A 2-Part, Non-randomized, Open-label Study to Evaluate the Effect of Itraconazole, Rifampicin, Rabeprazole, and Omeprazole on the Pharmacokinetics of Belumosudil (KD025)
Phase: PHASE1
Conditions: Drug-drug Interaction, Autoimmune Diseases, Fibrotic Disease
Sponsor: Kadmon Corporation, LLC

 
 
Protocol Number:  KD025-107 
 
Document Title:  A Two-part, Non-randomised, Open-label Study to Evaluate the 
Effect of Itraconazole, Rifampicin, Rabeprazole, and Omeprazole on the 
Pharmacokinetics of KD025 
 
Version Number:  2.0 
 
Date of Document:  25 Sep 2018 
 
NCT Number:  NCT03530995 

Quotient Sciences 
CLINICAL STUDY PROTOCOL 
A Two-Part, Non-Randomised, Open Label Study to Evaluate 
the Effect of Itraconazole, Rifampicin, Rabeprazole and 
Omeprazole on the Pharmacokinetics of KD025 
Quotient Study Number: 	
QSC200311 
Sponsor Study Number: 	
KDO25-107 
EudraCT Number: 	
2018-000316-16 
Clinical Study Site: 
Quotient Sciences 
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: 	
25 SEP 2018 
Status of Protocol: 	
Version 2.0 
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 T1 v15.0 03 Nov 2017 

Sponsor/Quotient Sciences Confidential 
Study Contacts 
Principal Investigator: 
Sub-Investigators: 
Scientific Lead: 
Programme Manager: 
Project Manager 
Study Monitor: 
Medical Monitor: 
Pharmacovigilance 
Provider: 
Nand Singh BSc, MD, DPM, MFPM 
Quotient Sciences 
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 
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 
Vincent Ukachukwu MRCGP, MSc, MMedSci 
Jonathan Whitton BMBS, BSc, MRCS, PGcert 
Naila Aslam BSc, MBBS, MRCPCH 
Quotient Sciences 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Vanessa Zann BSc (Hons), PhD 
Quotient Sciences 
Tel: +44 (0)115 974 9000 (day) 
Sue Melbourne PGCert, DipNurs 
Quotient Sciences 
Tel: +44 (0)115 931 5120 
Samantha Gott BSc (Hons) 
Quotient Sciences 
Tel: +44 (0)115 974 9000 
Stoneygate Clinical Research Ltd 
260 Kimberley Road 
Leicester 
LE2 1LJ 
Sanjay K Aggarwal, MD 
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 
Protocol KDO25-107 (QSC200311) Version 2.0 
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Sponsor/Quotient Sciences Confidential 
Central Laboratory: 
Bioanalytical 
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 
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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 	
Ah  
Principal Investigator 	
Signature 
Senior Clinical Research Physician 	
026 SP 20ig 
Date 
Protocol KDO25-107 (QSC200311) Version 2.0 
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Sponsor/Quotient Sciences Confidential 
Signatures for Sponsor 
Sanjay Aggarwal, MD 
Vice-President, Clinical Development 
Z. 5 3E-pr- zoir 
Date 
Protocol K0025-107 (QSC200311) Version 2.0 
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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 	
18 
5 	
Background Information 	
20 
5.1 	
Introduction 	
20 
5.2 	
Investigational and Non-Investigational Medicinal Products 	
21 
5.3 	
Previous Study Findings 	
21 
5.3.1 	
Nonclinical Data Summary 	
21 
5.3.2 	
Clinical Data Summary 	
22 
6 	
Rationale 	
23 
6.1 	
Study Rationale 	
23 
6.2 	
Dose Rationale 	
24 
6.2:1 	
KD025 	
24 
6.2.2 	
ltraconazole 	
24 
6.2.3 	
Rabeprazole 	
24 
6.2.4 	
Rifampicin 	
25 
6.2.5 	
Omeprazole 	
25 
6.3 	
Population Rationale 	
25 
6.4 	
Risks and Benefits 	
26 
6.4.1 	
Potential Risks associated with KD025 	
26 
6.4.2 	
Potential Risks associated with Non-Investigational Medicinal 
Products 	
26 
6.4.3 	
Other Considerations 	
27 
7 	
Objectives and Endpoints 	
27 
7.1 	
Objectives 	
27 
7.1.1 	
Primary Objective 	
27 
7.1.2 	
Secondary Objective 	
27 
7.2 	
Endpoints 	
28 
7.2.1 	
Primary Endpoint 	
28 
7.2.2 	
Secondary Endpoint 	
28 
8 	
Study Design 	
28 
8.1 	
Study Plan 	
28 
8.1.1 	
Study Plan Part 1 	
28 
8.1.2 	
Study Plan Part 2 	
30 
8.2 	
Criteria for In-Study Decisions 	
32 
8.3 	
Subject Withdrawal 	
33 
8.4 	
Subject Replacement 	
33 
8.5 	
Stopping Criteria 	
34 
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8.6 	
Study Termination 	
34 
8.7 	
Treatment Allocation 	
35 
8.7.1 	
Subject Numbers 	
35 
8.7.2 	
Blinding 	
35 
9 	
Selection of Subjects 	
35 
9.1 	
Informed Consent 	
36 
9.2 	
Inclusion Criteria 	
36 
9.3 	
Exclusion Criteria 	
36 
9.4 	
Contraception 	
37 
9.4.1 	
Exposure to Partners during the Study 	
38 
9.4.2 Sperm Donation 	
38 
9.5 	
Pregnancy 	
38 
9.6 	
Additional Study Restrictions 	
38 
10 	
Study Procedures 	
39 
10.1 	
Screening 	
39 
10.1.1 Subject Re-Screening 	
39 
10.2 	
Admission and Pre-dose Procedures 	
39 
10.3 	
Study Day Procedures 	
40 
10.3.1 Blood Volume 	
40 
10.3.2 Timing of Procedures 	
40 
10.3.3 Discharge from the Clinical Unit 	
40 
10.3.4 Outpatient Visits 	
40 
10.3.5 Medical Supervision 	
41 
10.3.6 Follow-up 	
41 
11 	
Dosing of Subjects 	
41 
11.1 	
Food and Fluid Intake 	
41 
11.1.1 Investigational Medicinal Product Dosing 	
41 
11.1.2 Non-Investigational Medicinal Product Dosing 	
42 
11.2 	
Administration of Test Preparations 	
42 
11.3 	
Dosing Compliance 	
43 
11.4 	
Prior and Concomitant Medications 	
44 
12 	
Assessment of Efficacy 	
44 
13 	
Assessment of Pharmacokinetics and Pharmacodynamics 	
44 
13.1 	
Assessment of Pharmacokinetics 	
44 
13.1.1 Pharmacokinetic Blood Sampling 	
44 
13.2 	
Assessment of Pharmacodynamics 	
44 
14 	
Assessment of Safety 	
44 
14.1 	
Definition and Classification of Adverse Events 	
44 
14.2 	
Assessment of Causality 	
45 
14.3 	
Recording Adverse Events 	
45 
14.4 	
Serious Adverse Events 	
46 
14.4.1 Definition of Serious Adverse Events 	
46 
14.4.2 Definition of Suspected Unexpected Serious Adverse 
Reactions 	
46 
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14.5 	
Laboratory Measurements 	
46 
14.5.1 Haematology and Clinical Chemistry 	
46 
14.5.2 Urinalysis 	
47 
14.5.3 Drug Screen 	
47 
14.5.4 Alcohol Breath Test 	
47 
14.5.5 Carbon Monoxide Breath Test 	
47 
14.5.6 Abnormal Laboratory Findings 	
47 
14.6 	
Vital Signs Measurements 	
48 
14.7 	
ECG Measurements 	
48 
14.8 	
Body Weight 	
48 
14.9 	
Physical Examination 	
48 
14.10 Additional Safety Procedures 	
49 
15 	
Statistics and Data Analysis 	
49 
15.1 	
Sample Size Justification 	
49 
15.2 	
Data Management 	
49 
15.3 	
Pharmacokinetic Data Analysis 	
50 
15.4 	
Statistical Data Analysis 	
51 
15.5 	
Interim Analysis 	
53 
16 	
Safety Reporting to Ethics Committees and Regulatory Authorities 	
53 
16.1 	
Events Requiring Expedited Reporting 	
53 
16.2 	
Urgent Safety Measures 	
53 
16.3 	
Reporting 	
54 
16.3.1 Reporting Serious Adverse Events 	
54 
16.3.2 Reporting of Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 	
54 
16.3.3 Expedited Reporting of Events 	
54 
16.3.4 Reporting of Urgent Safety Issues 	
55 
16.4 	
Serious Breaches 	
55 
17 	
Protocol Amendments and Deviations 	
55 
17.1 	
Amendments 	
55 
17.2 	
Protocol Deviations 	
55 
18 	
Regulatory 	
56 
18.1 	
Compliance 	
56 
18.2 	
Ethics Approval 	
56 
18.3 	
MHRA Approval 	
56 
18.4 	
Source Data 	
56 
18.5 	
Declaration of the End of the Study 	
56 
18.6 	
Document Storage and Archiving 	
57 
19 	
Quality Control and Quality Assurance 	
57 
19.1 	
Monitoring 	
57 
20 	
Finance and Insurance 	
57 
21 	
Publication 	
57 
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22 	
References 	
58 
Appendix 1 	
Clinical Laboratory Parameters 	
61 
Appendix 2 	
Part 1 Study Flow Chart 	
62 
Appendix 3 	
Part 2 Study Flow Chart 	
64 
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2 	
List of Tables and Figures 
2.1 	
Table of In-Text Tables 
Table 1 	
Investigational Medicinal Product 	
21 
Table 2 	
Non-Investigational Medicinal Products 	
21 
2.2 	
Table of In-Text Figures 
Figure 1 	
Part 1 Study Sequence 	
30 
Figure 2 Part 2 Study Sequence 	
32 
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Sponsor/Quotient Sciences Confidential 
3 Synopsis 
Sponsor: 
Kadmon Corporation, LLC 
Drug Substance: 
KD025 
EudraCT No.: 
2018-000316-16 
Title of Study: A Two-Part, Non-Randomised, Open Label Study to Evaluate the Effect of 
Itraconazole, Rifampicin, Rabeprazole and Omeprazole on the Pharmacokinetics of KD025 
Principal Investigator: Nand Singh BSc, MD, DPM, MFPM 
Study Centre: 	
• 
Quotient Sciences, Mere Way, Ruddington Fields, Nottingham, NG11 6J5, UK 
Objectives: 
The primary objective of Part 1 of the study is: 
• To 	
determine 	
the 	
effect 	
of 	
itraconazole, 	
rifampicin 	
and 	
rabeprazole 	
on 	
the 
pharmacokinetics (PK) of QD orally administered KD025, in healthy male subjects 
The secondary objective of Part 1 of the study is: 
• To provide additional information on the safety and tolerability of QD orally administered 
KD025, in healthy male subjects 
The primary objective of Part 2 of the study is: 
• To determine the effect of omeprazole on the PK of single day BID (every 12 hours [Q12h]) 
dose of KD025 administered orally, in healthy male subjects 
The secondary objective of Part 2 of the study is: 
• To provide additional information on the safety and tolerability of single day BID (Q12h) 
dose of KD025 administered orally, in healthy male subjects 
Methodology: 
This is a single centre, non-randomised, open label, two-part 
Part 1 
Part 1 is a single centre, non-randomised, 4-period sequential 
male subjects. In each period, subjects will receive a 
medicinal product (IMP), KD025 Tablet, in the fed state. 
effects of inhibition and induction of cytochrome P450 (CYP) 
pH on KD025 exposure, subjects will receive multiple doses 
a strong CYP3A4 inhibitor, 	
itraconazole, 	
in 	
Period 
rabeprazole, in Period 3; and a strong CYP3A4 inducer, 
study. 
dose assessment in healthy 
single dose of the investigational 
Additionally, in order to assess the 
3A4 and the elevation of gastric 
of non-(N)IMP in Periods 2 to 4; 
2; 	
a 	
proton 	
pump 	
inhibitor (PPI), 
rifampicin, in Period 4: 
to determine their eligibility for 
-2 of Period 1). For each period, 
to IMP administration (Day -1) for 
Period 
IMP/NIMP Dose 
1 
KD025 200 mg QD 
2 
itraconazole 200 mg QD for 7 days 
KD025 200 mg QD + itraconazole 200 mg QD on 8th day 
itraconazole 200 mg QD on 9th day 
3 
rabeprazole 20 mg BID for 3 days 
KD025 200 me QD + rabeerazole 20 m. QD on 4th day 
4 
rifampicin 600 mg QD for 9 days 
KD025 200 mg QD on 10th day 
QD: once daily; BID: twice daily 
Study Design: 
All subjects will undergo preliminary screening procedures 
Part 1 of the study at the screening visit (Day -28 to Day 
subjects will be admitted to the clinic on the day prior 
Protocol KDO25-107 (QSC200311) Version 2.0 
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Period 1 
Day -28 to -2 
Screening 
Period 2 
Days -6 to -2a 
ltraconazole 
(Home)  
confirmation of eligibility and baseline procedures; morning admission for Periods 1, 2 and 4; 
evening admission for Period 3. 
Prior to being admitted to the clinic in Periods 2 to 4, subjects will take multiple doses of the 
following NIMPs (see Part 1 overview below); itraconazole on Day 3 (Period 1; or Day -7 of 
Period 2 if washout period is extended) and continuing from Day -6 to -1 (Period 2); 
rabeprazole from Day -3 to -1 (Period 3); rifampicin from Day -9 to -1 (Period 4). Outpatient 
visits will take place on the mornings of Day -3 of Period 3 and Day -9 of Period 4, when the 
subjects will receive their morning dose of rabeprazole and rifampicin, respectively, and will 
be given sufficient supplies for home dosing. Subjects will also attend for an additional 
outpatient visit on the morning of Day -5 of Period 4 to receive their morning dose of rifampicin 
in the clinic, and will be given sufficient supplies for the remainder of the dosing period. 
On the morning following admission for each period (Day 1), subjects will receive a single 
dose of IMP, either alone (Periods 1 and 4) or co-administered with NIMP (itraconazole in 
Period 2 [at the same time as IMP; fed state] and rabeprazole in Period 3 [2 h prior to IMP; 
fasted state]). In Period 2, a further dose of itraconazole will be administered on the day after 
IMP administration (Day 2). All subjects will remain on site until 48 h post-IMP dose for safety 
and PK assessments. There will be a minimum washout of 2, 8 and 4 days following 
completion of dosing in Periods 1, 2 and 3, respectively. A follow-up visit will take place 3 to 
5 days post-final discharge. 
An overview of Part 1 of the study is presented below: 
Day -1 
Admission 
(morning) 
Day -1 
Admission 
(morning) 
ltraconazoleb 
Day -1 
Admission 
(evening) 
Rabeprazolec 
Period 3 
Day -3 
Rabeprazole 
(Outpatient Visit) 
Day -2 
Rabeprazole 
(Home)  
Period 4 
Day -9 and Day -5 
Rifampicin 
(Outpatient Visit) 
4, 
Days -8 to -6 and 
Days -4 to -2 
Rifampicin 
(Home)  
Day -1 
Admission 
(morning) 
Rifampicinb 
4, 
\ Day 1 
‘‘ KDO25 
Minimum 2 day 
washout period 
Day 3a 
Discharge 
(morning) 
ltraconazole 
Day 1 
KDO25 + 
ltraconazole 
4,  
Day 2 
ltraconazole 
Day 3 
Discharge 
(morning) 
4, 
r‘knimum 8 day 
washout period 
Day 1 
KDO25 + 
Ra be prazole 
Day 3 
Discharge 
(morning) 
4,  
Minimum 4 day 
washout period 
Day 1 
KDO25 
Day 3 
Discharge 
(morning) 
Follow-up Visit 
(3 to 5 days post- 
final discharge) 
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a  If the minimum washout period is extended, subjects will receive their first dose of itraconazole during a separate 
outpatient visit on Day -7 of Period 2 
b Subjects will take itraconazole (Period 2)/rifampicin (Period 4) in the clinic after admission 
Subjects will take the evening dose of rabeprazole at home, prior to admission 
Part 2 
Part 1 is a single centre, non-randomised, 2-period sequential dose assessment in healthy 
male subjects. 
In each period, subjects will receive a single day of BID dosing with IMP (KD025 tablet) in the 
fed state. Additionally, in order to assess the effect of a modest increase in gastric pH on the 
exposure of KD025, subjects will also receive multiple QD doses of the NIMP omeprazole, a 
PPI, in Period 2: 
Period 	
IMP/NIMP Dose 
1 	
KD025 200 mg BID (Q12h) on a single day only  
2 	
omeprazole 20 mg QD for 3 days 
KD025 200 mg single day, BID (Q12h) + omeprazole 20 mg QD on 4th day  
QD: once daily, BID: twice daily, Q12h: every 12 hours 
Study Design 
All subjects will undergo preliminary screening procedures to determine their eligibility for 
Part 2 of the study at the screening visit (Day -28 to Day -2 of Period 1). For each period, 
subjects will be admitted to the clinic on the evening of the day prior to IMP administration 
(Day-1) for confirmation of eligibility and baseline procedures. 
Prior to being admitted to the clinic in Period 2, subjects will take single daily doses of NIMP. 
At discharge from Period 1, subjects will receive their first dose of omeprazole and will be 
given sufficient supplies for home dosing on Days -2 and -1, returning to the clinic for 
admission on the evening of Day -1. If the minimum washout period is extended due to 
logistics, subjects will receive their first dose of omeprazole during a separate outpatient visit 
on Day -3 of Period 2 
On the day following admission for each period (Day 1), subjects will receive two doses of 
IMP (morning and evening, Q12h), either alone (Period 1) or with a NIMP (omeprazole) 
administered in the fasted state 2 h prior to planned morning IMP dose (Period 2). All IMP 
dosing will be in the fed state. All subjects will remain on site until 48 h post-IMP dose for 
safety and PK assessments. There will be a minimum washout of 2 days between dosing in 
Period 1 and starting dosing omeprazole in Period 2. 
A follow-up visit will take place 3 to 5 days post-final discharge. 
An overview of Part 2 of the study is presented below. 
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Period 2 
Day -3a  
Omeprazole 
(Outpatient Visit) 
V  
Day -2 
Omeprazole 
(Horne) 
Day 1 
Omeprazole 
KD025 
morning dose 
KD025 evening dose 
Day -1 
Omeprazole (Home) 
Admission 
(evening) 
Minimum 2 day washout 
period 
a  If the minimum washout period is extended, subjects will receive their first dose of omeprazole during a separate 
outpatient visit on Day -3 of Period 2. Otherwise, subjects will receive the first dose of omeprazole at discharge 
from Period 1. 
Period 
Day -28 to -2 
Screening 
Day 1 
KD025 morning dose 
KD025 evening dose 
17 
Day 3a  
Discharge 
(morning) 
Omeprazole 
Day 3 
Discharge 
(morning) 
Follow-up Visit 
(3 to 5 days post-final 
discharge) 
Day -1 
Admission 
(evening) 
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Number of Subjects Planned: 
Part 1 
It is planned to enrol 40 subjects to ensure there are 34 evaluable subjects; defined as those 
subjects who have sufficient PK data to assess the primary objective of Part 1 of the study. 
Up to 4 additional subjects may be enrolled in Part 1 of the study in order to achieve sufficient 
evaluable subjects per relevant comparison; the maximum number of subjects that may be 
dosed is 44. Any replacement subject will be required to complete the reference treatment 
period (Period 1) in addition to any further test periods (Period 2 to 4) not already completed 
by the replaced subject. 
Part 2 
It is planned to enrol 38 subjects to ensure there are 34 evaluable subjects; defined as those 
subjects who have sufficient PK data to assess the primary objective of Part 2 of the study. 
Up to 4 additional subjects may be enrolled in Part 2 of the study in order to achieve sufficient 
evaluable subjects; the maximum number of subjects that may be dosed is 42. 
Any replacement subject will be required to complete the reference treatment period 
(Period 1) in addition to Period 2. 
Duration of Study: 
Part 1 
Subjects will receive a single dose of KD025 on 4 separate occasions, and multiple doses of 
itraconazole, rabeprazole and rifampicin, on separate occasions, for 9, 4 and 9 consecutive 
days, respectively. 
The estimated duration from screening to discharge from Part 1 of the study is approximately 
10 weeks. 
Part 2 
Subjects will receive a single day BID (Q12h) dose of KD025 on 2 separate occasions, and 
single doses of omeprazole for 4 consecutive days. 
The estimated duration from screening to discharge from Part 2 of the study is approximately 
7 weeks. 
Main Inclusion Criteria: 
Healthy males aged 18 to 55 years 
Body weight .50 kg. Body mass index 18.0 to 32.0 kg/m2 or, if outside the range, considered 
not clinically significant by the investigator. 
Investigational Medicinal Product, Dose and Mode of Administration: 
The following IMP will be used in this clinical study: 
Investigational Medicinal Product 
Dose and Route of Administration 
KDO25 Tablet 
Part 1 
200 mg (as 1 x 200 mg tablets) Oral 
Part 2 
400 mg (1 x 200 mg tablet Q12h) Oral 
All doses of KD025 will be administered in the fed state; a total of 240 mL water will be given 
immediately following oral administration. 
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Sponsor/Quotient Sciences Confidential 
Non-Investigational Medicinal Product, Dose and Mode of Administration: 
The following NIMPs will be used in this clinical study: 
Product and Product Licence 
Number 
Active Component (Indication) 
Dose and Route of 
Administration 
Part 1 
Itraconazole 100 mg Capsules, 
hard; PL 20075/0900 
itraconazole (fungal infections) 
2 x 100 mg Capsule; Oral 
Rabeprazole 20 mg 
Gastro-resistant Tablets; 
PL 30306/0254 
rabeprazole sodium 
(gastroesophageal reflux 
disease) 
1 x 20 mg Tablet; Oral 
Rifadin 300 mg Capsules: 
PL 04425/5916R 
ri fampicin (antibiotic) 
2 x 300 mg Capsule; Oral 
Part 2 
Omeprazole 20 mg 
Gastro-resistant Tablets 
PL 14017/0042 
omeprazole (gastroesop hageal 
re flux d isease) 
 
1 x 20 mg Tablet; Oral 
A total of 240 mL water (approximately) will be given immediately following oral administration. 
Pharmacokinetic Assessments: 
Part 1 
Venous blood samples for PK assessments will be withdrawn at pre-dose, and 0.5, 1, 1.5, 2, 
3, 4, 5, 6, 8, 10, 12, 24, 36 and 48 h post-IMP dose in each period. 
Part 2 
Venous blood samples for PK assessments will be withdrawn at pre-dose, and 0.5, 1, 1.5, 2, 
3, 4, 5, 6, 8, 10, 12, 12.5, 13, 13.5, 14, 15, 16, 17, 18, 20, 22, 24, 36 and 48 h post-IMP 
morning dose in each period. 
The plasma concentration data for KD025 and metabolites KDO25m1 and KD025m2 will be 
analysed by Quotient Sciences using appropriate non-compartmental techniques to obtain, 
for Part 1, estimates of Cmax, AUC(0-last) and AUC(0-inf), and for Part 2, estimates of 
Cmax(first 	
dose), 	
Cmax(second 	
dose), 	
Tmax, 	
AUC(0-12), 	
AUC(12-24), 	
AUC(0-24) 
AUC(0-last; first dose) and AUC(0-inf; first dose); additional parameters will be estimated 
where possible and appropriate. 
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) 
• Vital signs 
• Electrocardiograms 
• Adverse events 
Statistical Methodology: 	
, 
Formal statistical analysis will be performed for KD025 and metabolites KDO25m1 and 
KD025m2 PK parameters as follows: 
• Part 1: Cmax, AUC(0-last) and AUC(0-inf) 
• Part 2: 
- 	
Primary: Cmax(first dose), Cmax(second dose) and AUC(0-24) 
- 	
Secondary: AUC(0-12), AUC(12-24), AUC(0-last; first dose) and AUC(0-inf; first 
dose) 
The PK parameters will undergo a natural logarithmic transformation and will be analysed 
using mixed effect modelling techniques. The mixed effects model will include terms for 
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treatment as a fixed effect and subject as a random effect. Adjusted geometric mean ratios 
(GMRs) and 90% confidence intervals (Cis) for the adjusted GMRs will be provided for the 
comparisons of interest, where the ratios are defined as test/reference. A separate model will 
be fitted for each comparison of interest and will only include subjects who complete both 
periods for the relevant comparison of interest. 
Part 1 
• Period 2 (KD025 + itraconazole) vs Period 1 (KD025 alone) 
• Period 3 (KD025 + rabeprazole) vs Period 1 (KD025 alone) 
• Period 4 (KD025 + rifampicin) vs Period 1 (KD025 alone) 
If the 90% Cls for each of KD025 (parent only) Cmax, AUC(0-last) and AUC(0-inf) lie within 
the acceptance interval of 70.00% to 143.00%, then the absence of an effect on PK can be 
concluded for the comparison of interest. 
Part 2 
• Period 2 (KD025 + omeprazole) vs Period 1 (KD025 alone) 
If the 90% Cls for each of KD025 (parent only) Cmax(first dose), Cmax(second dose) and 
AUC(0-24) lie within the acceptance interval of 70.00% to 143.00%, then the absence of an 
effect on PK can be concluded for the comparison of interest. 
Sample Size and Power: 
For the purposes of sample size calculation the following assumptions have been made: 
• Estimates of intra-subject variability (CVw) of 50% and 40% for Cmax and AUC(0-last), 
respectively. Data obtained from previous food effect study (QCL117415, data on file) 
• Two one-sided tests with a probability of type 1 error of 0.05 for PK endpoints Cmax and 
AUC(0-last), ie 90% Cl to be calculated 
• Acceptance interval of 70.00% to 143.00% 
• 80% power assuming the true ratio is between 95.00% and 105.00% 
Part 1 
Based on the above assumptions, 40 subjects are to be dosed to achieve 34 evaluable 
subjects for Cmax (PK parameter with highest CVw value). Evaluable subjects are defined as 
those subjects who have sufficient PK data to assess the primary objective of Part 1 of the 
study. 
Part 2 
Based on the above assumptions, 38 subjects are to be dosed to achieve 34 evaluable 
subjects for Cmax (PK parameter with highest CVw value). Evaluable subjects are defined as 
those subjects who have sufficient PK data to assess the primary objective of Part 2 of the 
study. 
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4 	
List of Abbreviations 
Abbreviation 
AE 
ALT 
AST 
AUC 
BID 
cGVHD 
CHMP 
Cl 
CLcr 
Cmax 
CV% 
CVw 
CYP 
EC 
ECG 
EMA 
FDA 
GCP 
GERD 
GMR 
HbsAg 
HCV Ab 
HIV 
ICF 
ICH 
IPF 
IL 
IMP 
MedDRA 
MHRA 
NIMP 
PI 
PK 
Definition 
adverse event 
alanine aminotransferase 
aspartate aminotransferase 
area under the concentration-time curve 
twice daily 
chronic graft versus host disease 
Committee for Medicinal Products for Human Use 
confidence interval 
creatinine clearance 
maximal plasma concentration 
coefficient of variation 
intra-subject variability 
cytochrome P450 
ethics committee 
electrocardiogram 
European Medicines Agency 
US Food and Drug Administration 
good clinical practice 
gastro-oesophageal reflux disease 
geometric mean ratio 
hepatitis B surface antigen 
hepatitis C virus antibody 
human immunodeficiency virus 
informed consent form 
International Council for Harmonisation 
idiopathic pulmonary fibrosis 
interleukin 
investigational medicinal product 
Medical Dictionary for Regulatory Activities 
Medicines and Healthcare products Regulatory Agency 
non-investigational medicinal product 
principal investigator 
pharmacokinetic(s) 
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PPI 	
proton pump inhibitor 
Q12h 	
every 12 hours 
QD 	
once daily 
QTc 	
corrected QT 
QTcF 	
QT interval corrected using Fridericia's formula 
RAP 	
Reporting and Analysis Plan 
ROCK 	
Rho-associated protein kinases 
SAE 	
serious adverse event 
SUSAR 	
suspected unexpected serious adverse reaction 
Th17 	
T helper 17 
Tregs 	
regulatory T cells 
Tmax 	
time to maximal plasma concentration 
ULN 	
upper limit of normal 
WHO DDE 	
World Health Organisation Drug Dictionary Enhanced 
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5 Background Information 
5.1 	
Introduction 
An immune response is often a delicate balancing act protecting the integrity of the host 
organism from foreign invaders while restricting damage due to autoimmune reactivity 
[1]. Autoimmunity is a pathological condition characterised by humoral or cell-mediated 
immune responses against the body's own tissues, underlying diseases such as 
psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. 
Patients who suffer from the more than 80 different types of autoimmune disorders are 
frequently treated with general immunosuppressive agents such as corticosteroids (eg 
prednisone) and nonsteroidal drugs (eg azathioprine, cyclophosphamide, methotrexate, 
sirolimus) that slow or stop the autoimmune attack, but do not allow for treatment 
discontinuation and can cause severe side effects such as infections and cancer [2]. 
Therefore, there is a need for effective and safe treatments for autoimmune disorders 
that produce remissions with fewer side effects. One approach is to develop therapies 
targeting specific immune cell subsets. 
T helper 17 (Th17) cells are a subset of CD4+ T lymphocytes producing the cytokine 
interleukin (IL)-17 and are implicated in the pathogenesis of a number of autoimmune 
conditions [3]. Autoimmunity also involves alterations to regulatory T cells (Tregs). Tregs 
are a small (<5%) subset of CD4+ T lymphocytes that suppress activation of the immune 
system and play a critical role in maintaining immunological tolerance to self-antigens 
and inhibiting autoimmune responses [4]. Diminished suppressive function of Tregs 
contributes to the pathogenesis of many autoimmune disorders. 
Rho-associated 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 [5][6]. Two ROCK isoforms have been identified, ROCK1 and 
ROCK2. Early work with nonspecific ROCK inhibitors suggested that both ROCK1 and 
ROCK2 are involved in Rho-mediated changes in the actin/myosin cytoskeletal network. 
More recent research has uncovered additional roles for ROCK signalling, particularly 
ROCK2, in conditions including autoimmune disease aggravated or caused by a 
Th17-polarised T-cell response [7], pulmonary fibrosis [8], and neurodegenerative 
conditions including Alzheimer's disease, in which ROCK2 contributes to overproduction 
of amyloid-6 [9]. 
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 [10]. Recent studies have demonstrated that aberrant activation of 
ROCK2 leads to induction of IL-17 and IL-21 via interferon regulatory factor 4-dependent 
mechanism [11]. Moreover, inhibition of ROCK effectively decreased IL-17 production in 
vivo and ameliorated the spontaneous development of arthritis, diabetes and lupus in 
mice. Additionally, ROCK activity was found to be up-regulated in patients with 
rheumatoid arthritis and systemic lupus erythematosus [12]. The specific inhibition of 
ROCK2 should therefore be examined for its potential as a therapy for autoimmune 
disorders. 
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. 
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5.2 Investigational and Non-Investigational Medicinal Products 
The investigational medicinal product (IMP) and non-investigational medicinal products 
(NIMPs), detailed in Table 1 and Table 2, respectively, will be used in this clinical study: 
Table 1 	
Investigational Medicinal Product 
Investigational Medicinal Product 
KD025 Tablet 
Dose and Route of Administration 
200 mg (as 1 x 200 mg tablets) Oral 
Table 2 	
Non-Investigational Medicinal Products 
Product and Product Licence 
Number 
Active Component (Indication) 
Dose and Route of 
Administration 
Part 1 
ltraconazole 100 mg Capsules, 
hard; PL 20075/0900 
itraconazole (fungal infections) 
2 x 100 mg Capsule; Oral 
Rabeprazole 20 mg 
Gastro-resistant Tablets; 
PL 30306/0254 
rabeprazole sodium 
(gastroesophageal reflux 
disease) 
1 x 20 mg Tablet; Oral 
Rifadin 300 mg Capsules: 
PL 04425/5916R 
rifampicin (antibiotic) 
2 x 300 mg Capsule; Oral 
Part 2 
Omeprazole 20 mg 
Gastro-resistant Tablets 
PL 14017/0042 
omeprazole (gastroesophageal 
reflux disease) 
1 x 20 mg Tablet; Oral 
All IMP/NIMPs will be reconciled and destroyed in accordance with the study-specific 
quality agreement and technical addendum. 
5.3 	
Previous Study Findings 
5.3.1 	
Nonclinical 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 [13]. 
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. Exposure levels for KD025m2, the only identified 
major metabolite in human subjects, in at least one species (rat) in the repeat-dose 
toxicology studies and both species (rat and rabbit) for embryo-foetal toxicity evaluation 
were sufficient to provide coverage relative to anticipated human exposure levels; 
therefore, KD025m2 is not considered a disproportionate human-only metabolite. In 
human liver microsomes, cytochrome P450 (CYP)-3A4 was the predominant CYP 
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isoform responsible for the metabolism of KD025, although other CYP or non-CYP 
mediated metabolism may also contribute. 
KD025 primarily distributes to the adrenal gland, fur, gastrointestinal tract, kidney, and 
liver. No appreciable distribution to the brain has been detected. KD025 and KDO25m1 
are >99% bound to human, dog and rat plasma proteins; KDO25m2 is >99% bound to 
human plasma protein. 
To date, Good Laboratory Practice-compliant general toxicology/toxicokinetic studies of 
acute, subchronic (1 and 3 month), and chronic (6 month rat and 9 month dog) duration 
have been completed in rats and dogs. In addition, safety pharmacology studies 
evaluating human ether-a-go-go related gene (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. 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. 
5.3.2 	
Clinical Data Summary 
To date, 7 clinical studies have been completed, consisting of 6 Phase 1 clinical studies 
(SLx-2119-09-01, KD025-101, KD025-102, KD025-103, KD025-105, and KD025-106) in 
healthy subjects, and 1 Phase 2a study (KD025-205) in subjects with psoriasis vulgaris. 
Additionally, a Phase 2 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, 3 Phase 2 studies are ongoing in subjects with chronic graft versus 
host disease (cGVHD; KD025-208), idiopathic pulmonary fibrosis (KD025-207) and 
psoriasis (KDO25-211). 
More than 300 subjects have received KD025 in completed studies with doses ranging 
from 20 to 1000 mg in single- and/or multiple-day dose regimens. Forty-eight subjects 
have received placebo. A total of 109 serious adverse events (SAEs) have been 
reported; 85 with the use of KD025, 22 with the use of placebo drug and 2 were blinded 
reports. The most common SAEs reported during use of KD025 were diarrhoea (4), 
nausea (3) and nasopharyngitis (3). No drug-related AEs have resulted in fatal 
outcomes. 
To date, AEs most frequently reported with KD025 dosing include increased aspartate 
aminotransferase (AST) and increased alanine aminotransferase (ALT). 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, catheter site infection, 
dizziness, and flatulence. 
To date, 17 subjects in KD025 clinical trials have experienced liver-related AEs. Most of 
these events were considered to be at least possibly related to study drug. The majority 
of liver related AEs have been mild or moderate in intensity; 5 were severe. These events 
generally occurred after 16 to 36 days of KD025 administration, and all events were 
reversible. None of the liver-related AEs were determined to be SAEs. 
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The identified and potential risks noted in association with KD025 are balanced by the 
anticipated benefits that may be afforded to subjects with psoriasis vulgaris, IPF and 
cGVHD. 
KD025 was the main analyte detected in all clinical studies, with maximal plasma 
concentration (Cmax) ranging from -100 ng/mL (20 mg once daily [QD] in 
SLx-2119-09-01) to -5300 ng/mL (500 mg twice daily [BID] in KD025-102), and median 
time to maximal plasma concentration (Tmax) ranging from -2 h to -8 h. Cmax and the 
area under the concentration-time curve (AUC) appear to be slightly greater than dose 
responsive over the 20 to 500 mg QD, but less than dose linear for doses > 500 mg. The 
half-life typically ranged from 4 h to 8 h, with a few reports greater than 8 h. 
Two metabolites, KDO25m1 and KD025m2, rapidly appeared in plasma and were readily 
eliminated. A major metabolite, KD025m2, was detected at Cmax levels -20% that of 
parent and AUC approximately 15% that of parent. A minor metabolite, KDO25m1, was 
detected at Cmax levels <5% of parent and AUC -2% parent. Accumulation of KD025m2 
was reported after multiple doses. KDO25m1 did not accumulate. 
In both Study KDO25-105 (a fed/fasted crossover study with KD025 capsules) and Study 
KDO25-106 (a fed/fasted crossover study with KD025 tablets), a high-fat meal given 
30 minutes prior to KD025 oral administration had a significant effect on the 
pharmacokinetics (PK) of KD025. Plasma systemic exposure (Cmax and AUCs) of 
KD025 was approximately 2- to 3-fold higher under the fed state compared with the 
fasted state, and the median Tmax value was delayed by 0.5 to 2 h with food. 
6 Rationale 
6.1 	
Study Rationale 
Preclinical data indicates that CYP3A4 plays a predominant role in the metabolism of 
KD025; therefore, drug-drug interactions will be investigated in this study to determine 
whether co-administration of KD025 with inhibitors or inducers of CYP3A4 results in 
altered exposure of KD025 and/or KDO25m1 and KD025m2. In the present study, 
itraconazole and rifampicin will be used because they are classed as a strong inhibitor 
and inducer of CYP3A4, respectively. 
In addition, the 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. Thus, the impact of a proton pump inhibitor 
(PPI), on the exposure of KD025 will also be assessed. Rabeprazole, a recognised PPI, 
suppresses the secretion of gastric acid by noncompetitive blockade of the H+/K+-
adenosine triphosphatase at the secretory surface of the gastric parietal cells and raises 
the intra-gastric pH above 3.0. As rabeprazole increases pH, co-administration of 
rabeprazole with KD025 could result in a decrease in exposure of KD025. 
Preliminary results from Part 1 (n=21) show that the exposure of KD025 is decreased 
(by approximately 80%) in subjects when taking rabeprazole (20 mg BID). Part 2 of the 
study has been designed to assess the impact of omeprazole (20 mg QD) on KD025 
exposure. Omeprazole is a PPI widely used in clinical settings for the treatment of 
gastro-esophageal reflux disease, and to manage upper GI involvement in patients with 
cGVHD and IPF. Omeprazole has a weaker anti-secretory effect on gastric acid than 
rabeprazole [14]. Co-administration of omeprazole with KD025 could result in a smaller 
decrease in exposure of KD025 than observed with rabeprazole. Therefore, omeprazole 
will allow assessment of a weaker PPI interaction with KD025. 
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6.2 Dose Rationale 
6.2.1 	
KD025 
KD025 in doses ranging from 20 to 1000 mg in single- and/or multiple-day dose regimens 
have generally been well tolerated. Single doses of 200 mg KD025 have been selected 
for Part 1 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 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. 
In Part 2, a BID (every 12 hours [Q12h]) 200 mg dose of KD025 has been selected, for 
a total of 400 mg per day on two separate occasions. The 400 mg dose has been well 
tolerated as a single dose and in repeat dosing in healthy volunteers and in patients with 
psoriasis and IPF. Repeat dosing of 200 mg BID has been well tolerated in patients with 
psoriasis and cGVHD [13]. 
6.2.2 	
Itraconazole 
ltraconazole is recommended in the 2017 US Food and Drug Administration (FDA) 
Clinical Drug Interaction Studies guidance document as being a strong inhibitor of 
CYP3A4 [15]. From the literature, a dose of 200 mg QD for a duration of 4 days is 
commonly used to achieve clinically relevant inhibition of CYP3A4 [16][17][18]. 
Furthermore, a dose of 200 mg QD is the recommended clinical dosing regimen for 
itraconazole [19]. 
However, itraconazole has time dependent kinetics, thus after 15 days of multiple dosing 
at 100 mg and 200 mg QD or 200 mg BID, there is greater accumulation than would be 
predicted from the single dose kinetics, and the half-life is increased from around 15 to 
25 h following single dosing, to around 35 to 40 h after multiple dosing [20]. Thus a dosing 
duration of 9 days was selected as a duration which would result in a clinically relevant 
inhibition of CYP3A4 with consideration given to the multiple dose kinetics of 
itraconazole. 
Dosing of itraconazole in Period 2 will continue on Day 1 of dosing with KD025, and on 
Day 2, ie during the washout phase of KD025, in order to maintain CYP3A4 inhibition 
during the elimination phase of KD025. 
6.2.3 	
Rabeprazole 
Rabeprazole, a potent PPI, suppresses the secretion of gastric acid by noncompetitive 
blockade of the H+/K+-adenosine triphosphatase at the secretory surface of the gastric 
parietal cells and raises the intra-gastric pH above 3.0. Rabeprazole has demonstrated 
anti-secretory activity, following single doses in healthy volunteers and patients with 
gastro-oesophageal reflux disease (GERD), but has less anti-secretory activity than 
esomeprazole on Days 1 and 5 after multiple doses in volunteers and patients with 
GERD. Rabeprazole has a rapid onset of action (within 4 h), and achieves maximal or 
near maximal effect after a single dose. After 3 to 5 days of single doses of rabeprazole, 
the intra-gastric pH is approximately 4 in healthy subjects. The effects of rabeprazole on 
acid secretion persist for several days after ceasing treatment [21]. 
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Sodium rabeprazole (immediate release form) is rapidly absorbed, with peak plasma 
concentrations occurring approximately 3.5 h after administration. The oral bioavailability 
of rabeprazole is unaffected by food. Rabeprazole displayed dose proportional PK over 
the dose range of 10 to 80 mg following single oral doses in healthy volunteers. 
Rabeprazole is largely excreted via the urine, and the elimination half-life is 
approximately 1 h. 
The recommended starting dose of sodium rabeprazole for patients with GERD or 
hypersecretory syndromes is 20 to 60 mg per day [22]. For the short duration of this drug 
interaction study, the proposed dose of rabeprazole is 20 mg BID for a total dose of 
40 mg per day for 3 consecutive days, followed by a QD dose prior to IMP. 
6.2.4 	
Rifampicin 
Rifampicin is recommended in the 2017 FDA Clinical Drug Interaction Studies guidance 
document as being a strong inducer of CYP3A4 [15]. A dosing regimen for rifampicin of 
600 mg QD for between 5 to 9 days has been modelled and shown to result in steady 
state induction of CYP3A4 activity [23]. This is also a clinically relevant dosing regimen 
[24] and therefore is considered to be an appropriate dosing regimen in this study. 
Rifampicin is also an inhibitor of the organic anion transporter protein; therefore, 
rifampicin will be dosed on Days -9 to -1 (Period 4), but not on Day 1 when KD025 will 
be administered. This is to avoid any confounding effects that may occur in data 
interpretation should KD025 be a substrate for the organic anion transporter protein in 
addition to CYP3A4 [15]. 
6.2.5 	
Omeprazole 
Omeprazole has a weaker anti-secretory effect on gastric acid than rabeprazole and 
supresses gastric acid secretion by noncompetitive blockade of the H+/K+ adenosine 
triphosphatase at the secretory surface of the gastric parietal cell. Omeprazole has 
demonstrated anti-secretory effects in healthy volunteers and patients with GERD [25], 
but has less of an anti-secretory effect than rabeprazole on Day 1 and 8 following multiple 
doses in health subjects [14]. Omeprazole has a rapid onset of action, within one hour, 
and achieves the maximum effect within 2 h. Following discontinuation, secretory activity 
returns to normal over 3 to 5 days. 
Omeprazole is rapidly absorbed, with peak plasma levels of omeprazole occurring within 
1 to 2 h after administration. The systemic availability (bioavailability) from a single oral 
dose of omeprazole is approximately 40%. The AUC of omeprazole increases with 
repeated administration. This increase is dose-dependent and results in a non-linear 
dose-AUC relationship after repeated administration. Omeprazole is largely excreted 
(80%) via urine, and the elimination half-life is less than 1 h [26]. 
The recommended starting dose of omeprazole for patients varies between 20 mg to 60 
mg once daily depending on indication [26]. For the short duration of this study, the 
recommended dose is 20 mg QD for 4 days. 
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 will be allowed. 
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As this is a Phase I study assessing the bioavailability, PK and safety of KD025, the most 
relevant population is healthy volunteers, as recommended by the FDA [27] and the EMA 
guidelines [28]. 
The purpose of this study is to show a difference between the applied conditions, and 
therefore it is an advantage to enrol a relatively homogeneous population and to 
minimise variability. Healthy male subjects, aged 18 to 55 years, will be therefore be 
enrolled. 
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. 
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. 
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, catheter site infection, 
dizziness, and flatulence. 
6.4.2 	
Potential Risks associated with Non-Investigational Medicinal Products 
6.4.2.1 	
Itraconazole 
The full reference safety information for itraconazole (ltraconazole 100 mg Capsules, 
hard) is provided in the Summary of Product Characteristics [19]. The most common side 
effects reported include: nausea, abdominal pain and rash. Rarely, itraconazole has 
been associated with serious hepatotoxicity, including liver failure and death. 
6.4.2.2 	
Rabeprazole 
The full reference safety information for rabeprazole (Rabeprazole 20 mg 
Gastro-resistant Tablets) is provided in the Summary of Product Characteristics [22]. The 
most common side effects reported include: infections, insomnia, headache, dizziness, 
aches, cough, pharyngitis, rhinitis, non-specific pain, back pain, effects on stomach or 
gut (flatulence, nausea, vomiting, diarrhoea, abdominal pain, benign fundic gland polyps 
and constipation), asthenia or influenza-like symptoms. Other side effects may include 
serious hypersensitivity (face swelling, dyspnoea or hypotension). 
6.4.2.3 	
Rifampicin 
The full reference safety information for rifampicin (Rifadin 300 mg Capsules) is provided 
in the Summary of Product Characteristics [24]. Common side effects include 
gastrointestinal reactions such as anorexia, nausea, vomiting, diarrhoea and abdominal 
discomfort. Skin reactions such as itching or flushing with or without a rash, as well as 
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urine discolouration (orange or reddish colour) have been observed. Additionally, 
hepatitis may also occur and liver function tests will be closely monitored in this study. 
Other rare side effects include acute renal failure, thrombocytopenia and haemolytic 
anaemia. 
6.4.2.4 	
Omeprazole 
The full reference safety information for omeprazole (Omeprazole 20 mg 
Gastro-Resistant Tablets) is provided in the Summary of Product Characteristics [26]. 
The most common side effects (1-10% of patients) are headache, abdominal pain, 
constipation, diarrhoea, flatulence and nausea/vomiting. Another common side effect is 
fundic gland polyps (benign). Uncommon (_1/1,000 to <1/100) side effects include: 
increased liver enzymes, dermatitis, pruritus, rash, urticarial, fracture of the hip, wrist or 
spine, malaise and peripheral oedema. 
6.4.3 	
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. 
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 Objective 
The primary objective of Part 1 of the study is: 
• To determine the effect of itraconazole, rifampicin and rabeprazole on the 
pharmacokinetics (PK) of QD orally administered KD025, in healthy male subjects 
The primary objective of Part 2 of the study is: 
• To determine the effect of omeprazole on the PK of a single day BID (Q12h) dose of 
KD025 administered orally, in healthy male subjects 
7.1.2 	
Secondary Objective 
The secondary objective of Part 1 of the study is: 
• To provide additional information on the safety and tolerability of QD orally 
administered KD025 in healthy male subjects 
The secondary objective of Part 2 of the study is: 
• To provide additional information on the safety and tolerability of a single day BID 
(Q12h) dose of KD025 administered orally, in healthy male subjects 
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7.2 	
Endpoints 
7.2.1 	
Primary Endpoint 
The primary endpoint of Part 1 of the study is: 
• A comparison of the PK profile of KD025 Tablets (QD) when co-administered with 
itraconazole, rifampicin and rabeprazole, compared to when administered alone, by 
assessing the following primary PK parameters for KD025, KDO25m1 and KDO25m2: 
Cmax, AUC(0-last) and AUC(0-inf), at a minimum. 
The primary endpoint of Part 2 of the study is: 
• A comparison of the PK profile of KD025 Tablets (BID; Q12h) when co-administered 
with omeprazole compared to administration of KD025 alone by assessing the 
following PK parameters for KD025, KDO25m1 and KDO25m2: Cmax(first dose), 
Cmax(second dose) and AUC(0-24). 
7.2.2 	
Secondary Endpoint 
The secondary endpoint of Part 1 of the study is: 
• Assess the safety and tolerability of KD025 (QD) by evaluating the following: safety 
laboratory tests, vital signs, electrocardiograms (ECGs), physical examinations and 
AEs 
The secondary endpoint of Part 2 of the study is: 
• Assess the safety and tolerability of BID (Q12h) dosing of KD025 by evaluating the 
following: safety laboratory tests, vital signs, ECGs, physical examinations and AEs 
8 	
Study Design 
8.1 	
Study Plan 
This is a single centre, non-randomised, open label, two-part study. 
8.1.1 	
Study Plan Part 1 
Part 1 is a single centre, non-randomised, 4-period sequential dose assessment in 
healthy male subjects. In each period, subjects will receive a single dose of IMP, KD025 
Tablet, in the fed state. Additionally, in order to assess the effects of inhibition and 
induction of CYP3A4 and the elevation of gastric pH on KD025 exposure, subjects will 
receive multiple doses of NIMP in Periods 2 to 4; a strong CYP3A4 inhibitor, itraconazole, 
in Period 2; a PPI, rabeprazole, in Period 3; and a strong CYP3A4 inducer, rifampicin, in 
Period 4: 
Period 
IMP/NIMP Dose 
1 
KD025 200 mg QD 
2 
itraconazole 200 mg QD for 7 days 
KD025 200 mg QD + itraconazole 200 mg QD on 8th day 
itraconazole 200 mg QD on 9th day 
3 
rabeprazole 20 mg BID for 3 days 
KD025 200 mg QD + rabeprazole 20 mg QD on 4" day 
4 
rifampicin 600 mg QD for 9 days 
KD025 200 mg QD on 10th day 
QD: once daily; BID: twice daily; details of the IMP and NIMPs are provided in Section 5.2. 
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It is planned to enrol 40 subjects to ensure there are 34 evaluable subjects; defined as 
those subjects who have sufficient PK data to assess the primary objective of Part 1 of 
the study. 
All subjects will undergo preliminary screening procedures to determine their eligibility 
for Part 1 of the study at the screening visit (Day -28 to Day -2 of Period 1). For each 
period, subjects will be admitted to the clinic on the day prior to IMP administration (Day 
-1) for confirmation of eligibility and baseline procedures; morning admission for Periods 
1, 2 and 4; evening admission for Period 3. 
Prior to being admitted to the clinic in Periods 2 to 4, subjects will take multiple doses of 
the following NIMPs; itraconazole on Day 3 (Period 1; or Day -7 of Period 2 if washout 
period is extended) and continuing from Day -6 to -1 (Period 2); rabeprazole from Day -3 
to -1 (Period 3); rifampicin from Day -9 to -1 (Period 4). Outpatient visits will take place 
on the mornings of Day -3 of Period 3 and Day -9 of Period 4, when the subjects will 
receive their morning dose of rabeprazole and rifampicin, respectively, and will be given 
sufficient supplies for home dosing. Subjects will also attend for an additional outpatient 
visit on the morning of Day -5 of Period 4 to receive their morning dose of rifampicin in 
the clinic, and will be given sufficient supplies for the remainder of the dosing period. 
On the morning following admission for each period (Day 1), subjects will receive a single 
dose of IMP, either alone (Periods 1 and 4) or co-administered with NIMP (itraconazole 
in Period 2 [at the same time as IMP; fed state] and rabeprazole in Period 3 [2 h prior to 
IMP; fasted state]). In Period 2, a further dose of itraconazole will be administered on the 
day after IMP administration (Day 2). All subjects will remain on site until 48 h post-IMP 
dose for safety and PK assessments. There will be a minimum washout of 2, 8 and 
4 days following completion of dosing in Periods 1, 2 and 3, respectively. A follow-up visit 
will take place 3 to 5 days post-final discharge. 
The Part 1 study design is presented in Figure 1. 
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Figure 1 	
Part 1 Study Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
Day -28 to -2 
Days -6 to -2a 
Day -3 
Day -9 and Day -5 
ltraconazole 
Rabeprazole 
Rifampicin 
Screening 
(Home) 
(Outpatient Visit) 
(Outpatient Visit) 
Day -2 
Days -8 to -6 and 
Days -4 to -2 
Rabeprazole 
Rifampicin 
(Home) 
(Home) 
• 
Day -1 
Day -1 
Day -1 
Day -1 
Admission 
Admission 
Admission 
Admission 
(morning) 
(morning) 
(evening) 
(morning) 
ltraconazoleb 
Rabeprazole 
Rifampicinb 
Day 1 
Day 1 
Day 1 
Day 1 
KDO25 
KDO25 + 
ltraconazole 
KDO25 + 
Rabeprazole 
KDO25 
Minimum 2 day 
washout period 
Day 2 
ltraconazole 
Day 3a 
Day 3 
Day 3 
Day 3 
Discharge 
Discharge 
Discharge 
Discharge 
(morning) 
ltraconazole 
(morning) 
(morning) 
(morning) 
Minimum 8 day 
washout period 
Minimum 4 day 
washout period 
Follow-up Visit 
(3 to 5 days post- 
final discharge) 
a If the minimum washout period is extended, subjects will receive their first dose of itraconazole during a 
separate outpatient visit on Day -7 of Period 2 
b Subjects will take itraconazole (Period 2)/rifampicin (Period 4) in the clinic after admission 
Subjects will take the evening dose of rabeprazole at home, prior to admission 
8.1.2 	
Study Plan Part 2 
Part 2 is a single centre, non-randomised, 2-period sequential dose assessment in 
healthy male subjects. In each period, subjects will receive a single day of BID dosing 
with IMP (KD025 tablet) in the fed state. Additionally, in order to assess the effect of a 
modest increase in gastric pH on the exposure of KD025, subjects will also receive 
multiple QD doses of the NIMP omeprazole, a PPI, in Period 2: 
Period 
IMP/NIMP Dose 
1 	
KD025 200 mg BID (Q12h) on a single day 
2 	
omeprazole 20 mg QD for 3 days 
KD025 200 mg single day, BID (Q12h) + omeprazole 20 mg QD on 4th day 
QD: once daily, BID: twice daily, Q12h: every 12 hours 
Details of the IMP and NIMPs are provided in Section 5.2 
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It is planned to enrol 38 subjects to ensure there are 34 evaluable subjects, defined as 
those subjects who have sufficient PK data to assess the primary objective of Part 2 of 
the study. 
All subjects will undergo preliminary screening procedures to determine their eligibility 
for the study at the screening visit (Day -28 to Day -2 of Period 1). For each period, 
subjects will be admitted to the clinic on the evening of the day prior to IMP administration 
(Day-1) for confirmation of eligibility and baseline procedures. 
Prior to being admitted to the clinic in Period 2, subjects will take single daily doses of 
the NIMP (omeprazole). At discharge from Period 1, subjects will receive their first dose 
of omeprazole and will be given sufficient supplies for home dosing on Days -2 and -1, 
returning to the clinic for admission on the evening of Day -1. If the minimum washout 
period is extended due to logistics, subjects will receive their first dose of omeprazole 
during a separate outpatient visit on Day -3 of Period 2. 
On the day following admission for each period (Day 1), subjects will receive two doses 
of IMP (morning and evening, Q12h), either alone (Period 1) or with a NIMP (omeprazole) 
administered in the fasted state 2 h prior to planned morning IMP dose (Period 2). All 
IMP dosing will be in the fed state (standard breakfast). All subjects will remain on site 
until 48 h post-IMP dose for safety and PK assessments. There will be a minimum 
washout of 2 days between dosing in Period 1 and the start of dosing omeprazole in 
Period 2. A follow-up visit will take place 3 to 5 days post-final discharge. 
The Part 2 study design is presented in Figure 2. 
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Period 1 
Day -28 to -2 
Screening 
V  
Day -2 
Omeprazole 
(Home) 
Figure 2 Part 2 Study Sequence 
Minimum 2 day washout 
period 
1 
• 
 
Day 1 
Omeprazole + KD025 
morning dose 
KD025 evening dose 
• 
 
Day -1 
Admission 
(evening) 
• 
 
Day 1 
KD025 morning dose 
KD025 evening dose 
4. 
• 
 
Day -1 
Omeprazole (Home) 
Admission 
(evening) 
Day 3a  
Discharge 
(morning) 
Omeprazole 
V  
Follow-up Visit 
(3 to 5 days post-final 
discharge) 
Day 3 
Discharge 
(morning) 
Period 2 
Day -3a  
Omeprazole 
(Outpatient Visit) 
Sponsor/Quotient Sciences Confidential 
a If the minimum washout period is extended, subjects will receive their first dose of onneprazole during a 
separate outpatient visit on Day -3 of Period 2. Otherwise, subjects will receive the first dose of omeprazole 
at discharge from Period 1. 
8.2 	
Criteria for In-Study Decisions 
Not applicable for this study. 
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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. 
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) 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 clinic and will return for the next study period/assessments, as planned. 
Subjects will be withdrawn from the study drugs 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 [mean of 
triplicate assessments, as applicable]) 
- 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 Period 1 admission/pre-dose measurement; for QTc withdrawal criteria, baseline will 
be considered as the mean value of the triplicate pre-dose Day 1 (Period 1) ECG 
measurement. 
	
8.4 	
Subject Replacement 
It is not anticipated that replacement subjects will be used in this study; however, in the 
event that a replacement will be required, this will be discussed with the investigator and 
sponsor. 
Part 1 
If replacement of subjects is invoked, up to 4 additional subjects may be enrolled in Part 
1 of the study in order to achieve sufficient evaluable subjects per relevant comparison; 
the maximum number of subjects that may be dosed is 44. Any subject withdrawn due 
to an IMP or NIMP-related AE or termination of the study will not be replaced. Subjects 
withdrawing for other reasons may be replaced at the discretion of the investigator and 
sponsor to ensure sufficient evaluable subjects. Any replacement subject will be required 
to complete the reference treatment period (Period 1) in addition to any further test 
periods (Period 2 to 4) not already completed by the replaced subject. 
A subject is considered to be evaluable if they have sufficient PK data to assess the 
primary objective of Part 1 of the study. It should be noted that 34 subjects are required 
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for each comparison of interest and therefore replacement subjects may be utilised, eg 
if only 32 subjects have evaluable data for Periods 1 and 4. 
Part 2 
If replacement of subjects is invoked, up to 4 additional subjects may be enrolled in Part 2 
of the study in order to achieve sufficient evaluable subjects per relevant comparison; 
the maximum number of subjects that may be dosed is 42. Any subject withdrawn due 
to an IMP or NIMP-related AE or termination of the study will not be replaced. Subjects 
withdrawing for other reasons may be replaced at the discretion of the investigator and 
sponsor to ensure sufficient evaluable subjects. Any replacement subject will be required 
to complete the reference treatment period (Period 1) in addition to Period 2. 
Evaluable subjects are defined as those subjects who have sufficient PK data to assess 
the primary objective of Part 2 of the study. 
8.5 	
Stopping Criteria 
The study will be halted, and the risk to other subjects evaluated, prior to a decision as 
to whether to terminate the study if any of the following criteria are met: 
• The occurrence of an SAE considered at least possibly related to the IMP 
administration in 1 subject. 
• The occurrence of severe, non-serious AEs considered at least possibly related to 
the IMP administration in 2 subjects in any treatment period. 
Relatedness will be determined by the investigator and/ or sponsor. 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 will not be resumed until a further substantial amendment to resume the study is 
submitted and approved by MHRA and EC. 
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 
and EC. 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 halted, clearly explaining the reasons. A 
description of follow-up measures taken for safety reasons if applicable, should also be 
provided. 
If the study is abandoned prior to commencement of any protocol activities, the 
investigator or sponsor must notify the EC and MHRA by letter outlining the reasons for 
abandonment of the trial. 
Once exposure to IMP dosing has begun, the study will be completed as planned unless 
the following criteria are satisfied that require temporary suspension or early termination 
of the study: 
• The occurrence of SAEs (s), as defined in Section 8.5, if considered to be related to 
the IMP, as defined in Section 14.2. 
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• 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 may 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 and EC 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 and sponsor. 
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 	
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. 
8.7.1 	
Subject Numbers 
Part 1 
Subject numbers will be allocated on the morning of IMP dosing according to the code 
001 to 040 using the lowest number available. If required, replacement subjects will be 
allocated subject numbers 901 to 940, where the last 2 digits are the same as those of 
the original subject (eg if Subject 005 withdraws, the replacement will have Subject 
Number 905 and will receive the reference treatment, as well as IMP/NIMP for at least 
one treatment period not already received by the replaced subject). 
Part 2 
Subject numbers will be allocated on the morning of IMP dosing according to the code 
201 to 238 using the lowest number available. If required, replacement subjects will be 
allocated subject numbers 801 to 838 where the last 2 digits are the same as those of 
the original subject (eg if Subject 205 withdraws, the replacement will have Subject 
Number 805 and will receive the reference treatment (Period 1), as well as the IMP/NIMP 
for Period 2. 
8.7.2 	
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 within the last 12 months, prior to enrolment in the study. 
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Subjects will be recruited from the Quotient Sciences panel or by direct advertising to the 
public. 
Before subjects are admitted to the clinic, 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). 
9.2 	
Inclusion Criteria 
1. Healthy males 
2. Age 18 to 55 years 
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 	
kg 
5. Body mass index of 18.0 to 32.0 kg/m2  or, if outside the range, considered not 
clinically significant by the investigator 
6. Miast be willing and able to communicate and participate in the whole study 
7. Must provide written informed consent 
8. Must adhere to the contraception requirements as defined in Section 9.4) 
Inclusion criteria 3 from the list above will be re-assessed at the Period 1 admission. 
9.3 	
Exclusion Criteria 
1. Subjects who previously participated in any other investigational study drug trial in 
which receipt of an investibational study drug occurred within 90 days prior to dosing 
(subjects who have previously received KD025 in Part 1 at least 90 days prior to 
dosing in Part 2 are eligible to participate). 
2. Subjects who are study site employees, or immediate family members of a study site 
or sponsor employee 
3. Subjects with pregnant partners 
4. History of any drug or alcohol abuse in the past 2 years 
5. 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) 
6. 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 
7. Current users of e-cigarettes and nicotine replacement products and those who have 
used these products within the last 12 months 
8. Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator at screening 
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9. Clinically significant abnormal biochemistry, haematology or urinalysis as judged by 
the investigator (laboratory parameters are listed in Appendix 1) 
10. Positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1) or 
alcohol breath test at screening and admission 
11. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or 
human immunodeficiency virus (HIV) results 
12. Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation 
13. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or 
gastrointestinal disease, neurological or psychiatric disorder, as judged by the 
investigator 
14. Subject has a history or presence of any of the following: 
- Active gastrointestinal 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 
15. Subjects with a history of cholecystectomy or gall stones 
16. Subject has QT interval corrected using Fridericia's formula (QTcF) intervals 
>450 msec at screening or admission 
17. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients; including intolerance to itraconazole, rabeprazole, rifampicin and 
omeprazole. 
18. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hayfever is allowed unless it is active 
19. Donation or loss of greater than 400 mL of blood within the previous 3 months 
20. Subjects who are taking, or have taken, any prescribed or over-the-counter drug 
(other than 4 g per day paracetamol) or herbal remedies in the 14 days before IMP 
administration (See Section 11.4). Exceptions may apply on a case by case basis, if 
considered not to interfere with the objectives of the study, as agreed by the principal 
investigator (PI) and sponsor's medical monitor. 
21. Failure to satisfy the investigator of fitness to participate for any other reason 
Exclusion criteria 6, 9, 10, 14, 16, 18, 20 and 21 from the list above will be re-assessed 
at admission/pre-dose, as applicable. 
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 
The following contraception requirements are aligned with guidance issued by the Heads 
of Medicines Agency: Clinical Trials Facilitation Group [29]. 
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: 
• Combined (oestrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
- oral 
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- intravaginal 
- transdermal 
• Progestogen-only hormonal contraception: 
- oral 
- injectable/implantable 
- intrauterine hormone-releasing system 
• Implantable intrauterine device 
• Surgical sterilisation (for example, vasectomy or bilateral tubal occlusion) 
• Male condom with either 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. 
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), including pregnant partners of male subjects. Therefore, a condom should be 
used by all male subjects throughout the study and for 90 days after study discharge. 
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 become 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 admission in Period 1, and 24 h prior to commencing NIMP treatment in Part 1 
Periods 2 to 4 and Part 2 Period 2, until discharge for each treatment period 
2. Subjects must not drink liquids or eat food containing grapefruit or cranberry from 
24 h prior to admission in Period 1, and 24 h prior to commencing NIMP treatment in 
Part 1 Periods 2 to 4 and Part 2 Period 2, until discharge for each treatment period 
3. Subjects must not drink liquids or eat food containing caffeine or other xanthines from 
24 h prior to admission until discharge for each treatment period 
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4. Subjects should refrain from eating food containing poppy seeds for 48 h prior to 
screening and for 24 h prior to admission until discharge for each treatment period 
5. Subjects must not take part in any unaccustomed or strenuous exercise from the 
72 h before the screening visit and then from 24 h prior to admission until discharge 
for each treatment period. 
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 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 and Appendix 3. 
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. 
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 Sections 9.2 and 9.3. 
Reserve subjects for the first dose occasion, in any group, will not require admission 
procedures to be repeated, if dosing is within 2 days. 
Part 1: subjects will be admitted to the clinical unit on the morning before IMP 
administration (Day -1) for Periods 1, 2 and 4, and on the evening before IMP 
administration (Day -1) for Period 3. 
Part 2: subjects will be admitted to the clinical unit on the evening before IMP 
administration (Day -1) for both periods. 
The admission and pre-dose procedures are presented in Appendix 2 and Appendix 3 
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10.3 	
Study Day Procedures 
10.3.1 	
Blood Volume 
The total blood volume for each subject will not exceed 550 mL in a 4 week period. 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: 
Pharmacokinetic samples should take priority over other procedures scheduled at the 
same time point. 
As guidance, the preferred order of assessments is: 
ECGs 	
Vitals 	
PK blood 
sampling 
Other assessments 
eg physical exams 
Electrocardiograms 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 will be timed and performed relative to the start of IMP dosing. 
10.3.3 	
Discharge from the Clinical Unit 
A subject will be allowed to leave the premises following completion of study-specific 
procedures at 48 h post-IMP dose (Day 3), 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. 
10.3.4 	
Outpatient Visits 
Part 1 
Subjects will be asked to attend the clinical unit for outpatient visits on Day-3 of Period 3, 
and Days -9 and -5 of Period 4 for NIMP administration and home supplies, as well as 
the assessments described in Appendix 2. 
Part 2 
If the minimum washout period is extended, subjects will be asked to attend the clinical 
unit for an outpatient visit on Day -3 of Period 2 for NIMP administration and home 
supplies, as well as the assessments described in Appendix 3. Otherwise, subjects will 
receive the first dose of omeprazole at discharge from Period 1. 
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10.3.5 	
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, each subject will receive a card stating the 
telephone number of the investigator. 
10.3.6 	
Follow-up 
A follow-up phone visit will take place 3 to 5 days after final discharge 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 visit (including any 
unscheduled) will be considered the end of the study. 
11 Dosing of Subjects 
11.1 	
Food and Fluid Intake 
Water will be allowed ad libitum on the day of dosing. For Part 1 decaffeinated fluids will 
be allowed ad libitum from lunch time on the day of IMP dosing. For Part 2, decaffeinated 
fluids will be allowed ad libitum from lunch time on the day of dosing until 1 h before and 
then from 1 h after the evening dose. 
If, for technical reasons, IMP dosing is delayed for more than 2 h beyond the expected 
dosing time, subjects may receive 200 mL of Lucozade Sport at the originally scheduled 
dosing time, or earlier if possible. 
11.1.1 	
Investigational Medicinal Product Dosing 
Part 1 
Breakfast will be controlled by clinical staff members on IMP dosing days for each 
treatment period (Day 1). The start and stop time of the breakfast must be recorded and 
where less than 100% of the breakfast has been consumed, the percentage consumed 
must be recorded. 
Subjects will be provided with a light snack on the evening of admission days for each 
treatment period (Day -1) 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 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. 
Lunch will be provided at approximately 4 h post-IMP dose, an evening meal at 
approximately 9 h post-IMP dose and an evening snack at approximately 14 h post-IMP 
dose. On subsequent days, meals will be provided at appropriate times. 
Part 2 
In Part 2 the IMP will be administered BID and given in the fed state. 
Breakfast will be controlled by clinical staff members on IMP dosing days for each 
treatment period (Day 1). The start and stop time of the breakfast must be recorded and 
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where less than 100% of the breakfast has been consumed, the percentage consumed 
must be recorded. 
Subjects will be provided with a light snack on the evening of admission days for each 
treatment period (Day -1) 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 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 
morning dosing should still occur 30 min after the start of breakfast. 
Subjects will be dosed in the evening following the evening meal. Evening dosing will 
occur 30 min after the start of the evening meal (ie, dosing at 12 h post-morning dose; 
meal to be started 11 h and 30 min post-morning dose). Decaffeinated fluids will be 
allowed ad libitum from lunch time on the day of dosing until 1 h before and then from 
1 h after the evening dose. 
Lunch will be provided at approximately 5 h post-morning IMP dose and an evening 
snack at approximately 14 h post-morning IMP dose. On subsequent days, meals will be 
provided at appropriate times. 
11.1.2 	
Non-Investigational Medicinal Product Dosing 
Part 1 
Subjects will take itraconazole for 9 consecutive days; on Day 3 of Period 1 and from 
Day -6 to Day 2 of Period 2. All doses of itraconazole should be taken with approximately 
240 mL water at approximately the same time each morning following breakfast; when 
co-administered with IMP on Day 1, a total of 240 mL water should be taken. 
Subjects will take rabeprazole for 4 consecutive days; from Day -3 to Day 1 of Period 3. 
All doses of rabeprazole should be taken with approximately 240 mL water. On Days -3 
to -1 (BID dosing days) subjects should take rabeprazole at approximately the same time 
each morning following breakfast, and following an evening meal. On Day 1, rabeprazole 
will be administered in the fasted state, approximately 2 h prior to IMP administration. 
Subjects will take rifampicin for 9 consecutive days; from Day -9 to Day -1 of Period 4. 
All doses of rifampicin should be taken with approximately 240 mL water at 
approximately the same time each morning, prior to eating breakfast. 
Part 2 
Subjects will take omeprazole for 4 consecutive days; from Day -3 to Day 1 of Period 2. 
All doses of omeprazole should be taken with approximately 240 mL water. On Days -3 
to -1 (Period 2 only) subjects should take omeprazole at approximately the same time 
each morning prior to eating breakfast. On Day 1, omeprazole will be administered in the 
fasted state, approximately 2 h prior to IMP administration. Decaffeinated fluids will not 
be allowed from 1 h prior until 1 h post-omeprazole administration (except on Day 1; see 
Section 11.1.1 Part 2 for details). 
11.2 	
Administration of Test Preparations 
Specific details of the IMP and NIMPs, and doses to be administered are provided in 
Section 5.2 and Section 8.1, respectively. 
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Part 1 
On IMP dosing days (Day 1), subjects will be dosed in the morning and receive KD025 
alone (Periods 1 and 4) or in combination with itraconazole (at the same time as IMP; 
Period 2), or rabeprazole (approximately 2 h prior to IMP; Period 3); a total of 240 mL 
water will be given immediately following oral administration. The exact time of dosing 
will be decided based on logistics and will be documented. 
On NIMP dosing days, subjects will take treatments at approximately the same time each 
day with approximately 240 mL water. When NIMP is taken at home, subjects will record 
the time of administration in a diary card. 
Subjects will receive a total of 4 single doses of KD025, each on a separate occasion 
and multiple doses of itraconazole, rabeprazole and rifampicin, on separate occasions, 
for 9, 4 and 9 consecutive days, respectively. 
The minimum washout period between treatment periods may be changed, if data 
collected during the study support the change. However, the minimum washout period 
will not be reduced to less than 5 half-lives of the IMP. 
Part 2 
On Day 1, Period 1, subjects will be dosed in the morning and will receive KD025 alone 
with a total of 240 mL water given immediately following oral administration. A second 
dose of IMP will be administered approximately 12 h after morning dose. 
On Day 1, Period 2, subjects will be dosed in the morning with the NIMP approximately 
2 h prior to IMP administration. Approximately 240 mL of water will be given immediately 
following oral administration. A second dose of IMP will be administered approximately 
12 h after morning IMP dose. When NIMP is taken at home, subjects will record the time 
of administration in a diary card. 
All IMP doses in Part 2 will be given in the fed state, relative to dosing. See Section 11.1.1 
for details. 
The exact time of dosing will be decided based on logistics and will be documented. 
Subjects will receive a single day BID (Q12h) dose of KD025 on 2 separate occasions, 
and single doses of omeprazole for 4 consecutive days. 
The minimum washout period between treatment periods may be changed, if data 
collected during the study support the change. However, the minimum washout period 
will not be reduced to less than 5 half-lives of the IMP. 
11.3 	
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 conthicted after dosing to ensure the tablet/capsule has 
been swallowed. 
When NIMP is taken at home, subjects will record the time of administration in a diary 
card. 
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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. 
11.4 	
Prior and Concomitant Medications 
No medication will be permitted from 14 days before IMP administration until the 
follow-up visit except 4 g per day paracetamol and those deemed necessary by the 
investigator to treat AEs (see also Section 9.3). Any medications used will be recorded. 
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. 
13 Assessment of Pharmacokinetics and Pharmacodynamics 
13.1 	
Assessment of Pharmacokinetics 
13.1.1 	
Pharmacokinetic Blood Sampling 
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 post-dose blood sampling times are as 
follows: 
• The pre-dose blood sample will be taken 	
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 
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 and 
metabolites KDO25m1 and KD025m2. 
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. 
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An adverse drug reaction is any AE where a causal relationship with the IMP is at least 
a reasonable possibility (possibly related or related). 
Adverse events 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 
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 
Adverse events will be recorded from the time of providing written informed consent until 
discharge from the study at the follow-up visit. During each study visit the subject will be 
questioned directly regarding the occurrence of any adverse medical event according to 
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the schedule in the source data. All AEs, whether ascribed to study procedures or not, 
will be documented immediately. 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. 
14.4 	
Serious Adverse Events 
14.4.1 	
Definition of Serious Adverse Events 
A serious adverse event 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 Investigator's Brochure) 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 
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: 
• 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. 
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Creatinine clearance (CLcr) will be calculated at screening by using the Cockcroft-Gault 
equation and body weight for eligibility purposes: 
CLcr (mL/min) = (140-age [years') x (body weight [kg]) (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: 
• 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 general 
practitioner 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. 
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. 
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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 52 h before dosing 
• Post-dose vital signs measurements will be taken ± 15 min from the nominal 
post-dose time points 
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 
Twelve-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. 
In Part 1, single ECGs will be measured at all time points with the exception of pre-dose 
and 4 h post-dose on Day 1 of each period, during which times ECGs will be measured 
in triplicate, a minimum of 2 min apart. 
In Part 2, single ECGs will be measured at all time points with the exception of 
pre-morning dose, 4 h post-morning dose, pre-evening dose and 2 h post-evening dose 
on Day 1 of each period, during which times ECGs will be measured in triplicate, a 
minimum of 2 min apart. 
The acceptable deviations from the nominal ECG measurement time points are: 
• The pre-dose ECG measurements will be taken 52 h before dosing 
• Post-dose ECG measurements will be taken ± 15 min from the nominal post-dose 
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 
The subject's body weight 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 3. 
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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/NIMPs 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 
For the purposes of sample size calculation the following assumptions have been made: 
• Estimates of intra-subject variability (CVw) of 50% and 40% for Cmax and 
AUC(0-last), respectively. Data obtained from previous food effect study 
(QCL117415, data on file) 
• Two one-sided tests with a probability of type 1 error of 0.05 for PK endpoints Cmax 
and AUC(0-last), ie 90% Cl to be calculated 
• Acceptance interval of 70.00% to 143.00% 
• 80% power assuming the true ratio is between 95.00% and 105.00% 
Part 1 
Based on the above assumptions, 40 subjects are to be dosed to achieve 34 evaluable 
subjects for Cmax (PK parameter with highest CVw value). Evaluable subjects are 
defined as those subjects who have sufficient PK data to assess the primary objective of 
Part 1 of the study. 
Part 2 
Based on the above assumptions, 38 subjects are to be dosed to achieve 34 evaluable 
subjects for Cmax (PK parameter with highest CVw value). Evaluable subjects are 
defined as those subjects who have sufficient PK data to assess the primary objective of 
Part 2 of the study. 
	
15.2 	
Data Management 
Data management will be performed by Quotient Sciences. 
All study data recorded in the source will be transcribed into a validated study database 
which has an audit trail to log all subsequent changes to the data. All queries will be 
resolved within the study database with the assistance of clinical staff and reference to 
the source data. 
Adverse events and medications will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) (v21.0) and the World Health Organisation Drug 
Dictionary Enhanced (WHO DDE) Drug Reference List (2017 or a more recent version), 
respectively. An independent coding review will also be performed within the Data 
Sciences department. 
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Clinical chemistry and haematology data (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 are met. 
Further details are addressed in the Data Management Plan. 
15.3 	
Pharmacokinetic Data Analysis 
The plasma concentration data for KD025 and metabolites KDO25m1 and KDO25m2, 
provided by Covance Laboratories Ltd, will be analysed by Quotient Sciences using 
Phoenix WinNonlin v8.0 or a more recent version (Certara USA, Inc., USA). 
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: 
Part 1 
Primary Parameters 
Cmax 	 Maximum observed drug concentration 
AUC(0-last) 	
Area under the concentration vs time curve from time zero to the 
last sampling time with quantifiable drug 
AUC(0-inf) 	
Area under the concentration vs time curve from time zero 
extrapolated to infinity 
Secondary Parameters 
Tlag 
Tmax 
AUC(0-12) 
AUC(0-24) 
AUC%extrap 
Frel 
Lambda-z 
T1/2 
MRT 
Elapsed time from dosing at which the drug was first quantifiable in 
a concentration vs time profile following oral dosing 
Elapsed time from dosing at which Cmax (the maximum drug 
concentration) was apparent 
Area under the concentration vs time curve from time zero to 12 h 
post-dose 
Area under the concentration vs time curve from time zero to 24 h 
post-dose 
Percentage of AUC(0-inf) accounted for by extrapolation 
Relative bioavailability of (test) to (reference) for Cmax, AUC(0-last) 
and AUC(0-inf), where test is the exposure in the presence of 
itraconazole (Period 2), rabeprazole (Period 3), rifampicin 
(Period 4) and reference is the exposure of KD025 administered 
alone (Period 1). 
Slope of the regression line passing through the apparent 
elimination phase in a concentration vs time plot 
Apparent elimination half-life 
Mean residence time 
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CL/F 
Vd/F 
MPR 
Part 2 
Primary Parameters 
Cmax (first dose) 
Cmax (second dose) 
AUC(0-24) 
Secondary Parameters 
hag 
Tmax 
AUC(0-12) 
AUC(12-24) 
AUC(0-last; first dose) 
AUC(0-inf; first dose) 
AUC%extrap 
Frel 
Lambda-z 
T1/2 
MRT 
MPR 
Maximum observed drug concentration following the first dose 
Maximum observed drug concentration following the second 
dose 
Area under the concentration vs time curve from time zero to 
24 h post-dose 
Elapsed time from dosing at which the drug was first 
quantifiable in a concentration vs time profile following oral 
dosing 
Elapsed time from dosing at which Cmax (the maximum drug 
concentration) was apparent 
Area under the concentration vs time curve from time zero to 
12 h post-dose 
Area under the concentration vs time curve from 12 h to 24 h 
post-dose 
Area under the concentration vs time curve from time zero to 
the last sampling time with quantifiable drug from first dose 
Area under the concentration vs time curve from time zero 
extrapolated to infinity from first dose 
Percentage of AUC(0-inf) accounted for by extrapolation 
Relative bioavailability of (test) to (reference) for Cmax (first 
dose and last dose), AUC(0-24), AUC(0-12), AUC(12-24), 
AUC(0-last) and AUC(0-inf), where test is the exposure in the 
presence of omeprazole (Period 2) and reference is the 
exposure of KD025 administered alone (Period 1). 
Slope of the regression line passing through the apparent 
elimination phase in a concentration vs time plot 
Apparent elimination half-life 
Mean residence time 
Molecular weight corrected metabolite to parent ratio 
Apparent plasma clearance 
Apparent volume of distribution based on the terminal phase 
Molecular weight corrected metabolite to parent ratio 
Further details of the PK data analysis will be included in the reporting and analysis plan 
(RAP). 
15.4 	
Statistical Data Analysis 
Statistical analysis and 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). 
In general terms, categorical data (including treatment-emergent AEs) will be presented 
using counts and percentages, while continuous variables will be presented using the 
mean, median, standard deviation, minimum and maximum. Additional statistics will be 
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provided for PK-related data including coefficient of variation (CV%), geometric mean, 
geometric CV% and geometric n (ie the number of subjects with an observation that were 
included in the natural logarithmic transformation). 
Descriptive summaries for all safety data (AEs, vital signs, ECGs and safety laboratory 
assessments) by regimen will be provided (including changes from baseline as required). 
Descriptive summaries for all PK data by regimen will be provided. 
Formal statistical analysis will be performed for KD025 and metabolites KDO25m1 and 
KD025m2 PK parameters as follows: 
• Part 1:Cmax, AUC(0-last) and AUC(0-inf) 
• Part 2: 
- Primary: Cmax(first dose), Cmax(second dose) and AUC(0-24) 
- Secondary: AUC(0-12), AUC(12-24), AUC(0-last; first dose) and AUC(0-
inf; first dose) 
The PK parameters will undergo a natural logarithmic transformation and will be 
analysed using mixed effect modelling techniques. The mixed effects model will include 
terms for treatment as a fixed effect and subject as a random effect. Adjusted geometric 
mean ratios (GMRs) and 90% confidence intervals (Cis) for the adjusted GMRs will be 
provided for the comparisons of interest, where the ratios are defined as test/reference. 
A separate model will be fitted for each comparison of interest and will only include 
subjects who complete both periods for the relevant comparison of interest. 
Part '1 
• Period 2 (KD025 + itraconazole) vs Period 1 (KD025 alone) 
• Period 3 (KD025 + rabeprazole) vs Period 1 (KD025 alone) 
• Period 4 (KD025 + rifampicin) vs Period 1 (KD025 alone) 
If the 90% Cls for each of KD025 (parent only) Cmax, AUC(0-last) and AUC(0-inf) lie 
within the acceptance interval of 70.00% to 143.00%, then the absence of an effect on 
PK can be concluded for the comparison of interest. 
Part 2 
• Period 2 (KD025 + omeprazole) vs Period 1 (KD025 alone) 
If the 90% Cls for each of KD025 (parent only) Cmax(first dose), Cmax(second dose), 
and AUC(0-24) lie within the acceptance interval of 70.00% to 143.00%, then the 
absence of an effect on PK can be concluded for the comparison of interest. 
Populations for analysis will be determined for safety and PK data after database lock 
when the relevant data are available using the criteria defined in the RAP; the RAP will 
be signed off prior to database lock. 
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 
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• 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 and PK data will be listed. 
15.5 	
Interim Analysis 
No formal interim analyses are planned for this study. 
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. 
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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. 
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, M.D. 
Kadmon Corporation, LLC 
55 Cambridge Parkway, Suite 300E 
Cambridge, MA 02142 
Telephone: Direct: 724-778-6129 
Mobile: 857-253-8642 
E-mail: Sanjay.Aggarwal@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. 
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. 
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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. 
The investigator is required to notify the EC of any other SUSAR as soon as possible, 
but no later than 15 calendar days after they first became aware of the reaction. 
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. 
If the participant information sheet 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 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 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 
[30] 
• The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 
2004 No. 1031 [31] 
• The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2006 No. 1928 [32] 
• The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984 [33] 
• The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941 [34] 
In addition, the study will be performed according to the ethical principles outlined in the 
World Medical Association Declaration of Helsinki and its amendments [35]. 
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 	
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. 
18.5 	
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 assessment). 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. 
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18.6 	
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) [30], The Medicines for Human Use 
(Clinical Trials) Regulations 2004 [31] and The Medicines for Human Use (Clinical Trials) 
Amendment Regulations 2006 [32][33]. 
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. 
19 Quality Control and Quality Assurance 
Quality control of all data collected from this study will be performed in accordance with 
Quotient standard operating procedures. This study (or elements thereof) may be subject 
to Quotient quality assurance audit, in line with current internal auditing procedures. 
Similarly, the study (or elements thereof) may be subject to sponsor quality assurance 
audit. 
	
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 data 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 2012 edition [36]. 
21 Publication 
Please refer to the Master Services Agreement for information on publication. 
Quotient Sciences shall have the right to publish the results of the research, subject to 
the sponsor's prior written consent, which shall not be unreasonably withheld or 
delayed. Following the receipt of such consent, Quotient Sciences shall submit a copy 
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of the proposed publication to the sponsor who shall have 30 days in which to request 
amendments thereto which, to the extent that such proposed amendments are 
reasonable, Quotient shall be obliged to incorporate prior to such publication. 
The sponsor undertakes that, prior to publication of any information, article, paper, report 
or other material concerning the research, it will submit a copy of such publication to 
Quotient Sciences who shall have 30 days in which to request amendments thereto 
which, to the extent that such proposed amendment are reasonable, the sponsor shall 
be obliged to incorporate prior to such publication. 
22 References 
[1] 
Cohen IR. Discrimination and dialogue in the immune system. Semin lmmunol. 
2000; 12(3):215-9; discussion 57-344. 
[2] 
Steinman L, Merrill JT, McInnes IB et al. Optimization of current and future 
therapy for autoimmune diseases. Nat Med. 2012; 18(1):59-65. 
[3] 
Korn T, BetteIli E, Oukka M, et al. IL-17 and Th17 Cells. Annu Rev lmmunol. 
2009; 27:485-517. 
[4] 
Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune 
tolerance. Cell. 2008; 133(5):775-787. 
[5] 
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 
[6] 
Nakagawa 0, Fujisawa K, lshizaki T, et al. 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. 
[7] 
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 S A. 2014; 111(47):16814-16819. 
[8] 
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. 
[9] 
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. 
[10] 
Tybulewicz VL, Henderson RB. Rho family GTPases and their regulators in 
lymphocytes. Nat Rev Immunol. 2009; 9(9):630-644. 
[11] 
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. 
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[12] 
Isgro 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. 
[13] 
Investigator's Brochure for KD025. Edition 7.0; 14 Apr 2017. 
[14] 
Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial 
to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 
24-h intragastric acidity and plasma gastrin concentrations in young healthy male 
subjects. Aliment Pharmacol Ther. 1998.12(11):1079-1089. 
[15] 
FDA Center for Drug Evaluation and Research: Draft Guidance: Clinical Drug 
Interaction Studies — Study Design, Data Analysis, and Clinical Implications 
Guidance for Industry. October 2017. 
[16] 
Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the 
pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998 Jul; 64(1):58-65. 
[17] 
Lebrun-Vignes B, Archer VC, Diquet B, Let al. Effect of itraconazole on the 
pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion 
in healthy subjects. Br J Clin Pharmacol. 2001; 51(5):443-450. 
[18] 
Jalava KM, Olkkola KT, Neuvonen PJ Effect of itraconazole on the 
pharmacokinetics and pharmacodynamics of zopiclone. Eur J Clin Pharmacol. 
1996;51(3-4):331-334 
[19] 
Summary of Product Characteristics: Itraconazole 100 mg Capsules, hard. 
Actavis UK Ltd. Updated 24 Aug 2017. Accessed at 
https://www.medicines.org.uk/emc/medicine/24176.  
[20] 
Hardin TC et al; PK of ltraconazole following oral administration to normal 
volunteers. Antimicrobial Agents and Chemotherapy. 1988; 32(9) 1310-1313. 
[21] 
Baldwin CM and Keam SJ. Rabeprazole: A review of its use in the management 
of gastric acid-related diseases in adults. Drugs 2009; 69:1373-1401. 
[22] 
Summary of Product Characteristics: Rabeprazole 20 mg Gastro-resistant 
Tablets. Actavis UK Ltd. Updated 05 May 2017. Accessed at 
https://www.medicines.org.uk/emc/medicine/27143/SPC/Rabeprazole+20mg+G  
astro-resistant+Tablets/. 
[23] 
Yamashita F et al. Modelling of Rifampicin-Induced CYP3A4 activation dynamics 
for the prediction of clinical drug-drug interactions from In vitro data; PLOS ONE 
2013; 8(9) e70330. 
[24] 
Summary of Product Characteristics: Rifadin 300 mg Capsules. Sanofi. 
Updated 22 Mar 2017. Accessed at: 
https://www.medicines.org.uk/emc/medicine/3960/PIURifadin+300mg+Capsules.  
[25] 
Highlights of prescribing information, PRILOSEC. AstraZeneca Pharmaceuticals 
LP. 	
Last 	
updated 	
September 	
2012. 	
Accessed 	
at 
https://www.accessdata.fda.gov/drugsatida_docs/labe1/2012/019810s0961b1.pdf  
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[26] 
Summary of. Product Characteristics: Omeprazole 20 mg Gastro-resistant 
tablets. DEXCEL-PHARMA Ltd. Last Updated 20 Feb 2017. Accessed at 
https://www.medicines.org.uldemc/product/663/smpc  
[27] 
FDA Guidance: Food effect, bioavailability and fed bioequivalence studies. 
2002. 
[28] 
EMA — Guidance on the investigation of bioequivalence. 20 January 2010. 
[29] 
Heads of Medicines Agency: Clinical Trials Facilitation Group guidance. 
Accessed at: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf  
[30] 
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. 
[31] 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031. 
[32] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2006 No. 1928. 
[33] 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984. 
[34] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2008 No. 941. 
[35] 
World Medical Association, Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects (and all subsequent amendments). 
[36] 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2012 Edition (as amended 12/11/2014). 
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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 
Aspartate 
Leukocytes 
Marijuana/Cannabis. 
Lymphocytes 
Am inotransferase (AST) 
Nitrites 
Methadone 
Mean Cell Haemoglobin (MCH) 
Bicarbonate 
pH 
Methamphetamine/ 
Mean Cell Haemoglobin Concentration 
Bilirubin (Total) 
Protein 
Ecstasy 
(MCHC) 
Bilirubin (Direct) (only if 
Specific gravity 
Morphine/Opiates 
Mean Cell Volume (MCV) 
Total is elevated) 
Urobilinogen 
Phencyclidine 
Monocytes 
Calcium 
At discretion of 
Tricyclic 
Neutrophils 
Chloride 
investigator based on 
Antidepressants 
Platelet Count 
Creatine Kinase (CK) 
urinalysis results 
Red Blood Cell (RBC) Count 
Creatininea 
Microbiology 
White Blood Cell (WBC) Count 
Gamma Glutannyl 
Urine Microscopy 
Transferase (GGT) 
Glucose 
Glucose (Fasting) 
Potassium 
Phosphate (Inorganic) 
Protein (Total) 
Sodium 
Urea 
a Creatinine clearance will be calculated at screening using the Cockcroft-Gault equation for eligibility purposes 
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Appendix 2 	
Part 1 Study Flow Chart 
Screening Outpatient Visit 
Periods Ito 4 
Admissiona 
Resident in Clinic 
Discharge Follow- 
up 
Vtb 
Study Day 
-28 to -2 
-3 (Period 3) 
-9 (Period 4) 
-5 (Period 4) 
-1 
1 	
2 
3 
Pre-dose 
Time Relative to KD025 Dosing (h) 
0 0.5 1 1.5 2 3 4 5 6 8 10 12 24 36 
48 	
- 
General Assessments 
Informed Consent 
X 
Medical History 
X 
X 
Weight and Height 
X 
X° 
Vein Assessment 
X 
Carbon Monoxide Breath Test 
X 
X 
Drug Screen 
X 
X 
Alcohol Breath Test 
X 
X 
Non-IMP Administrationd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
IMP Administration° 
X 
Safety Assessments 
. 
Physical Examination 
X 
X 
Safety Labs f 
X 
Xg 
Xh 
X 
X 
Urinalysis 
X 
Xg 
Xh 
X 
X 
ECG I 
X 
X 
Xi 
X 
Xi 
X 
X 
Vital Sign& 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
4 
Adverse Events 
4 
PK Assessments 
Plasma Samples for KD025 and 
metabolites KDO25m1 and KDO25m2 
X 
X X 
X XXXXXXXXX X 
X 
Footnotes on next page 
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a Morning of Periods 1, 2 and 4, evening of Period 3 
h A follow-up visit will take place 3 to 5 days post-final discharge 
° Weight only at admission 
d Itraconazole on Day 3 (of Period 1; or Day -7 of Period 2 if washout period is extended) and continuing from Day -6 to -1 (Period 2); rabeprazole from Day -3 to -1 
(Period 3); rifampicin from Day -9 to -1 (Period 4). On Day -1, subjects will take itraconazole (Period 2) and rifampicin (Period 4) in the clinic after admission, and 
rabeprazole (Period 3) at home prior to admission. 
e IMP will be administered in the fed state. Co-administration with NIMP in Periods 2 and 3; itraconazole will be administered at the same time as IMP in Period 2 
(fed state) and rabeprazole will be administered approximately 2 h prior to IMP in Period 3 (fasted state) 
f Haematology and clinical chemistry; virology and creatinine clearance at screening only 
g Day -3 (Period 3) and Day -5 (Period 4) only 
h Periods 1, 2 and 4 only 
Twelve-lead ECGs will be measured after the subject has been in the supine position for a minimum of 5 min. Single ECGs will be measured at all time points with 
the exception of pre-dose and 4 h post-dose on Day 1 of each period, during which times ECGs will be measured in triplicate, a minimum of 2 min apart 
Blood pressure, heart rate and oral temperature 
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Appendix 3 	
Part 2 Study Flow Chart 
S 
0 
Periods 1 and 2 
Aa 
Resident in Clinic 
D 
RP' 
Study Day 
-28 to 
-2 
-3 
(Period 2) 
-1 
1 	
2 
3 
6-8 
Pre- 
dose 
Time Relative to KD025 Dosing (h) 
0 0.5 1 1.5 2 3 4 5 6 8 10 12 12.5 13 13.5 14 15 16 17 18 20 22 24 36 
48 
General 
Assessments 
Informed Consent 
X 
Medical History 
X 
X 
Weight and Height 
X 
Xh 
Vein Assessment 
X 
CO Breath Test 
X 
X 
Drug Screen 
X 
X 
Alcohol Breath Test 
x 
X 
Non-IMP 
Administrationd 
xd 
xd 
xd 
IMP Administrationd 
X 
X 
Safety 
Assessments 
Physical 
Examination 
X 
X 
Safety Labe 
X 
Xg 
X" 
X 
X 
Urinalysis 
X 
Xg 
Xh 
X 
X 
ECG i 
X 
X 
Xi 
X 
Xi 
Xi 
Xi 
X 
Vital Signe 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
41 
Adverse Events 
-4 
PK Assessments 
Plasma Samples for 
KD025, KDO25m1 
and KDO25m2 
X 
XXX XXX XX XX X XXX X XXX XX X X X 
X 
S: Screening, 0: Outpatient visit, A: Admission, D: Discharge, FUP: Follow-up visit. Footnotes on next page 
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a Evening admission 
h A follow-up visit will take place 3 to 5 days post-final discharge 
c Weight only at admission 
d Subjects will take omeprazole either at discharge from Period 1 or at a separate outpatient visit (Period 2, Day -3), then at horrid, once daily until Day -1 prior to 
admission. 
a Subject will receive IMP BID (Q12h). IMP will be administered in the fed state. For Period 2 only, an NIMP (omeprazole) will be administered in the fasted state 
2 h prior to planned morning IMP dose 
f Haematology and clinical chemistry; virology and creatinine clearance at screening only 
g Day -3 Period 2 only 
h Periods 1 and 2 
Twelve-lead ECGs will be measured after the subject has been in the supine position for a minimum of 5 min. Single ECGs will be measured at all time points with 
the exception of pre-morning dose, 4 h post-morning dose, pre-evening dose and 2 h post-evening dose on Day 1 of each period, during which times ECGs will be 
measured in triplicate, a minimum of 2 min apart 
Blood pressure, heart rate and oral temperature 
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