drug interaction phase 1 study 
is currently ongoing (KDO25-107). 
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KD025 was generally well-tolerated, with most adverse events (AEs) considered mild or 
moderate in severity and a low incidence of serious adverse events (SAEs) overall. An 
increase in liver function test AEs at the highest dose tested in Phase 2 studies (400 mg 
twice daily [BID]) (Study KD025-206) led to this dose no longer being used in subsequent 
studies. 
The most common (5% overall) AEs were alanine aminotransferase (ALT) increased 
(10.8%), nausea (9.7%), diarrhoea (8.9%), upper respiratory tract infection (8.9%), 
fatigue (7.8%), aspartate aminotransferase (AST) increased (7.8%), gamma-
glutamyltransferase increased (7.8%), headache (6.3%), cough (6.3%), and dyspnoea 
(5.2%). 
The most common AEs were generally also the most common treatment related AEs. 
The majority of these events were mild to moderate in severity. 
To date no clinically significant AEs suggestive of photo-toxicity have been reported in 
KD025 studies. All but one of the skin and subcutaneous tissues system organ class 
(SOC) events reported to date have been mild to moderate in severity (the exception 
being a Grade 3 "rash erythematous" likely related to progression of cGVHD). Of note, 
most of the subjects treated with KD025 have been enrolled into studies of psoriasis and 
GVHD. 
No treatment related deaths have occurred to date. 
The identified and potential risks noted in association with KD025, detailed in the IB [12], 
are balanced by the anticipated benefits that may be afforded to subjects with psoriasis 
vulgaris, IPF and cGVHD. 
6 Rationale 
6.1 	
Study Rationale 
This study is being conducted to investigate the oral pharmacokinetics (PK), intravenous 
(IV) PK, mass balance recovery and metabolite profiling and identification of 14C-KD025. 
Kadnnon Pharmaceuticals LLC. is developing KD025, a ROCK2 selective inhibitor, for 
the treatment of autoimmune diseases. 
Part 1 
Knowing the absolute bioavailability of an oral drug product is a regulatory requirement 
in some regions, eg Australia. In addition, understanding the bioavailability of a drug and 
the factors that influence absorption, may guide the formulation development strategy. 
The IV microtracer technique is an established methodology for measuring the IV and 
oral kinetics of a drug in the same individuals in a single dosing period. The technique 
involves concurrent administration of a microdose of the drug containing microtracer 
amounts of 14C with a single oral therapeutic dose, which avoids the concerns of 
dose-dependent kinetics when extrapolating IV PK from a microdose, as the systemic 
exposure is at therapeutic concentrations. This design enables measurement of 
14C-labelled drug in the plasma following IV dosing via sensitive accelerator mass 
spectrometry (AMS) techniques, and measurement of the unlabelled parent in the 
plasma by standard high performance liquid chromatography mass spectrometry/mass 
spectrometry (HPLC MS/MS) techniques. Thus, it is possible to obtain the IV PK 
parameters with the associated variability, and calculate the absolute bioavailability. In 
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addition, because the IV dose administration involves giving a low volume of a low 
concentration of parent drug, an advantage of this approach is that it is much easier to 
develop an IV formulation for microdosing than it would be for a higher clinical dose. 
Part 2 
The current study is designed to collect samples and to generate data for the absorption, 
distribution, metabolism and elimination (ADME) of KD025 in humans, as well as 
generating samples for metabolite profiling and structural identification. 
6.2 Dose Rationale 
Part 1 
KD025 in doses ranging from 20 to 1000 mg once daily (QD) to 500 mg BID have 
generally been well tolerated. A single oral dose of 200 mg of KD025 followed by an 
100 pg IV dose of [14C]-KD025, given 1.75 h after the oral dose has been administered 
(estimated to end at the time of maximum plasma concentration [Tmax] for the oral dose 
[2 h]), has been selected for Part 2 of this study. The 200 mg dose has been well tolerated 
as a.  single dose and in repeat dosing in healthy subjects and patients with psoriasis and 
cGVHD; repeat dosing at 400 mg QD has been well tolerated in patients with cGVHD 
and IPF. The 200 mg dose provides a clear PK profile, in the linear range, well above 
the lower limit of quantification, and is in the expected therapeutic range. 
Part 1 is the absolute bioavailability part of the study where an IV micro dose of KD025 
containing microtracer amounts of 14C is administered following administration of an oral 
dose of KD025 to determine the bioavailability of the oral dose compared with the IV 
dose. According to the International Council for Harmonisation (ICH) M3 guidance, a 
micro dose is a dose that is <1/100th of the pharmacologically active dose up to a 
maximum of 100 pg. In addition, to ensure that the IV micro dose does not contribute 
significantly to the exposure following oral dosing, the IV dose is reduced further and in 
this study will be 1/1000th of the oral dose. 
An IV microtracer dose is one that contains not more than (NMT) 37.0 kBq (1000 nCi). 
This has been selected as it is the standard radioactive dose used in this type of study 
and will be sufficient to meet the objectives of Part 1, but contains a low enough amount 
of radioactivity so as not to cause a significant risk to the subjects. 
Therefore the IV dose for this study will be 100 pg  [14q_KD025 containing NMT 37.0 kBq 
(1000 nCi). This IV dose is 1/2000th of the oral dose administered in this study and 
<1/ 100th of the likely therapeutic dose, and hence is an appropriate 'IV microtracer dose'. 
Part 2 
KD025 in doses ranging from 20 to 1000 mg QD to 500 mg BID have generally been 
well tolerated. A single dose of 200 mg [14q-KD025 has been selected for Part 2 of this 
study. The 200 mg dose has been well tolerated as a single dose and in repeat dosing 
in healthy subjects and patients with psoriasis and cGVHD; repeat dosing at 400 mg QD 
has been well tolerated in patients with cGVHD and IPF. The 200 mg dose provides a 
clear PK profile, in the linear range, well above the lower limit of quantification, and is in 
the expected therapeutic range. 
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The dose of radioactivity for Part 2 has been determined following review of human 
dosimetry calculations provided by Public Health England (PHE). In accordance with the 
'as low as reasonably practical' principle, the lowest amount of radioactivity will be 
administered that gives confidence that the study objectives will be met. Based on the 
human dosimetry calculations, a radioactive dose of no more than 9.8 MBq (215 pCi) by 
the oral route will be necessary. Adequate metabolite profiling of some key plasma 
samples may not be possible at a radioactive dose less than this. 
Subjects will be participating in both study Parts 1 and 2, therefore the radioactive dose 
for Part 2 will be adjusted to take into account the microtracer amount of radioactivity 
that the subjects will receive in Part 1 of the study (37 kBq/1000 nCi). Thus the oral dose 
for Part 2 will have a radioactive dose containing NMT 9.8 MBq (215 pCi). The total 
committed effective dose subjects will receive is 3 mSv, falling within International 
Commission on Radiological Protection (1992) Guidelines for Category Ilb studies (1 to 
10 mSv). 
To ensure that the [14C] drug products do not exceed the limit for radioactive dose 
approved by the Administration of Radioactive Substances Advisory Committee 
(ARSAC), the target specific activity of the [14C] drug substance will be set at 90% of 90% 
of the threshold radioactive dosing limit. This will ensure provision for a ± 10% range on 
the [14C] drug substance specification for specific activity and a ± 10% range on the [14C] 
drug substance assay in the drug product, thereby providing continued assurance for 
compliance with the ARSAC-approved limit for drug product radioactivity dose. 
A positive food effect has been reported in previous studies and current dosing 
instructions in on-going Phase 2 studies recommend administration of KD025 with food 
[12]. Therefore oral administration of KD025 in this study will be performed in the fed 
state, to ensure characterisation of absorption, metabolism and excretion in conditions 
that best mimic intended clinical use. 
6.3 	
Population Rationale 
The European Medicines Agency (EMA) propose to include subjects in the age group 18 
to 55 years with normal weight who are non-smokers without a history of alcohol or drug 
abuse. The latter criteria are proposed to avoid interaction on drug metabolism and to 
avoid non-compliance. In order to avoid any interaction with other medication, no 
co-medication except 4 g of paracetamol per day (within 24 h) will be allowed. 
We acknowledge the ARSAC Notes for Guidance recommend that wherever possible, 
healthy subjects selected for research projects should be aged over 50 years [13]. 
However, Part 2 of this study is designed to generate data for supporting the investigation 
of the human ADME of a drug, as well as generating samples for metabolite profiling and 
structural identification. 
There are 2 main reasons for generating these data within a clinical development 
programme. The first is to provide human metabolite data that can be used to interpret 
the metabolism profiles seen in the preclinical species employed in the longer term 
toxicity studies, to ensure that there is adequate toxicology coverage for the safe 
development of the drug in patients. The second is to provide data to understand how 
the drug is processed in physiologically normal subjects, because understanding the 
routes of metabolism and elimination in a healthy population generates the appropriate 
data to guide the clinical pharmacology package required to fulfil the regulatory 
requirements of a New Drug Application (NDA). 
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In order to address these 2 main aims of an ADME study, investigation of the drug under 
development is required in a population with normal physiological function, as it is 
recognised that certain physiological processes eg renal function, deteriorate with age 
and therefore it is preferable to use as healthy as possible population, to mitigate against 
factors which may make interpretation of the data difficult. Also, healthy subjects as a 
trial population are ideal since they have a relatively stable physiological, biochemical 
and hormonal status, which removes any disease-related variations and variations due 
to concomitant medications. Therefore given the aims of this ADME study our target age 
range for this study will be 30 to 65 years. 
Formal rat and rabbit embryo-foetal developmental toxicology studies with KD025 
demonstrated potential for embryo-foetal toxicity and/or malformations at clinically 
relevant exposures. Therefore subjects with pregnant partners will be excluded from this 
study. 
The purpose of this study is to investigate the oral pharmacokinetics (PK), intravenous 
(IV) PK, mass balance recovery and metabolite profiling and identification of 14C-KD025. 
It is therefore an advantage to enrol a relatively homogeneous population and to 
minimise variability. Based on the above considerations and target population, healthy 
male subjects, aged 30 to 65 years are considered suitable for this study. 
6.4 	
Risks and Benefits 
6.4.1 	
Potential Risks associated with KD025 
KD025 has generally been well tolerated across the clinical studies conducted. No 
drug-related AEs have resulted in fatal outcomes. The most common AEs associated 
with KD025 administration are liver-related, specifically increased ALT and AST levels, 
but no Hy's Law cases. Subjects will receive single doses of KD025 in this study and will 
be closely monitored throughout the study for any changes in liver enzymes, and no 
subject with a history or presence of hepatic disease or ALT/AST values > the upper limit 
of normal (ULN) will be enrolled in the study (see Section 9.3). 
Other commonly reported events include rash, pruritus, upper respiratory infection, joint 
aches and swelling, headache, fatigue, back pain, leg weakness, diarrhoea, nausea, 
vomiting, upper abdominal pain, increase in white blood cell count, cannula site infection, 
dizziness, and flatulence. 
6.4.2 	
Risks associated with Radiation Exposure 
The [14q-KD025 solution for infusion and [14q-KD025 capsule will contain a radionuclide 
(NMT 9.8 MBq [267 pa]) so subjects will be exposed to ionising radiation. The effective 
dose that each subject will receive from one administration will not exceed 3 mSv. This 
is approximately 1 year and 1 month of the average radiation exposure received in the 
UK each year (2.7 mSv). It is believed that any increase in the amount of radiation that 
is received above natural radiation carries a risk of later developing serious and possibly 
fatal conditions. The risk associated with the maximum possible dose of radiation in this 
study is very small indeed and is considered to be acceptable. 
6.4.3 	
Risks associated with exposure to Radiation Microdose 
The IV micro dose to be administered is 2000-fold lower than the oral dose and the 
exposure to [14q-KD025 originating from the infused micro dose is therefore considered 
negligible and no AEs are expected to occur. 
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6.4.4 	
Other considerations 
During cannulation, more than one attempt may be needed to insert the cannula in a 
vein of a subject and it is possible that bruising and/or inflammation may be experienced 
at the site of cannulation. 
Electrocardiogram stickers on the subjects' chests and limbs may cause some local 
irritation and may be uncomfortable to remove but subjects will be closely monitored to 
ensure any local irritation does not persist. 
Although KD025 nonclinical data suggests the potential for phototoxicity, in standard 
reporting of AEs in Phase 1/2 clinical studies, KD025 has not demonstrated any clinically 
significant phototoxicity. Therefore, for this study no restrictions have been applied. 
The blood volume taken for each subject will be approximately 583.5 mL in a 4 week 
period. To account for this, subjects with blood platelet count, haemoglobin and red blood 
cells lower than the reference range will be excluded from the study. 
There is no benefit to the subjects from taking part in this study. The development of a 
ROCK2-selective small molecule drug has the potential for effectiveness in multiple 
disease indications and will be of benefit to the wider community. 
The overall risk benefit balance is therefore considered to be acceptable. 
7 	
Objectives and Endpoints 
7.1 	
Objectives 
7.1.1 	
Primary Objectives 
• To determine the absolute oral bioavailability of KD025 (Part 1) 
• To determine the mass balance recovery after a single oral dose of [14q-KD025 
(Part 2) 
• To provide plasma, urine and faecal samples for metabolite profiling and structural 
identification (Part 2) 
7.1.2 	
Secondary Objectives 
• To obtain information regarding the oral PK of total radioactivity, KD025 and its 
metabolites KD025m1 and KD025m2, in plasma 
• To obtain information regarding the IV PK of [14q-KD025 in plasma (Part 1) 
• To determine the routes and rates of elimination of [14q-KD025 and associated total 
radioactivity (Part 2) 
• To evaluate the extent of distribution of total radioactivity into blood cells (Part 2) 
• To assess the qualitative and quantitative metabolic profile of [14q-KD025 and carry 
out the structural elucidation of the main metabolites in plasma (accounting for 10% 
of circulating total radioactivity) and in urine and faecal samples (accounting for 
10% of administered dose; Part 2) 
• To provide additional safety and tolerability information for KD025 
7.2 	
Endpoints 
7.2.1 	
Primary Endpoints 
• Absolute bioavailability (F) of KD025 
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Treatment 
Investigational Medicinal Product (IMP) 
A 	
KD025 Tablet, 200mg 
[14q-KD025 solution for infusion, 20 pg/nriL (100 pg in 5mL), 
containing NMT 37 kBq (1000 nCi) [14C], as a 15 min IV 
infusion, 100 pg 
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• Mass balance recovery of total radioactivity in all excreta (urine and faeces): Ae, 
%Ae, Cum Ae and Cum %Ae 
• Collection of plasma, urine and faeces for metabolite profiling and structural 
identification 
7.2.2 	
Secondary Endpoints 
• Assessment of oral PK of KD025, KDO25m1 and KD025m2 and total radioactivity by 
calculation of: Tlag, Tmax, Cmax, AUC(0-last), AUC(0-inf), AUC%extrap, lambda-z, 
T1/2, CL/F (KD025 only), Vz/F (KD025 only) and MRT. 
• Assessment of IV PK of [14q-KD025 by calculation of: Tmax, Cmax, AUC(0-last), 
AUC(0-inf), AUC%extrap, lambda-z, T1/2, CL, Vz, Vss and MRT. 
• Determination of routes and rates of elimination of 14C- by metabolite profiling and 
structural identification in plasma, urine and faeces. 
• Evaluation of whole blood:plasma concentration ratios for total radioactivity 
• Amount and structure of metabolites in plasma (accounting for 10% of circulating 
total radioactivity), urine and faeces (accounting for ?. 10% of administered dose). 
• To provide additional safety and tolerability information for KD025 by assessing: AEs, 
vital signs, electrocardiograms (ECGs), physical examinations and laboratory safety 
tests. 
8 	
Study Design 
8.1 	
Study Plan 
This is a single centre, non-randomised, open-label, two-part study in healthy male 
subjects. Six subjects will participate in both parts of the study. 
8.1.1 	
Study Plan Part 1 
Part 1 is an open-label, non-randomised single oral dose followed by an IV microtracer 
assessment in 6 healthy male subjects. On Day 1 subjects will receive a single dose of 
KD025 (Treatment A), in the fed state. Subjects will then receive an IV dose of 
[14q-KD025 (100 pg, a `microdose1) containing NMT 37 kBq (1000 nCi) [14C], as a 15 
min IV infusion (Treatment B), 1.75 h after the oral dose administration (Treatment A) ie, 
15 min before the expected Tmax (2 h) for the oral dose. 
14C: carbon-14, kBq: Ki obecquerel, IV: Intravenous, pCi: Microcurie, nCi: Nanocurie, NMT: Not more than. 
All IMPs are described as free base equivalent. 
Details of IMPS can be found In Section 5.2 
It is planned to enrol 6 subjects so there are 4 evaluable subjects. An evaluable subject 
for Part 1 is defined as a subject who has sufficient data for evaluation of the primary 
bioavailability objective of the study. 
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All subjects will undergo preliminary screening procedures to determine their eligibility 
for Parts 1 and 2 of the study at the screening visit (Day -28 to Day -2 of Part 1). Subjects 
will be admitted to the clinical unit on the evening prior to IMP(s) administration (Day -1) 
for confirmation of eligibility and baseline procedures. Subjects will be dosed on the 
morning following admission (Day 1). Following an overnight fast (approximately 10 h), 
subjects will consume a standard breakfast and will receive a single dose of KD025 
(Treatment A) 30 min after the start of breakfast. One hour and 45 min post Treatment A 
administration, subjects will receive an IV infusion of [14C]-10025 solution (Treatment B). 
Subjects will remain resident in the clinic until up to 48 h post-oral dose (up to Day 3). 
The minimum washout period between dose administrations in Part 1 and 2 will be 
7 days. 
8.1.2 	
Study Plan Part 2 
Part 2 is an open-label, non-randomised ADME assessment in 6 healthy male subjects. 
Following a minimum washout period of 7 days, subjects who participated in Part 1 of 
the study will be admitted to the clinical unit for participation in Part 2 of the study. On 
Day 1 each subject will receive a single oral administration of 200 mg [14q-KD025 
capsule containing (NMT 9.8 MBq) (215 pCi) [14C] (Treatment C) on the morning of Day 1 
after a standard breakfast. 
Treatment 	
IMP Dose 
[14q-KD025 capsule, containing NMT 9.8 MBq (215 pCi) 14C, 
200 mg 
14C:carbon-14, MBq: megabecquerel, pCi: Microcurie, NMT: not more than. IMP is described as free base 
equivalent. 
Details of IMPs can be found in Section 5.2 
A subject in Part 2 will be considered evaluable if they have provided biological samples 
for up to 168 h after drug administration or have demonstrated >90% mass balance 
recovery, or have <1% of the administered dose eliminated in excreta for two consecutive 
days, whichever is the sooner. 
Approximately 7 days after subjects have been discharged from Part 1 of the study, 
subjects will be admitted to the clinical unit on the evening of the day prior to IMP 
administration (Day -1) for the confirmation of eligibility and baseline procedures. 
Subjects will be dosed on the morning following admission (Day 1). Following an 
overnight fast (approximately 10 h), subjects will consume a standard breakfast and will 
receive a single dose of [14q-KD025 capsule (Treatment C) 30 min after the start of 
breakfast. Subjects will remain resident in the clinic until up to 168 h after dosing (up to 
Day 8). It is planned that subjects will be released as a group when all subjects have 
achieved a mass balance cumulative recovery of >90% or if <1% of the dose 
administered has been collected in urine and faeces within 2 separate, consecutive 24 h 
periods. This may result in the subjects being discharged as a group prior to completion 
of the planned residency period. Once the discharge criteria or the planned residency 
period has been achieved, the subjects will undergo discharge assessments and 
collection of all samples (blood, urine and faeces) will be stopped. 
If mass balance criteria have not been met by all subjects on Day 8, the residency period 
for the subjects not achieving the release criteria may be extended up to a maximum of 
216 h post-dose (Day 10). During the additional residency period only urine and/or 
faeces will be collected. If the criterion is still not met by Day 10, or if additional residency 
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Day 1 
[14q-KD025 capsule, 
200 mg  
st, 
 
Day 8C 
Discharge (morning) 
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is not considered appropriate or necessary, then home collections of urine and/or faeces 
may be requested at the discretion of the investigator for individual subjects. To ensure 
ongoing wellbeing of the subjects, a follow-up phone call will take place 5 to 7 days 
post-discharge from the study or after the end of the last collection period. 
An overview of the study is presented below (Figure 1): 
Figure 1 Study Sequence 
Part 2 
Day -1 b  
Admission (evening) 
Part 1 
-1 
Day -28 to Day -2 
Screening 
Day -1 
Admission (evening) 
Day 1 
KD025 Tablet, 200 mg 
+ [14C]-KD025 
20 pg/mL solution for 
IV infusion 
Day 3 
Discharge (morning)a 
Follow-Up Call 
(5 to 7 days post- 
discharge/ after the 
end of the final 
collection period) 
Minimum 7 day 
washout period 
a Discharge time relative to oral dose, 48 h post-dose. 
b Subjects who participated in Part 1 will be admitted to the clinical unit on Day -1 of Part 2 after a minimum 
washout period of 7 days. 
c If mass balance criteria have not been met by all subjects on Day 8, the residency period for the subjects 
not achieving the release criteria may be extended up to a maximum of 216 h post-dose (Day 10). During 
the additional residency period only urine and/or faeces will be collected. If the criterion is still not met by 
Day 10, or if additional residency is not considered appropriate or necessary, then home collections of urine 
and/or faeces may be requested at the discretion of the investigator for individual subjects. 
8.2 	
Criteria for In-Study Decisions 
Not applicable for this study. 
8.3 	
Subject Withdrawal 
If a subject wishes to leave the study at any time, they will be permitted to do so. Every 
reasonable effort will be made by Quotient Sciences to complete a final 
assessment/discharge procedures. Quotient Sciences will advise the sponsor of the 
withdrawal of any subject from the study. 
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Early withdrawal is defined as the date of the decision to withdraw the subject from the 
study. Subject completion is defined as the date of the last procedure conducted or last 
contact (ie phone call/visit) for that subject. 
If a subject requests to leave the clinical unit earlier than the planned discharge time eg 
due to unforeseen personal circumstances, but aims to return to the unit to complete the 
study, this will be documented as a subject self-discharge and a protocol deviation. The 
subject must complete the planned assessments/discharge procedures before discharge 
from the clinical unit and will return for the next study period/assessments, as planned. 
Subjects will be withdrawn from the study drug(s) for the following reasons: 
• Experiencing a serious or severe AE including but not limited to: 
- corrected QT (QTc) interval of >500 msec or increase in QTc interval of 
>60 msec from baseline (confirmed following a repeat ECG) 
- ALT concentration >3 x the upper limit of the reference range 
• Termination of the study 
• Upon the subject's request (withdrawal of consent) 
• Significant deviation from the protocol 
• Concurrent illness or requirement for prohibited medication 
• At the discretion of the investigator/sponsor 
For the purpose of withdrawal criteria in Parts 1 and 2, baseline will be considered as 
the pre-dose Day 1 measurement for each part. 
8.4 	
Subject Replacement 
No replacement subjects are to be used in this study. 
8.5 	
Stopping Criteria 
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met: 
• A serious adverse reaction (le, a serious adverse event considered at least possibly 
related to the IMP administration) in one subject. 
• Severe non-serious adverse reactions (le, severe non-serious adverse events 
considered as, at least possibly related to the IMP administration) in two subjects in 
the same cohort of the study, independent of within or not within the same system 
organ class. 
Relatedness will be determined by the investigator. 
If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a 
substantial amendment. The study may be resumed or terminated; however, it will not 
be resumed until a further substantial amendment to resume the study is submitted and 
approved by MHRA and EC. 
The ARSAC Practitioner will also be informed of the temporary halt 
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8.6 	
Study Termination 
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the MHRA, 
EC and ARSAC practitioner or ARSAC. The end of the trial must be notified to the MHRA 
and EC immediately and at the latest within 15 days after the study is terminated, clearly 
explaining the reasons. A description of any follow-up measures taken for safety reasons 
if applicable, will also be provided. The ARSAC Practitioner and ARSAC will also be 
notified within an appropriate timeframe. 
If the study is abandoned prior to commencement of any protocol activities, the Principal 
Investigator (PI) or sponsor must notify the EC, MHRA, ARSAC practitioner and ARSAC 
(if ARSAC research application has been submitted or approved) in writing outlining the 
reasons for abandonment of the trial. 
Once exposure to ionising radiation and/or dosing has begun, the study will be completed 
as planned unless the following criteria are satisfied that require a temporary halt or early 
termination of the study: 
• The occurrence of serious or severe adverse event(s), as defined in Section 8.5, if 
considered to be related to the IMP, as defined in Section 14.2. 
• New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer acceptable 
for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 6.4 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. The 
MHRA, EC, ARSAC practitioner and ARSAC will be informed of study termination. 
If it becomes necessary to consider termination of the study after dosing has begun, 
dosing may be suspended pending discussion between the investigator, sponsor and 
potentially the ARSAC practitioner (where discussion is related to administration of 
radiation). Dosing will be stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC. 
8.7 	
Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to return for scheduled visits and 
cannot be contacted by the clinical unit. 
If a subject fails to return to the clinical unit for a required study visit: 
The clinical unit must attempt to contact the subject and reschedule the missed visit as 
soon as possible 
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (eg 3 telephone calls on 3 separate 
occasions and, if necessary, an email or letter to the participant's last known email/postal 
address). These contact attempts should be documented in the subject's source. 
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If the subject cannot be contacted, they will be considered lost to follow-up. 
8.8 	
Treatment Allocation 
This is an open-label, non-randomised study, therefore a randomisation schedule will not 
be produced. A treatment allocation list will be produced prior to dosing with IMP, which 
will dictate the order in which the treatments should be administered to each subject. The 
treatment allocation list will be retained in the Investigator Site File (ISF). 
8.8.1 	
Subject Numbers 
Subject numbers will be allocated on the morning of dosing in Part 1 according to the 
code 001 to 006 using the lowest number available. 
8.8.2 	
Blinding 
This is an open-label, non-randomised study and therefore blinding is not required. 
9 	
Selection of Subjects 
Quotient Sciences must have a full medical history from each subject's general 
practitioner (GP) within the last 12 months, prior to enrolment for the study. 
Subjects will be recruited from the Quotient Sciences panel or by direct advertising to the 
public. 
Before subjects are admitted to the clinical unit, The Over Volunteering Prevention 
System (TOPS) will be checked to ensure that each subject has not participated in a 
study at another site within at least 3 months of the dosing date. 
9.1 	
Informed Consent 
Subjects will be provided with a written explanation of the study at least the day before 
the screening visit. A physician or nurse will explain to each subject the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation. Subjects will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies in the local area. Subjects will then be given the opportunity to ask 
questions and will be informed of their right to withdraw from the study without prejudice. 
After this explanation and before entering the study, the subject will voluntarily sign an 
informed consent form (ICF). Until written consent has been obtained from the subject 
no study specific procedure or investigation will be performed. If an amendment is made 
to the participant information sheet (PIS), participants will be re-consented to the most 
current version of the ICF(s) where appropriate. 
9.2 	
Inclusion Criteria 
1. Healthy males 
2. Age 30 to 65 years of age 
3. Good state of health (mentally and physically) as indicated by a comprehensive 
clinical assessment (detailed medical history and a complete physical examination), 
ECG and laboratory investigations (haematology, clinical chemistry and urinalysis) 
4. Body weight 50 kg 
5. Body mass index (BMI) of 18.0 to 35.0 kg/m2  
6. Must be willing and able to communicate and participate in the whole study 
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7. Must have regular bowel movements (le, average stool production of 	
and 
53 stools per day) 
8. Subjects must have participated in Part 1 in order to be eligible for Part 2 
9. Must provide written informed consent 
10. Must agree to adhere to the contraception requirements defined in Section 9.4. 
9.3 	
Exclusion Criteria 
1. Subjects who previously participated in any other investigational study drug trial in 
which receipt of an investigational study drug occurred within 90 days prior to dosing 
2. Subjects who have previously participated in a study where subjects were dosed with 
KD025 (QSC200311 and QCL117415). 
3. Subjects who are study site employees, or immediate family members of ,a study site 
or sponsor employee 
4. Subjects with pregnant partners 
5. History of any drug or alcohol abuse in the past 2 years 
6. Regular alcohol consumption in males >21 units per week (1 unit = 1/2  pint beer, or a 
25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) 
7. Current smokers and those who have smoked within the last 12 months. A breath 
carbon monoxide reading of greater than 10 ppm at screening and admission 
8. Current users of e-cigarettes and nicotine replacement products and those who have 
used these products within the last 12 months 
9. Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic x-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed 
worker, as defined in the Ionizing Radiation Regulations 2017, shall participate in the 
study. 
10. Subjects who have been enrolled in an ADME/IV microtracer study in the last 12 
months 
11. Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator or delegate at screening 
12. Clinically significant abnormal biochemistry, haematology or urinalysis as judged by 
the investigator (laboratory parameters are listed in Appendix 1). Subjects with blood 
platelet count, haemoglobin and red blood cells lower than the reference range will 
be excluded 
13. Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in 
Appendix 1) 
14. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or 
human immunodeficiency virus (HIV) results 
15. Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance (CLcr) of <80 mUmin using the Cockcroft-Gault equation 
16. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or 
GI disease, neurological or psychiatric disorder, as judged by the investigator 
17. Subject has a history or presence of any of the following: 
- Active GI disease requiring therapy 
- Hepatic disease and/or ALT or AST > ULN 
- Renal disease and/or serum creatinine > ULN 
- Other condition known to interfere with the absorption, distribution, 
metabolism or excretion of drugs 
18. Subject has QT interval corrected using Fridericia's formula (QTcF) intervals 
>450 msec at screening or admission 
19. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients 
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20. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hayfever is allowed unless it is active 
21. Donation or loss of greater than 400 mL of blood within the previous 3 months 
22. Subjects who are taking, or have taken, any prescribed or over-the-counter drug 
(other than 4 g of paracetamol per day) or herbal remedies in the 14 days before IMP 
administration (See Section 11.2). Exceptions may apply on a case by case basis, if 
considered not to interfere with the objectives of the study, as agreed by the PI and 
sponsor's medical monitor. 
23. Failure to satisfy the investigator of fitness to participate for any other reason 
Exclusion criteria 7, 13, 18, 21, 22 and 23 from the list above will be re-assessed at 
admission/pre-dose for Part 1 and 2. 
Healthy subjects who do not meet the inclusion/exclusion criteria for a study should not 
be enrolled into the study without exception. 
9.4 	
Contraception 
Male subjects who are sexually active with a partner of child bearing potential must use, 
with their partner, a condom plus an approved method of effective contraception from 
the time of informed consent until 90 days after study discharge. The following methods 
are acceptable: 
• Partner's use of combined (oestrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: 
- oral 
- intravaginal 
- transdermal 
• Partner's use of progestogen-only hormonal contraception: 
- oral 
- injectable/implantable 
- intrauterine hormone-releasing system 
• Partner's use of implantable intrauterine device 
• Surgical sterilisation (for example, vasectomy or partner's bilateral tubal occlusion) 
• Partner's use of female cap or diaphragm (double barrier) 
Alternatively, true abstinence is acceptable when it is in line with the subject's preferred 
and usual lifestyle. If a subject is usually not sexually active but becomes active, they, 
with their partner, must comply with the contraceptive requirements detailed above. 
These contraception requirements are aligned with guidance issued by the Heads of 
Medicines Agency: Clinical Trials Facilitation Group [14]. 
9.4.1 	
Exposure to Partners During the Study 
There is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomised males) that might be harmful to the sexual partners (both male and 
female). Therefore, a condom should be used by all male subjects throughout the study 
and for 90 days after study discharge. 
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9.4.2 	
Sperm Donation 
Male subjects should not donate sperm for the duration of the study and for at least 
90 days after study discharge. 
9.5 	
Pregnancy 
Subjects will be instructed that if their partner becomes pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the 
event that a subject's partner is subsequently found to be pregnant after the subject is 
included in the study, then consent will be sought from the partner and, if granted, any 
pregnancy will be followed and the status of mother and/or child will be reported to the 
sponsor after delivery. 
A pregnancy notification form and follow-up will be completed. 
9.6 	
Additional Study Restrictions 
The following additional restrictions will be in place for the duration of the study: 
1. Subjects must abstain from alcohol during the 24 h prior to screening and the 24 h 
prior to each admission until discharge from each part of the study. 
2. Subjects must not drink liquids or eat food containing grapefruit, cranberry, caffeine 
or other xanthines from 24 h prior to each admission until discharge from each part 
of the study. 
3. Subjects should refrain from eating food containing poppy seeds for 48 h prior to 
screening and for 48 h prior to each admission until discharge from each part of the 
study. 
4. Subjects must not take part in any unaccustomed strenuous exercise from the 72 h 
before the screening visit and then from 72 h prior to each admission until discharge 
from each part of the study. 
10 Study Procedures 
Study procedures will be performed as detailed in the study schedule of assessments in 
Appendix 2 and Appendix 3 and in accordance with Quotient Sciences standard 
operating procedures (SOPs) unless otherwise stated in this protocol. 
10.1 	
Screening 
Within the 28 days preceding first dose, all subjects will be required to undergo a 
screening visit. Screening procedures will be carried out in accordance with the study 
flow chart in Appendix 2. 
If the start of the study is delayed for any reason so that the interval between screening 
and first dose exceeds 28 days, all or part of the screening procedures may be repeated 
at the discretion of the investigator. 
Subjects previously screened generically may participate in this study provided they 
meet the subject selection criteria. Procedures required by this protocol will only be done 
if they were not performed during generic screening. All screening data must be obtained 
within 28 days prior to administration of study medication, as stipulated above. 
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Screening safety procedures such as safety bloods, ECGs, vital signs and urinalysis can 
be repeated as clinically indicated under the discretion of the investigator or sub-
investigator if there is a concern regarding a subject's safety or eligibility to participate in 
the trial. 
10.1.1 	
Subject Re-Screening 
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (ie subject has not been treated); the reason for failure must be 
temporary and expected to resolve. If re-screened, the subject must be re-consented. 
10.2 Admission and Pre-dose Procedures 
The identity of the subjects will be confirmed at admission and pre-dose. 
In addition, the ongoing eligibility of subjects will be re-assessed at admission/pre-dose, 
as described in Section 9.3. 
Admission safety procedures such as safety bloods, ECGs, vital signs, urinalysis and 
drugs of abuse tests can be repeated as clinically indicated under the discretion of 
investigator or sub-investigator if there is a concern regarding a subject's safety or 
eligibility to participate in the clinical trial. 
Subjects will be admitted to the clinical unit on the evening before dosing (Day -1) for 
both Parts 1 and 2. 
The admission and pre-dose procedures are presented in Appendix 2 and Appendix 3. 
10.3 Study Day Procedures 
10.3.1 	
Blood Volume 
The total blood volume for each subject will be approximately 583.5 mL in a 4 week 
period. Subjects with a low blood count will be excluded from participation in this study 
(exclusion criterion 12). The first 0.5 mL of blood withdrawn via cannula will be discarded. 
10.3.2 	
Timing of Procedures 
There are times where the protocol requires more than one procedure to be completed 
at the same time point. In these instances the following will apply to post-dose time 
points: 
PK samples should take priority over other procedures scheduled at the same time point. 
As guidance, the preferred order of assessments is: 
PK blood 
ECGs 	
Vitals 	
eg physical exams 
sampling 
ECGs should be taken prior to vital signs when both measurements are scheduled at the 
same time point. Other assessments, eg physical examinations, will be performed within 
the required time windows. 
All safety assessments in Part 1 will be timed according to the schedule in Appendix 2. 
All safety assessments in Part 2 will be timed and performed relative to the start of 
dosing. 
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10.3.3 	
Discharge from the Clinical Unit 
Part 1 
A subject will be allowed to leave the premises following completion of study-specific 
procedures at 48 h post-dose providing that: 
• no AEs have been reported during the study visit 
• the subject responds in the affirmative when asked if they are feeling well 
If any of these conditions are not met, then the subject will only be allowed to leave the 
clinical unit with the authorisation of the investigator or appropriately qualified delegate. 
There will be no continued provision of the study intervention or treatment for subjects 
as this study involves healthy volunteers only. 
Part 2 
A subject will be allowed to leave the premises following completion of study-specific 
procedures at 168 h post-dose providing that: 
• no AEs have been reported during the study visit 
• the subject responds in the affirmative when asked if they are feeling well 
Subjects will be dosed on the morning of Day 1 following a standard breakfast, and will 
remain resident in the clinical unit until up to 168 h after dosing (up to Day 8). It is planned 
that subjects will be released as a group when all subjects have achieved a mass balance 
cumulative recovery of >90% or if <1% of the dose administered has been collected in 
urine and faeces within 2 separate, consecutive 24 h periods. This may result in the 
subjects being discharged as a group prior to completion of the planned residency 
period. Once the discharge criteria or the planned residency period has been achieved, 
the subjects will undergo discharge assessments and collection of all samples (blood, 
urine and faeces) will be stopped. If mass balance criteria have not been met by all 
subjects on Day 8, the residency period for the subjects not achieving the release criteria 
may be extended up to a maximum of 216 h post-dose (Day 10, 2 additional 24 h 
periods). If the criterion is still not met by Day 10, or if additional residency is not 
considered appropriate or necessary, then home collections of urine and/or faeces may 
be requested at the discretion of the investigator for individual subjects. 
If any of these conditions are not met, then the subject will only be allowed to leave the 
clinical unit with the authorisation of the investigator or appropriately qualified delegate. 
There will be no continued provision of the study intervention or treatment for subjects 
as this study involves healthy volunteers only. 
	
10.3.4 	
Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available 
at all times during the study. In accordance with the current Association of the British 
Pharmaceutical Industry guidelines [16], each subject will receive a card stating the 
telephone number of the investigator. 
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10.3.5 	
Follow-up 
A follow-up phone call will take place 5 to 7 days after discharge/after the final collection 
period to ensure the ongoing wellbeing of the subjects. If a subject reports any AEs which 
can present a cause for concern, they will be required to attend the clinic for a further 
follow-up assessment (as an unscheduled visit). Completion of the last follow-up call or 
unscheduled follow-up visit will be considered the end of the study. 
11 	
Dosing of Subjects 
11.1 	
Food and Fluid Intake 
Subjects will be allowed water up to 1 h before the scheduled dosing time and will be 
provided with 240 mL of water at 1 h post-dose. Water will be allowed ad libitum after 1 h 
post-dose. Decaffeinated fluids will be allowed ad libitum from lunch time on the day of 
dosing. In Part 1, the water restrictions before and after dosing only apply to the oral 
dose. If, for technical reasons, dosing is delayed for more than 2 h beyond the expected 
dosing time, subjects will receive 200 mL of Lucozade Sport at the originally scheduled 
dosing time, or earlier if possible. 
Breakfast will be controlled by clinical staff members on Day 1 for both study Parts. The 
start and stop time of the meal and the percentage consumed must be recorded in the 
source. 
Subjects will be provided with a light snack and will fast from all food and drink (except 
water) until the following morning, when they will be provided with a standard breakfast. 
The breakfast should be consumed over a maximum period of 25 min, with oral dosing 
occurring 30 min after the start of breakfast. Subjects should be encouraged to eat their 
meal evenly over the 25 min period. It is acknowledged that some subjects will take less 
time to eat, but dosing should still occur 30 min after the start of breakfast. 
The acceptable deviation for the pre-dose meal from the nominal time point is: 
• Pre-dose meal will be provided within ± 5 min of the nominal time point 
Lunch will be provided at approximately 4 h post-dose, an evening meal at approximately 
10 h post-dose and an evening snack at approximately 14 h post-dose. On subsequent 
days, meals will be provided at appropriate times. 
Part 2 only: If an individual subject has not experienced a bowel movement in any 36-h 
period post-dose, fluid intake should be increased and administration of a mild laxative 
(eg, prune juice or a mild stool softener) should be implemented. 
11.2 	
Administration of Test Preparations 
Specific details of IMPs and doses to be administered are provided in Section 5.2 and 
Section 8.1.1, respectively. Subjects will be dosed on the morning of Day 1 of each study 
part. 
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Part 1 
Subjects will receive a single oral dose of KD025 in the fed state. 240 mL of water will 
be given immediately following oral administration. One hour and 45 min after the oral 
dose has been administered, an 14C radiolabelled IV dose will be infused over 15 min. 
This infusion will be in the opposite arm being used for PK sampling. 
To assess tolerability of the IV administration, the first subject will be dosed at least 
30 min prior to dosing the second subject. All subsequent dosing of the IV formulation 
will be staggered by at least 15 min. 
The exact time of dosing will be decided based on logistics and will be documented in 
the source. 
Part 2 
Subjects will receive a single oral dose of [14q-KD025 in the fed state on one dosing 
occasion. 240 mL of water will be given immediately following oral administration. 
The exact time of dosing will be decided based on logistics and will be documented in 
the source. 
11.1 Dosing Compliance 
During all clinical phases of the study, subjects will be observed by study staff to assure 
compliance to all study procedures, including dose administration. 
Mouth and hand checks will be conducted after dosing to ensure the tablet/capsule has 
been swallowed. 
Part 1 only: The IV dose will be administered by trained staff to ensure dosing 
compliance. 
The date and time that each subject is dosed will be recorded in the subject's source 
data. Any violation of compliance will require evaluation by the investigator and sponsor 
to determine if the subject can continue in the study. 
11.2 	
Prior and Concomitant Medications 
No medication will be permitted from 14 days before IMP administration until the 
follow-up call except 4 g of paracetamol per day and those deemed necessary by the 
investigator to treat AEs (see also Section 9.3). Any medications used will be recorded 
in the source. 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the unlikely event that they are required, their use will be 
documented. 
12 Assessment of Efficacy 
Not applicable for this Phase I study. 
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13 Assessment of Mass Balance, Pharmacokinetics, Metabolic 
Profiling and Identification and Pharmacodynamics 
13.1 	
Assessment of Mass Balance, Pharmacokinetics and Metabolic Profiling 
and Identification 
13.1.1 	
Blood Sampling 
Venous blood samples will be collected from the subjects by a trained member of the 
clinical team. Consent will be collected from the subjects for use of these samples for the 
purposes of the proposed study. Pharmacokinetic analysis will be carried out on blood 
samples. 
Blood samples are sent for laboratory testing in linked anonymised form (subject number 
and initials only). This information is able to be linked directly to the volunteer by the 
Quotient research team and study monitor, however not by the laboratory staff or 
sponsor. 
Venous blood samples will be withdrawn via an indwelling cannula or by venepuncture 
according to the time schedule presented in Appendix 2 and Appendix 3. 
The acceptable deviations from the nominal blood sampling times are as follows: 
• The pre-dose blood sample will be taken 51 h before dosing 
• 0 to 1 h post-dose samples will be taken within ± 2 min of the nominal post-dose 
sampling time 
• >1 to 12 h post-dose samples will be taken within ± 10 min of the nominal post-dose 
sampling time 
• >12 h post-dose samples will be taken within ± 30 min of the nominal post-dose 
sampling time if subjects are resident in the clinical unit 
For timings of PK sampling relative to dosing, see Appendix 2 and Appendix 3. 
Samples will be collected into appropriate tubes as specified by the bioanalytical 
laboratory. Details of sample tubes and processing will be contained in the 
Clinical Sample Processing Manual. 
Samples will be shipped to Covance Laboratories Ltd for the analysis of KD025 (Part 1 
and 2) and metabolites KDO25m1 and KDO25m2 (Part 2 only). Samples will be shipped 
to Xceleron Inc., A Pharmaron Company for the analysis of [14C]-KD025 (Part 1 only). 
Samples will be shipped to Pharmaron for the analysis of plasma and whole blood total 
radioactivity. 
13.1.2 	
Urine Sampling (Part 2 only) 
Urine samples will be collected according to the time schedule presented in Appendix 3. 
A single urine sample will be taken at pre-dose (the first void of the day). Where a sample 
is not provided, this will not be considered a deviation. All individual urine voids will be 
collected and shipped to the bioanalytical laboratory for analysis, according to Quotient 
Sciences SOPs, unless indicated otherwise by the sponsor. 
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Samples will be collected into appropriate containers as specified by the bioanalytical 
laboratory. Details of sample containers and processing will be contained in the Clinical 
Sample Processing Manual. 
Samples will be shipped to Pharmaron for the analysis of total radioactivity, metabolite 
profiling and identification in urine. 
13.1.3 	
Faecal Sampling (Part 2 Only) 
Faecal samples will be collected according to the time schedule presented in Appendix 3. 
The pre-dose faecal sample will be taken from admission until dosing. If a pre-dose 
faecal sample cannot be obtained, the subject will still be dosed. Where a sample is not 
provided, this will not be considered a deviation. 
Samples will be collected into appropriate pots/containers as specified by the 
bioanalytical laboratory. Details of sample containers and processing will be contained 
in the Clinical Sample Processing Manual. 
Samples will be shipped to Pharmaron for the analysis of total radioactivity, metabolite 
profiling and identification in faeces. 
13.1.4 	
Unexpected Sources of Elimination 
During the study, other accidental sources of elimination will be collected as voided (eg 
emesis). 
Samples will be shipped to Pharmaron for the analysis of total radioactivity. 
13.2 Assessment of Pharmacodynamics 
Not applicable for this Phase I study. 
14 Assessment of Safety 
14.1 	
Definition and Classification of Adverse Events 
An AE is any untoward medical occurrence in a subject that occurs either before dosing 
(referred to as a pre-dose AE) or once a medicinal product has been administered, 
including occurrences which are not necessarily caused by or related to that product. 
An adverse drug reaction (ADR) is any AE where a causal relationship with the IMP is at 
least a reasonable possibility (possibly related or related). 
AEs will be monitored from the time the subject signs the ICF until after the final follow-up 
call. The severity of AEs should be assessed as follows: 
Mild 	
An AE that is easily tolerated by the subject, causes minimal discomfort and 
does not interfere with everyday activities 
Moderate An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed 
Severe 	
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 
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14.2 	
Assessment of Causality 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the IMP. The temporal relationship of the event to IMP 
administration should be considered in the causality assessment (ie if the event starts 
soon after IMP administration and resolves when the IMP is stopped). 
Causality should be assessed using the following categories: 
Unrelated: 
Clinical event with an incompatible time relationship to IMP 
administration, and that could be explained by underlying 
disease or other drugs or chemicals or is incontrovertibly not 
related to the IMP 
Possibly related: 	
Clinical event with a reasonable time relationship to IMP 
administration, and that is unlikely to be attributed to concurrent 
disease or other drugs or chemicals 
Related: 
Clinical event with plausible time relationship to IMP 
administration and that cannot be explained by concurrent 
disease or other drugs or chemicals 
The degree of certainty with which an AE is attributed to IMP administration (or 
alternative causes, eg natural history of the underlying disease, concomitant therapy, 
etc) will be determined by how well the experience can be understood in terms of one or 
more of the following: 
• known pharmacology of the IMP 
• reactions of a similar nature have been previously observed with the IMP or this class 
of drug 
• the experience being related by time to IMP administration, terminating with IMP 
withdrawal or recurring on re-challenge 
• alternative cause 
14.3 	
Recording Adverse Events 
AEs will be recorded from the time of providing written informed consent until discharge 
from the study at the follow-up call. During each study visit the subject will be questioned 
directly regarding the occurrence of any adverse medical event according to the 
schedule in the source. All AEs, whether ascribed to study procedures or not, will be 
documented immediately in the source. This will include the date and time of onset, a 
description of the AE, severity, duration, actions taken, outcome and an investigator's 
current opinion on the relationship between the study drug and the event. A diagnosis 
and final opinion on the relationship between the study drug and the event will be 
provided at the end of the study by the investigator. 
Any subject who withdraws from the study due to an AE will be followed up until the 
outcome is determined and written reports provided by the investigator. 
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14.4 	
Serious Adverse Events 
14.4.1 	
Definition of Serious Adverse Events 
A SAE is defined as any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
• requires hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability or incapacity 
• consists of a congenital anomaly or birth defect 
• an important medical event as recognised by the PI 
SAEs must be immediately reported to the sponsor. 
14.4.2 	
Definition of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed 
to be related to an IMP and are both unexpected (ie the nature or severity is not expected 
from the information provided in the IB) and serious. SUSARs are subject to expedited 
reporting to the MHRA, EMA and EC (see Section 16.3.2 for details on reporting 
SUSARs). 
14.5 	
Laboratory Measurements 
Venous blood, urine and faecal samples will be collected from the subjects by a trained 
member of the clinical team. Consent will be collected from the subjects for use of these 
samples for the purposes of the proposed study. 
Blood, urine and faecal samples are sent for laboratory testing in linked anonymised form 
(subject number, initials, and the subjects' gender and date of birth for analytical 
reasons). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor, however not by the laboratory staff or sponsor. 
Safety laboratory tests and virology will be carried out on blood samples, and drugs of 
abuse tests and urinalysis will be carried out on urine samples. Urine and faecal samples 
will be analysed for total radioactivity. The research will not involve analysis or use of 
human DNA. 
Blood and urine samples results will be reviewed by a physician and acted upon before 
the subject is dosed or receives their next dose, or is released from the study, as is 
appropriate. A list of the laboratory parameters measured is presented in Appendix 1. 
14.5.1 	
Haematology and Clinical Chemistry 
Laboratory tests will be performed by The Doctors Laboratory according to the time 
schedule presented in Appendix 2 and Appendix 3. Blood samples will be collected and 
processed as detailed in the Clinical Sample Processing Manual. Scheduled blood 
samples will be taken following an 8 h fast. 
The acceptable deviations from the nominal blood sampling time points for laboratory 
assessments are: 
• The pre-dose blood sample will be taken h before dosing 
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• Post-dose blood samples will be taken ± 1 h from the nominal blood sampling time 
except when the time point coincides with the PK blood sampling time. In this 
situation, the time window for the PK sample applies 
CLcr will be calculated at screening by The Doctors Laboratory using the Cockcroft-Gault 
equation and body weight. 
CLcr (mUmin) = (140-aqe Eyears1) x (body weight fkcii) (x 1.23) 
serum creatinine (pmol/L) 
14.5.2 	
Urinalysis 
Urinalysis will be performed on-site using a dipstick according to the time schedule 
presented in Appendix 2 and Appendix 3. Urine samples will be collected and processed 
as detailed in the Clinical Sample Processing Manual. If microscopy is required, a urine 
sample will be sent to The Doctors Laboratory. 
The acceptable deviations from the nominal urine sampling time points for urinalysis are: 
• The pre-dose urine sample will be taken s3 h before dosing or the first void of the 
day 
• Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time 
14.5.3 	
Drug Screen 
A urine drug screen will be performed on-site using a dipstick method according to the 
time schedule presented in Appendix 2 and Appendix 3. The sample will be collected 
and processed as detailed in the Clinical Sample Processing Manual. Subjects will be 
screened for the drugs of abuse listed in Appendix 1. 
14.5.4 	
Alcohol Breath Test 
An alcohol breath test will be performed according to the time schedule presented in 
Appendix 2 and Appendix 3. A positive result will exclude the subject from dosing during 
that admission. 
14.5.5 	
Carbon Monoxide Breath Test 
A carbon monoxide breath test will be performed according to the time schedule 
presented in Appendix 2 and Appendix 3. A result of greater than 10 ppm will exclude 
the subject from the study. 
14.5.6 	
Abnormal Laboratory Findings 
In cases where laboratory findings are outside the normal range and the investigator 
believes that the results may be of clinical significance, repeat sampling may be 
requested as clinically indicated. If the abnormal finding is clinically significant, 
appropriate actions will be taken eg, the subject will not be entered into the study or the 
subject may be withdrawn from the study. The subject will be referred to their GP or other 
appropriate provider for further care. The same will apply if the results of the HBsAg, 
HCV Ab or HIV test are positive and in addition the investigator will ensure that adequate 
counselling is available if requested. 
Abnormal results at follow-up assessments will also require repeat testing if the 
investigator believes the results may be of clinical significance. 
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Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
Additional blood and/or urine samples may be taken for safety tests. Furthermore, 
additional assays outside those specified in the protocol may be performed for safety 
reasons as requested by the investigator. 
	
14.6 	
Vital Signs Measurements 
Blood pressure and heart rate will be measured by an automated recorder after the 
subject has been in a supine position for a minimum of 5 min according to the time 
schedule presented in Appendix 2 and Appendix 3. Oral temperature will also be 
measured. The acceptable deviations from the nominal vital signs measurement time 
points are: 
• The pre-dose vital signs measurements will be taken 5.2 h before dosing 
• Post-dose vital signs measurements will be taken ± 15 min from the nominal 
post-dose time points 
• Discharge vital signs measurements will be taken ± 1 h from the nominal time point 
If a subject shows an abnormal assessment at any stage, repeat measurements may be 
made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator. 
Any clinically significant abnormality, including changes from baseline, must be reported 
as an AE. 
14.7 ECG Measurements 
12-lead ECGs will be measured after the subject has been in the supine position for a 
minimum of 5 min according to the time schedule presented in Appendix 2 and 
Appendix 3. 
The acceptable deviations from the nominal ECG measurement time points are: 
• The pre-dose ECG measurements will be taken h before dosing 
• Post-dose ECG measurements will be taken ± 15 min from the nominal post-dose 
time point 
• Discharge ECG measurements will be taken ± 1 h from the nominal time point. 
If a subject shows an abnormal assessment at any stage, repeat measurements may be 
made and the abnormality followed to resolution if required. Additional measurements 
may be taken as deemed necessary by the investigator. 
Any clinically significant abnormality, including changes from baseline, will be reported 
as an AE. 
	
14.8 	
Body Weight and Height 
The subject's body weight and height will be measured as detailed in Appendix 2 and 
Appendix 3. 
	
14.9 	
Physical Examination 
Subjects will undergo a physical examination as detailed in Appendix 2 and Appendix 1 
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14.10 Additional Safety Procedures 
Additional non-invasive procedures that are already specified in the protocol may be 
performed, if it is believed that an important effect of the IMP(s) is occurring or may occur 
at a time when no measurements are scheduled, or if extra procedures are needed in 
the interests of safety. 
Additional blood samples for safety assessments may be taken if required by the 
investigator at any point. 
15 Statistics and Data Analysis 
15.1 	
Sample Size Justification 
No sample size calculation was performed. For a study of this type, a sample size of 6 
subjects, to ensure data in 4 evaluable subjects is considered appropriate to meet the 
objectives of the study. 
15.2 	
Data Management 
Data management will be performed by Quotient Sciences. 
All study data recorded in the source, will be recorded in a validated study database that 
has an audit trail to log all subsequent changes to the data. All queries will be resolved 
within the study database. 
AEs and medications will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) (v22.0 or a more recent version) and the World Health Organisation (WHO) 
Drug Dictionary Global Drug Reference (2019 or a more recent version), respectively. An 
independent coding review will also be performed within the Data Sciences department. 
Clinical chemistry and haematology (and other safety laboratory data) will be collected 
by a central laboratory (The Doctors Laboratory) and stored electronically in their clinical 
pathology system. The data will be transferred electronically to Quotient Sciences and 
all demographic details and sample dates will be cross-referenced with the 
corresponding data on the study database. All queries will be resolved with the 
assistance of laboratory staff, or if necessary, clinical staff. 
The database will be closed after all queries have been resolved. The database will be 
locked when all criteria listed in the Data Management Plan (DMP) are met. 
Further details are addressed in the DMP. 
15.3 	
Mass Balance and Pharmacokinetic Data Analysis 
15.3.1 	
Mass Balance Data Analysis 
Urine and faecal samples will be collected for the analysis of total radioactivity in Part 2. 
The following mass balance parameters will be calculated by Quotient Sciences from 
urine and faeces separately and total (urine and faeces combined): Ae, %Ae, Cum Ae 
and Cum %Ae. 
Ae(urine), Cum Ae(urine), Ae(faeces), Cum Ae(faeces), Ae(total) and Cum 
Ae(total): amount excreted and cumulative amount excreted in urine, faeces and total 
(urine and faeces combined). 
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%Ae(urine), Cum %Ae(urine), %Ae(faeces), Cum %Ae(faeces), %Ae(total) and 
Cum %Ae (total): amount excreted and cumulative amount excreted in urine, faeces 
and total (urine and faeces combined) expressed as a percentage of the administered 
dose. 
For Urine: 
• Ae: Total radioactivity 
• %Ae: Total radioactivity expressed as a percentage of the dose 
• Cum Ae: Cumulative recovery of total radioactivity 
• Cum %Ae: Cumulative recovery expressed as a percentage of the dose 
For Faeces: 
• Ae: Total radioactivity 
• %Ae: Total radioactivity expressed as a percentage of the dose 
• Cum Ae: Cumulative recovery of total radioactivity 
• Cum %Ae: Cumulative recovery expressed as a percentage of the dose 
For Mass Balance Recovery of Total Radioactivity from all excreta: 
• Ae: Total radioactivity 
• %Ae: Total radioactivity expressed as a percentage of the dose 
• Cum Ae (Total): Cumulative recovery of total radioactivity 
• Cum %Ae (Total): Cumulative recovery expressed as a percentage of the dose 
Further analysis details will be included in the Reporting and Analysis Plan (RAP). 
15.3.2 	
Pharmacokinetic Data Analysis 
The plasma concentration data for KD025, KDO25m1 and KDO25m2 provided by 
Covance Laboratories Ltd, the plasma [14q-KD025 concentration data provided by 
Xceleron Inc., A Pharmaron Company and the plasma and whole blood total radioactivity 
data provided by Pharmaron will be analysed by Quotient Sciences, using 
Phoenix WinNonlin v8.0 or a more recent version (Certara USA, Inc., USA). 
Calculated KD025, KDO25m1 and KDO25m2 concentrations in plasma may be corrected 
for specific activity of the administered radiolabelled oral dose by the Data Sciences 
department at Quotient Sciences. 
Part 1 
Plasma concentration data will be tabulated and plotted for each subject for whom 
concentrations are quantifiable. PK analysis of the concentration time data obtained will 
be performed using appropriate non-compartmental techniques to obtain estimates of 
the following PK parameters where possible and appropriate: 
For Plasma [14q-KD025 following IV administration 
• Tmax: Time of maximum observed concentration 
• Cmax: The maximum observed plasma concentration 
• AUC(0-last): Area under the curve from 0 time to the last measurable concentration 
• AUC(0-inf): The area under the concentration-time curve from dosing extrapolated 
to infinity 
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• AUC%extrap: Percentage of AUC(0—inf) extrapolated beyond last measured time 
point 
• lambda-z: The first order rate constant associated with the terminal (log-linear) 
portion of the curve 
• T1/2: The apparent terminal elimination half-life 
• CL: Total clearance 
• Vz: Volume of distribution based on area 
• Vss: Volume of distribution at steady state 
• MRT: Mean residence time 
For Plasma KD025 following oral administration 
• Tlag: Time prior to the first measurable (non-zero) concentration 
• Tmax: Time of maximum observed concentration 
• Cmax: The maximum observed plasma concentration 
• AUC(0-last): Area under the curve from 0 time to the last measurable concentration 
• AUC(0-inf): The area under the concentration-time curve from dosing extrapolated 
to infinity 
• AUC%extrap: Percentage of AUC(0—inf) extrapolated beyond last measured time 
point 
• lambda-z; The first order rate constant associated with the terminal (log-linear) 
portion of the curve 
• 
T112: The apparent terminal elimination half-life 
• F: Bioavailability of oral formulation compared to IV 
• CL/F: Apparent clearance 
• Vz/F: Apparent volume of distribution 
• MRT: Mean residence time 
Part 2 
Plasma concentration data will be tabulated and plotted for each subject for whom 
concentrations are quantifiable. PK analysis of the concentration time data obtained will 
be performed using appropriate non-compartmental techniques to obtain estimates of 
the following PK parameters where possible and appropriate: 
For Total Radioactivity, KD025, KDO25m1 and KDO25m2 in plasma: 
• Tlag: Estimated time from dosing at which the analyte was first quantifiable in a 
concentration versus time profile 
• Tmax: Time of maximum observed concentration 
• Cmax: The maximum observed plasma concentration 
• AUC(0-last): Area under the curve from 0 time to the last measurable concentration 
• AUC(0-inf): The area under the concentration-time curve from dosing extrapolated 
to infinity 
• AUC%extrap: Percentage of AUC(0—inf) extrapolated beyond last measured time 
point 
• lambda-z: The first order rate constant associated with the terminal (log-linear) 
portion of the curve 
• 
T112: The apparent terminal elimination half-life 
• Cl/F: Apparent clearance KD025 only 
• Vd/F: Apparent volume of distribution KD025 only 
• MRT: Mean residence time 
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• Metabolite:Parent ratio for KD025m1 and KD025m2 
• whole blood/plasma total radioactivity concentration ratios will be calculated at 
selected time points. 
Further details of the PK data analysis will be included in the RAP. 
15.3.3 	
Metabolite Profiling and Identification 
Metabolite profiling of plasma, urine and faeces will be performed using liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate. 
Identification of the chemical structure of each metabolite accounting for greater than 
10% of circulating radioactivity in plasma ("AUC pool") and accounting for greater than 
10% of the dose in the urine and faeces (from urine pools and faeces homogenate pools) 
will be performed. 
These aspects will be reported separately from the clinical study report as a standalone 
document. 
15.4 	
Statistical Data Analysis 
Production of summary tables, figures and listings for this study will be performed by 
Quotient Sciences using the statistical package SAS (v9.4 or more recent version). 
No formal statistical analysis will be performed for this study. Descriptive statistics 
(eg mean, median, standard deviation [SD], minimum, maximum and number of subjects 
with an observation [n]) are considered adequate for a study of this type. Additional 
statistics will be provided for PK-related data, including coefficient of variation (CV%), 
geometric mean, geometric CV% and geometric n (ie number of subjects with an 
observation that are included in the natural logarithmic transformation). 
Populations for analysis will be determined for safety, PK, and mass balance data after 
database lock using the criteria defined in the RAP; the RAP will be signed off prior to 
database lock. 
All populations will be defined after database lock when the relevant data are available. 
Further details relating to the statistical analysis will be included in the study-specific RAP 
including the following: 
• Criteria to be used to define each of the analysis populations 
• Additional detail covering the analyses and/or description of primary and secondary 
analyses and safety data 
• Handling of missing data, unused or spurious data 
• Handling of data from withdrawn subjects 
All safety, mass balance recovery and PK data will be listed. 
15.5 	
Interim Analysis 
No formal interim analyses are planned for this study. 
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16 Safety Reporting to Ethics Committees and Regulatory 
Authorities 
16.1 	
Events Requiring Expedited Reporting 
SUSARs (Section 14.4.2) are subject to expedited reporting to the MHRA, EMA and EC. 
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would 
be sufficient to consider changes in the IMPs administration or in the overall conduct of 
the study, for instance: 
• an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important 
• SAEs that occur after the subject has completed the clinical study where the sponsor 
considers them to be a SUSAR 
• new events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the subjects, such as: 
- an SAE which could be associated with the study procedures and which 
could modify the conduct of the study 
- a major safety finding from a newly completed animal study (such as 
carcinogenicity) 
- any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor 
16.2 	
Urgent Safety Measures 
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined as: 
• An immediate hazard to the health or safety of subjects participating in a clinical study 
• A serious risk to human health or potentially a serious risk to human health 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe 
conduct of the study or that pose a risk to study subjects. 
In exceptional circumstances of imminent hazard and in order to safeguard the health or 
safety of individuals, Quotient Sciences may take urgent safety measures before 
informing the sponsor, but the sponsor must be informed immediately after the hazard 
has resolved. 
Quotient Sciences will take responsibility for informing appropriate competent 
authorities, and the EC. 
16.3 	
Reporting 
16.3.1 	
Reporting Serious Adverse Events 
The investigator is required to notify the study sponsor within 24 h of becoming aware of 
the occurrence of an SAE or serious adverse reaction. A copy of the written report of the 
event should promptly be sent to the study sponsor for information purposes, in 
accordance with ICH guidelines for GCP. 
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Contact information for SAE/SUSAR reporting: 
APCER Life Sciences, LLC 
Fax: +44-3308084297 
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, MB BChir (Cantab) MRCP (UK). 
Kadmon Corporation, LLC 
55 Cambridge Parkway, Suite 300E 
Cambridge, MA 02142 
Telephone: Direct: 724-778-6129 
Mobile: 857-253-8642 
E-mail: Sanjay.AgganNal@kadmon.com  
	
16.3.2 	
Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) 
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible. 
	
16.3.3 	
Expedited Reporting of Events 
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. Any additional relevant information should be sent within 
8 days of the report. This responsibility may be delegated to the pharmacovigilance 
provider. 
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction. Any additional 
relevant information should be sent within 8 days of the report. 
The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity 
Other SUSARs 
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of the 
reaction. This responsibility may be delegated to the pharmacovigilance provider. 
The investigator is required to notify the EC of other SUSARs as soon as possible, but 
no later than 15 calendar days after they first became aware of the reaction. 
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The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity 
16.3.4 	
Reporting of Urgent Safety Issues 
Quotient Sciences is required to inform the appropriate competent authorities and the 
EC within 3 calendar days of the urgent safety issue. 
16.4 	
Serious Breaches 
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the subjects of the study or the scientific value of the study. 
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach. 
17 Protocol Amendments and Deviations 
17.1 	
Amendments 
After the protocol has been submitted to the MHRA and/or EC, any amendment must be 
agreed by the investigator after discussion with the sponsor and will be formally 
documented. 
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations. Any amendments relating to the administration of 
radioactive substances will be reviewed by the ARSAC practitioner prior to submission 
to ARSAC as required by the current ARSAC Notes for Guidance. The ARSAC 
practitioner will also be notified of any substantial amendments to the PIS and ICF and/or 
protocol. 
If the PIS and ICF are updated as a result of the substantial amendment, the new 
approved versions will be used to re-consent currently enrolled subjects and must be 
provided to additional subjects prior to their entry into the study. 
17.2 	
Protocol Deviations 
The study must be conducted in accordance with the Clinical Protocol. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of these 
non-compliances should be reported to the MHRA as a serious breach of GCP and the 
Clinical Protocol. 
Protocol waivers are not acceptable. 
Deviations from the protocol will be recorded in the source as noted by the clinical staff. 
If necessary, the sponsor will be informed of the deviation. 
Any protocol deviations assessed as major will be discussed with the sponsor in order 
to determine if the withdrawal criteria stated in Section 8.3 have been met. 
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18 Regulatory 
18.1 	
Compliance 
This study will be conducted in accordance with the protocol and with the following 
legislation: 
• International Council for Harmonisation Good Clinical Practice (GCP) Guidelines 
approved by the Committee for Medicinal Products for Human Use (CHMP) on 
17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated 
Addendum E6 (R2) dated 09 Nov 2016 [16] 
• The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 
2004 No. 1031 [17] 
• The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2006 No. 1928 [18] 
• The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984 [19] 
• The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941 [20] 
• Health and Safety. The Ionising Radiations Regulations 2017. Statutory Instrument 
2017 No. 1075 [21] 
• Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322 [22] 
In addition, the study will be performed according to the ethical principles outlined in the 
World Medical Association Declaration of Helsinki and its amendments [23]. 
	
18.2 	
Ethics Approval 
Prior to the initiation of the study, the protocol and associated documentation must be 
given a favourable opinion by an EC. A copy of this written approval and any 
correspondence with the EC will be provided to the sponsor. 
18.3 MHRA Approval 
Prior to the initiation of the study, the Clinical Trial Authorisation application must be 
approved by the MHRA. A copy of this approval and any correspondence with the MHRA 
will be available at the clinical and sponsor sites. A copy of the MHRA approval will be 
provided to the EC. 
	
18.4 	
Administration of Radiation 
Dr Stuart Mair will be the ARSAC practitioner for this study, which includes the 
administration of radiation at Quotient Sciences. Administration will be conducted in 
accordance with Dr Mair's ARSAC practitioner licence (P66) and Quotient's ARSAC 
Employer licence (E8). Additionally a research application will be submitted to ARSAC 
to obtain approval for the conduct of the study before dosing. 
Before submitting to the ARSAC, a summary of available nonclinical tissue distribution 
and excretion information on [14C]-KD025 will be submitted to the Radiation Protection 
Division of PH E for human dosimetry calculations in order to facilitate the selection of the 
dose of radioactivity to be administered. The final report from the PHE will be included in 
the application to the ARSAC. 
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The protocol will be reviewed and the final version will be approved by the ARSAC 
practitioner, Dr Stuart Mair. 
18.5 	
Source Data 
A study-specific source document identification list will be finalised with the sponsor prior 
to the start of the clinical phase of the study. The document will identify what data should 
be considered source data for this study. 
For this study, electronic data capture will be used where possible and data will be 
automatically recorded into an electronic case report form. In instances where paper 
source documents are used, data to be transcribed into the electronic case report form 
will be identified using a Source Document Identification List, as governed by Quotient 
Sciences SOPs. 
18.6 	
Declaration of the End of the Study 
The definition of the end of the study is defined as the last visit of the last subject 
(eg follow-up phone call). Any changes to this definition will be notified as a substantial 
amendment (see Section 17.1). 
The EC and MHRA should be notified in writing of the conclusion of the study within 
90 days of the end of the study, or within 15 days if the study is terminated early, clearly 
explaining the reasons for the termination. 
ARSAC and the ARSAC Practitioner will also be notified of the end of trial or early 
termination of the trial in writing within an appropriate timeframe. 
18.7 	
Document Storage and Archiving 
All documentation and correspondence pertaining to the study (source data, raw data, 
letters etc) will be kept in accordance with the ICH guidelines for Good Clinical Practice 
1996, updated 2002 (ICH GCP Section 4.9.5) [16], The Medicines for Human Use 
(Clinical Trials) Regulations 2004 [17] and The Medicines for Human Use (Clinical Trials) 
Amendment Regulations 2006 [18][19]. 
All study related documents will be retained for a minimum period of 5 years. After this 
time, the sponsor will be contacted to ascertain whether continued storage or destruction 
is required in accordance with current regulations. 
18.8 	
Protection of Personal Data and Confidentiality 
Personal data are securely stored to prevent unauthorised access, disclosure, 
dissemination, alteration or loss of information and unauthorised personal data 
processing. Access to personal information is restricted so that only personnel who are 
required to access personal data as part of their job role can do so. All personnel who 
access personal information are bound by a duty of confidentiality. 
Technical arrangements surrounding the electronic storage and use of data are as 
follows: 
• Computers storing electronic personal data are protected by antivirus software and 
the network on which computers are linked are protected by industry grade firewalls 
• Off-site personnel can only access networked computers through a virtual private 
network (VPN) 
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• Electronic access of data is limited according to user roles 
• All data are stored on password protected computers 
Organisational arrangements are as follows: 
• All buildings are secured by key-card access 
• Manual files of personal data are stored within locked cabinets that can only be 
accessed by authorised personnel 
• Data security and/or confidentiality provisions are utilised in agreements with third 
parties 
• Documented Back-up and disaster recovery procedures are in place 
• Internal audit and compliance functions provide regulatory oversight 
The personal data of volunteers will be pseudonymised in that they will only include 
health, initials, date of birth and demographics (gender and ethnicity) and cannot be 
linked back to the individual by the recipient. The Sponsor shall be the data controller in 
respect of the personal data of the study subjects collected in connection with the study, 
and shall act in accordance with the relevant data protection laws in relation to the 
collection and processing of those personal data. The study subjects' pseudonymised 
personal data shall be collected and processed for the purposes of the study and may 
also be added to research databases and used in the future by the Sponsor and its 
affiliates for certain additional clinical research, for product regulation and safety 
reporting purposes and for ensuring compliance with legal requirements. The study 
subjects' pseudonymised personal data may be processed for such purposes by other 
parties including: the Sponsor's affiliates and licensing partners, its business partners, 
regulatory agencies and other health authorities, and ECs. The study subjects' 
authorisation for such use and disclosure shall be obtained by the study subjects signing 
the ICF for the study. 
Additionally, Quotient personnel are contractually bound by a duty of confidentiality and 
receive training in this matter. 
18.9 	
Data Security Breach 
Quotient has a comprehensive process in place for identifying, assessing, resolving and 
reporting any potential data security breach. All staff are trained in the identification of 
potential data security breaches. Potential breaches are managed by appropriately 
trained quality assurance (QA) personnel in accordance with Quotient Sciences standard 
operating procedures. After robust assessment of data breaches, those deemed serious 
will be reported to the Sponsor and Information Commissioner's Office, as applicable. 
19 Quality Control and Quality Assurance 
Quality control (QC) of all data collected from this study will be performed in accordance 
with Quotient SOPs. This study (or elements thereof) may be subject to QA audit, in line 
with current internal auditing procedures. Similarly, the study (or elements thereof) may 
be subject to sponsor QA audit. 
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19.1 	
Monitoring 
GCP requires that studies are adequately monitored. The sponsor should determine the 
appropriate extent and nature of monitoring. A study monitor, independent of Quotient 
Sciences, will be appointed to verify that the study is conducted in accordance with 
current GCP, regulatory requirements, the protocol and that the data are authentic, 
accurate and complete. 
The investigator agrees to receive visits from a study monitor and provide assistance to 
verify protocol implementation, source completion and transcription of data into the 
electronic case report form, document storage and AE reporting. 
Quotient Sciences will extend the professional privilege of access to the subjects' clinical 
source documents to the study monitor, EC, regulatory bodies or other authorised 
personnel (eg auditor) for the purposes of source data verification. 
Following completion of the study both study related documents and subject data may 
be sent to the sponsor at a location outside of the UK where data protection laws differ. 
In the interests of confidentiality, subjects will not be identified on any such documents 
or data, and specific subject consent for such a disposition will be obtained. 
20 Finance and Insurance 
The sponsor (Kadmon Corporation LLC) has funded this study. A no-fault clinical trials 
insurance has been obtained by the sponsor. The sponsor insurance will compensate 
subjects in accordance with the Association of the British Pharmaceutical Industry 
Guidelines for Phase I Clinical Trials 2018 edition [15]. 
21 Publication 
Please refer to the Master Services Agreement for information on publication. 
22 References 
[1] 
Leung T, Manser E, Tan L, et al. A novel serine/threonine kinase binding the Ras-
related RhoA GTPase which translocates the kinase to peripheral membranes. J 
Biol Chem. 1995;270(49):29051-29054 
[2] 
Nakagawa 0, Fujisawa K, Ishizaki T, et at. ROCK-I and ROCK-II, two isoforms 
of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. 
FEBS Lett. 1996; 392(2):189-193. 
[3] 
Herskowitz JH, Feng Y, Mattheyses AL, et al. Pharmacologic inhibition of ROCK2 
suppresses amyloid-beta production in an Alzheimer's disease mouse model. J 
Neurosci. 2013; 33(49):19086-19098. 
[4] 
Noguchi M, Hosoda K, Fujikura J, et at. Genetic and pharmacological inhibition 
of Rho-associated kinase II enhances adipogenesis. J Biol Chem. 2007; 282(40): 
29574-29583. 
[5] 
Shi J, Surma M, Zhang L, et al. Dissecting the roles of ROCK isoforms in stress-
induced cell detachment. Cell Cycle. 2013; 12(10): 1492-1500. 
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[6] 
Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor 
down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent 
mechanism. Proc Natl Aced Sci U SA. 2014; 111(47):16814-16819. 
[7] 
Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in 
myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013; 
123(3):1096-1108. 
[8] 
Tybulewicz VL, Henderson RB. Rho family GTPases and their regulators in 
lymphocytes. Nat Rev Immunol. 2009; 9(9):630-644. 
[9] 
Biswas PS, Gupta S, Chang E, et al. Phosphorylation of IRF4 by ROCK2 
regulates IL-17 and IL-21 production and the development of autoimmunity in 
mice. J Clin Invest. 2010; 120(9):3280-3295. 
[10] 
lsgro J, Gupta S, Jacek E, et al. Enhanced rho-associated protein kinase 
activation in patients with systemic lupus erythematosus. Arthritis Rheum. 2013; 
65(6):1592-1602. 
[11] 
Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune 
tolerance. Cell. 2008; 133(5):775-787. 
[12] 
Investigator's Brochure for KD025. Edition 8.0; 06 Jul 2018. 
[13] 
Notes for guidance on the clinical administration of radiopharmaceuticals and use 
of sealed radioactive sources. Administration of Radioactive Substances 
Advisory Committee. March 2018. 
[14] 
Heads of Medicines Agency: Clinical Trials Facilitation Group. Recommendations 
related to contraception and pregnancy testing in clinical trials. 15 Sep 2014 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf  
[15] 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2018 Edition (publication date 29 May 2018). 
[16] 
International Council for Harmonisation Good Clinical Practice (GCP) Guidelines 
approved by the Committee for Medicinal Products for Human Use (CHMP) on 
17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated 
Addendum E6 (R2) dated 09 Nov 2016. 
[17] 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031. 
[18] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2006 No. 1928. 
[19] 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984. 
[20] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2008 No. 941. 
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[21] 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory 
Instrument 2017 No. 1075. 
[22] 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322. 
[23] 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects (and all subsequent amendments). 
1 
1 
1 
1 
t 
[ 
1 
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Appendix 1 	
Clinical Laboratory Parameters 
Haematology 
Clinical Chemistry 
Virology 
Urinalysis 
Drugs of Abuse 
Basophils 
Alanine Aminotransferase 
Hepatitis B Surface 
Bilirubin 
Amphetamines 
Eosinophils 
(ALT) 
Antigen 
Blood 
Barbiturates 
Haematocrit 
Albumin 
Hepatitis C Antibody 
Glucose 
Benzodiazepines 
(Packed Cell Volume- PCV) 
Alkaline Phosphatase 
HIV Antibody 
Ketones 
Cocaine 
Haemoglobin 
(ALP) 
Leukocytes 
Marijuana/Cannabis 
Lymphocytes 
Mean Cell Haemoglobin (MCH) 
Mean Cell Haemoglobin Concentration 
Aspartate 
Aminotransferase (AST) 
Bicarbonate 
Nitrites 
pH 
Protein 
Methadone 
Methamphetamine/ 
Ecstasy 
(MCHC) 
Bilirubin (Total) 
Specific gravity 
Morphine/Opiates 
Mean Cell Volume (MCV) 
Monocytes 
Neutrophils 
Bilirubin (Direct) (only if 
Total is elevated) 
Calcium 
Urobilinogen 
At discretion of 
Phencyclidine 
Tricyclic 
Antidepressants 
Platelet Count 
Chloride 
investigator based on 
Red Blood Cell (RBC) Count 
Creatine Kinase (CK) 
urinalysis results 
White Blood Cell (WBC) Count 
Creatininea 
Microbiology 
Gamma Glutamyl 
Urine Microscopy 
Transferase (GGT) 
Glucose 
Glucose (Fasting) 
Potassium 
Phosphate (Inorganic) 
Protein (Total) 
Sodium 
Urea 
.Creatinine clearance will be calculated at screening using the Cockcroft-Gault equation 
^1 
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Appendix 2 
Part 1 Study Flow Chart 
Study Day 
S 
A 
Resident in Clinic 	
--, 
-28 to -2 
-1 
1 
Timepoint relative Oral Dosing (h) 
P 
0 
0.5 0.75 
1 
1.5 
1.75 
1.83 
1.92 
2 
2.08 2.16 2.25 2.5 
2.75 
TImepoint relative to end of IV infusion (h) 
-0.25 
-0.16 
-0.08 
0 
0.08 0.16 0.25 0.5 
0.75 
Gene'falASSeeerneil 
Informed Consent 
X 
Medical History 
X 
X 
Weight and Height (including BMI) 
X 
Vein Assessment 
X 
CO Breath Test 
X 
X 
Drug Screen 
X 
X 
Alcohol Breath Test 
X 
X 
KD025 Oral Administration 
X 
14C]-KD025 IV Administration 
X' 
Safely AeSeSSiteritel: , 
Physical Examination 
X 
Safety Labe' 
X 
X 
Urinalysis 
X 
X 
ECG 
X 
X 
X 
Vital Signs. 
X 
X 
X 
Adverse Events 
4 	
0. 
Prior and Concomitant Medication 
4 	
0. 
Plc ono Total Ratootmei4* 	
tont* 
 
_ 
Plasma Samples for KDO25d 
X 
X 
X 
X 
X 
Plasma samples for [14C]-KD025° 
X 
X 
X 
X 
X 
X 
X 
x 
X 
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Appendix 2 
Part 1 Study Flow Chart (Continued) 
Study Day 
Resident In Clinic 
D 
1 
2 
. .3 
Timepoint relative Oral Dosing (h) 
3 
3.5 3.75 
4 
5 
5.75 
6 
7 
8 
10 
12 
14 
24 
36 
48g 
Timepoint relative to end of IV infusion (h) 
1 
1.5 1.75 
2 
3 
3.75 
4 
5 
6 
8 
10 
12 
22 
34 
469  
Safety Assessments 	
- 
Physical Examination 
V 
Safety Labs, 
 
X 
Urinalysis 
X 
ECG 
X 
X 
X 
X 
Vital Signs. 
X 
X 
X 
X 
Adverse Events 
4 	
0. 
Prior and Concomitant Medication 
4 
picaild Total Radioactivity Assessments 
Plasma Samples for KDO25d 
X 
X 
X 
X 
X 
X 
X 
X 
x 
X 
Plasnia samples for [14C1-KDO25' 
X 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
x 
X 
14C: carbon-14, A: Admission, BMI: Body mass index, CO: carbon monoxide, D: Discharge, ECG: Electrocardiogram; IV: intravenous, P: pre-dose, S: Screening, 
0.08 h: 5 mm, 0.16 h: 10 min. Footnotes on next page 
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.15 min IV infusion of [14q-KD025 solution to be given 1.75 h post oral dose. 
Haematology and clinical chemistry at each time point including virology at screening. Creatinine clearance will be estimated at screening from serum creatinine 
using the Cockcroft-Gault equation. 
d Blood pressure, heart rate and oral temperature will be measured at the time points indicated above relative to the start of the infusion. 
d All post-dose time points are relative to the oral KD025 dose 
'All post-dose time points are relative to the end of the r4C1-KD025 infusion. 
'Targeted (symptom driven) physical examination 
9 Discharge from clinical unit 
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1 	
Appendix 3 
Study Day 
Aa 
Resident In Clinic 
LP 
MP' 
-1 
1 	
1 	
2 	
1 	
3 	
1 4 1 	
5 	
1 	
6 	
1 	
7 
8 
13-15 
P 
Time Relative to KD025 Dosing (h) 
0 
0.5 1 1.5 
2 
3 4 
5 
6 
8 10 12 
24 36 
48 72 96 
120 144 168 
Geheral Msessments- 
Medical History 
X 
Body Weight 
X 
CO Breath Test 
X 
Drug Screen 
X 
Alcohol Breath Test 
X 
[14C)-KD025 Administration 
X 
af6tY.Ases.§.nlent 	
- 
Physical Examlnationd 
X 
Safety Labs° 
X 
X 
Urinalysis 
X 
X 
ECG 
X 
X 
X 
X 
X 
X 
Vital Signs, 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
4 
0- 
Prior and Concomitant Medication 
Mass,Balande•and.PK 	
- 
Assessments 
- 
, 
Plasma Samples for KDO25, KDO25m1, 
10025m2 and TR 
X 
X 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood samples for TR • 
X 
X 
X 
X 
X 
X 
XX 
X 
X 
X 
X 
Plasma Samples for Metabolite Profiling 
and ID 
X 
X 
X 
X 
X 
X 
XX 
X 
X 
X 
X 
Urine Samples for TR9 
4 	
0- 
Faecal Samples for-IR, 
0- 
: ca on- , : Admission, 	
: carbon monoxide, : Discharge, CG: Electrocardiogram, FUP: Follow-up visit/call, ID: Identification, P: Pre-dose, TR: total 
radioactivity Footnotes on next page 
Sponsor/Quotient Sciences Confidential 
Part 2 Study Flow Chart 
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°Subjects who participated in Part 1 will be admitted to the clinical unit after a minimum washout period of 7 days. 
Discharge from clinical unit. Subjects may be discharged as a group earlier if a cumulative mass balance recovery of >90% has been achieved or if <1% of the 
dose administered has been collected in urine and faeces within 2 separate, consecutive 24 h periods. If the mass balance criteria have not been met by all subjects 
on Day 8, the residency period for the subjects not achieving the release criteria may be extended by up to a maximum of 2 additional 24 h periods (up to 216 h 
post-dose, Day 10) for further collection of urine and faeces. If the criteria are not met by Day 10, or if any additional residency is not considered appropriate or 
necessary, then home collections of urine and/or faeces may be requested at the discretion of the investigator for individual subjects. 
A follow-up phone call will take place 5 to 7 days after discharge or after the end of the last collection period. 
d Targeted (symptom driven) physical examination 
°Haematology and clinical chemistry at each time point 
,Blood pressure, heart rate and oral temperature will be measured at each time point 
5A single urine sample will be collected at pre-dose (the first void of the day) and then during the following collection periods 0-6, 6-12, 12-24 h post-dose and then 
daily (24 h collections) until Day 8/Discharge. 
h Faeces will be collected from admission until pre-dose and then daily (24 h collections) until Day 8/Discharge. 
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