Clinical trial NCT05427253
Conditions: Safety Issues Tolerance Idiopathic Pulmonary Fibrosis Pulmonary Hypertension
Sponsor: Vicore Pharma AB
Start date: 2022-06-08; Completion date: 2023-06-22
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a FIH, double-blind, placebo-controlled, within-group randomised, trial designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending oral doses of compound 106 (C106) in healthy females of non-childbearing potential and healthy males.

The trial will be conducted in 2 parts:

Part A, single ascending dose (SAD) including a food interaction cohort: safety, tolerability, and PK in healthy males and healthy females of non-childbearing potential receiving single ascending doses of C106.

Part B, multiple ascending dose (MAD): safety, tolerability, and PK in healthy males and healthy females of non-childbearing potential receiving twice daily multiple ascending doses of C106 for 8 days.

Detailed description:

Arms: arm 1: Part A: Oral administration start dose, Single dose 5 mg Part B: Oral administration start dose 20 mg twice daily for 8 days arm 2: Part A and B: Placebo to C106 without the active pharmaceutical ingredient
Interventions: intervention 1: C106 solution intervention 2: Placebo
Intervention descriptions: intervention 1: selective nonpeptide angiotensin II type 2 receptor (AT2R) agonist intervention 2: Placebo for C106 solution

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Trial Protocol VP-C106-101 Final v4.0 
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Clinical Trial Protocol 
EudraCT No. 
2021-006014-36 
Investigational Medicinal 
Product 
C106 
Sponsor trial code 
VP-C106-101 
Protocol Version and Date 
Final v4.0; 27FEB2023 
 
A double-blind, placebo-controlled, within-group randomised, 
first-in-human, single-centre trial to evaluate the safety, tolerability and 
pharmacokinetics of single and multiple ascending oral doses of C106 in 
healthy male and female subjects 
 
 
Phase 
1, First-In-Human (FIH) 
Indication 
N/A 
Test product 
C106 
Comparator product 
Placebo (inactive control) 
Sponsor signatories 
 
 
 
 
 
Principal Investigator 
 
 
 
Clinical trial conduct and management 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance 85, 2nd level 
SE-751 85 Uppsala, Sweden 


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This clinical trial protocol is the property of Vicore Pharma AB and is a confidential 
document. It is not to be copied or distributed to other parties without written approval from 
Vicore Pharma AB. 
The following amendments have been made to the first regulatory approved version of this 
Clinical Trial Protocol (version 2.0). 
Table 4.1-1 Changes to the clinical trial protocol 
Type of change 
Summary of changes 
Revised protocol 
version 
Substantial amendment 
The proposed doses for the remaining planned SAD cohorts are 
240 mg and 300 mg. 
Version 2.0 
The maximum daily dose of C106 is changed from 200 mg 
(100 mg BID) to 480 mg (240 mg BID). One (1) cohort is added 
to the MAD part (cohort B:4). 
The pre-dose ECG recordings will be done on Day 1 instead of 
Day- 1. 
ECG recordings and vital signs assessments will be done 
40 minutes post-dose instead of 1-hour post-dose in order to 
perform the assessments closer to the assumed Cmax timepoint, as 
recommended by the iSRC. 
Risk-assessments regarding COVID-19 has been updated 
according to current recommendations. 
Substantial amendment 
An exploratory, non-invasive pharmacodynamic (PD) assessment 
of endothelial function will be performed using EndoPAT in 
Part B, cohort B:4 before the first IMP administration (Day -1 or 
Day 1) and 30±10 minutes after IMP administration on Day 7. 
The Sponsor address has been updated. 
The planned trial period has been extended until Q3 2023. 
Version 3.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
TRIAL SYNOPSIS 
 
Trial title 
A double-blind, placebo-controlled, within-group randomised, first-in-human, single-centre trial to 
evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of 
C106 in healthy male and female subjects. 
Trial code 
VP-C106-101 
EudraCT No 
2021-006014-36 
Planned trial period 
Q2 2022 to Q3 2023 
Phase of development 
1, first-in-human (FIH) 
Principal Investigator 
Helena Litorp, MD, PhD 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance 85, 2nd level 
SE-751 85 Uppsala, Sweden 
Trial design 
This is a FIH, double-blind, placebo-controlled, within-group randomised, trial designed to evaluate 
the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending oral doses of 
compound 106 (C106) in healthy females of non-childbearing potential and healthy males. 
The trial will be conducted in 2 parts: 
Part A, single ascending dose (SAD) including a food interaction cohort: safety, tolerability, and PK 
in healthy males and healthy females of non-childbearing potential receiving single ascending doses 
of C106. 
Part B, multiple ascending dose (MAD): safety, tolerability, and PK in healthy males and healthy 
females of non-childbearing potential receiving twice daily multiple ascending doses of C106 for 
8 days. 
Objectives 
Primary objective 
To evaluate the safety and tolerability of single and multiple oral doses of C106 in healthy subjects. 
Secondary objectives 
• 
To characterise the PK of single and multiple oral doses of C106 in plasma and urine of 
healthy subjects. 
• 
To evaluate the effect of a high fat meal on PK after a single oral dose of C106 in healthy 
subjects (Part A). 
Exploratory objectives 
• 
To evaluate the metabolite profile of C106 in plasma of healthy subjects at steady state 
(Part B) 
• 
To estimate the excreted C106 and its metabolites, and the metabolite profile of C106 in urine 
of healthy subjects at steady state (Part B). 


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• 
To collect and store electrocardiogram (ECG) data for potential future evaluation of the effect 
of C106 on ECG parameters, including concentration-QTc analysis using Expert Precision 
QT (EPQT) assessment (Part A) 
• 
To evaluate the pharmacodynamic (PD) effect of C106 on endothelial function in healthy 
subjects at steady state (Part B, cohort B4). 
Endpoints 
Primary endpoints 
• 
Treatment Emergent adverse events (AEs) and serious AEs (SAEs). 
• 
Clinically relevant changes in: 
o 12-lead electrocardiograms (ECGs). 
o Vital signs (blood pressure, heart rate (HR), body temperature and respiratory rate 
o Laboratory safety variables (haematology, coagulation, clinical chemistry, and urine 
analysis). 
o Physical examination. 
Secondary endpoints 
Part A 
• 
PK parameters: 
o Area under the plasma concentration vs. time curve (AUC) from time 0 to infinity 
(AUCinf) and AUC from time 0 to the time of the last quantifiable concentration 
(AUClast,). 
o Plasma half-life associated with the terminal elimination phase (T½(z)), maximum plasma 
concentration (Cmax), and time to Cmax (Tmax). 
o Total clearance of the drug from plasma following oral administration (CL/F) and 
apparent volume of distribution associated with the terminal elimination phase (Vz/F). 
o % of dose excreted unchanged in urine and renal clearance. 
o Relative bioavailability of C106 in fasted versus fed conditions. 
• 
Dose proportionality after a single oral dose based on AUCinf and Cmax. 
Part B 
• 
PK parameters after the first dose: 
o AUC over the dosing interval (AUCtau), AUCinf, T½(z), Cmax, Tmax, CL/F, Vz/F. 
• 
PK parameters after the last dose: 
o AUC at steady state (AUCtau), T½(z), Cmax, Tmax, CL/F, Vz/F. 
• 
Dose proportionality (based on AUCtau and Cmax) and accumulation ratios (based on AUCtau 
and Cmax). 
• 
% of dose excreted unchanged in the urine and renal clearance. 
• 
Observed concentration at the end of a dosing interval, immediately before next 
administration (Ctrough). 
Exploratory endpoints 
• 
Metabolite In Safety Testing (MIST) analysis of the metabolite profile in plasma in 
comparison with the metabolite profile in plasma from non-clinical safety studies. 
• 
Profile of excreted metabolites in urine. Cardiodynamic ECG parameters. 
• 
Change from baseline in reactive hyperemia index (RHI) and augmentation index (AI) scores 
at Day 7 as measured by EndoPAT. 


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Number of subjects planned 
Approximately 160 subjects will be screened to achieve 80 randomised subjects. 
Part A: 48 subjects will be randomised and dosed in 6 cohorts (Cohorts A1 to A6, each of 8 subjects 
with 6 subjects receiving C106 and 2 subjects receiving placebo). 
Part B: 32 subjects will be randomised and dosed in 4 cohorts (Cohorts B1 to B4, each of 8 subjects 
with 6 subjects receiving C106 and 2 subjects receiving placebo). 
If indicated by emerging data and recommended by the internal safety review committee (iSRC), 
2 cohorts (8+8 subjects) may be added to Part A, and 1 cohort (8 subjects) may be added to Part B. 
Diagnosis and main eligibility criteria 
• 
Healthy females of non-childbearing potential and healthy males, 18 to 65 years of age. 
• 
Has provided signed informed consent. 
• 
Body mass index (BMI) ≥18.5 and ≤30.0 kg/m2. 
• 
Agree to use sufficient contraception as defined in this clinical trial protocol (CTP). 
• 
Good general health and fulfilling all the inclusion criteria and none of the exclusion criteria. 
Methodology 
This is a double-blind, placebo-controlled, within-group randomised, FIH trial in which the safety, 
tolerability, and PK of orally administered C106 will be assessed in healthy subjects. The trial 
consists of 2 parts: a SAD part (Part A) and a MAD part (Part B). One cohort participating in Part A 
will receive C106 under both fasted and fed conditions to investigate the effect of a high-fat meal on 
the single dose PK of orally administered C106. 
Part A (SAD): 
In Part A, single, oral doses of C106 will be administered in 6 sequential dose cohorts, each of 
8 subjects. Within each cohort, subjects will be randomised to receive either C106 (n=6) or placebo 
(n=2) in the fasted state. The proposed doses are: 5, 30, 60, 180, 240 and 300 mg C106. Up to 
2 additional dose cohorts can be explored based on emerging safety, tolerability and PK of the drug, 
if recommended by the iSRC. The maximum oral dose in Part A will not exceed 480 mg C106. 
Subjects will come for 3 visits to the Clinical Research Unit (CRU). Screening (Visit 1) will take 
place within 4 weeks of the planned dose (Day -28 to Day -1) and will include the subject’s signing 
of the informed consent and an eligibility check. At Visit 2, subjects will reside at the CRU from 
Day -1 (the day before investigational medicinal product [IMP] administration) until Day 3 for single 
dose IMP administration, safety, tolerability, and PK assessments. The subjects must fast for at least 
10 hours before until 4 hours after the anticipated dosing time on Day 1. During fasting, water, but no 
other drinks, is allowed as desired. No drinks are allowed for 1 hour before and 1 hour after dosing. 
The first 2 subjects in each cohort will be dosed in a sentinel fashion, 1 subject will receive C106 and 
the other will receive placebo as randomised. The subjects will be carefully monitored by clinical 
staff during and after dosing. Vital signs and ECG will be checked at regular intervals. Ambulatory 
ECG telemetry will be used for cardiac surveillance up to 24 hours after IMP administration. There is 
immediate access to equipment, qualified staff and an intensive care unit (ICU) in case of an acute 
emergency. To give sufficient time for observation of any reactions there will be at least 24 hours 
before dosing of the remaining 6 subjects, who will be dosed in groups of 3 subjects at least 24 hours 
apart. A final end-of-trial visit (Visit 3) will take place on Day 7 (±2 days) or after early withdrawal. 
Cardiodynamic ECG assessments (collect and store) will be performed in all cohorts (except the first 
cohort A1) where C106 is given in the fasted state (i.e., not in the fed period of the fasted/fed cohort) 
and will include serial ECG extractions at baseline (prior to dosing) and at the same time points as PK 
sampling during the first 24 hours post-dose. 


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The doses given after the starting dose and time points for safety and PK sampling may be adjusted as 
recommended by the iSRC following evaluation of emerging safety, tolerability, and PK data. If 
needed, one visit for additional safety and PK assessments may be added based on recommendations 
from the iSRC. 
Before initiating a new dose cohort, all subjects in the previous cohort must have been treated and all 
available safety, tolerability, and plasma concentration data up until and including 48 hours post dose 
must have been evaluated by the iSRC. After collection of the last available 48-hour data, there will 
be at least one week between dose escalations. In case of dosed dropouts, available data for the 
dropouts will be included in the iSRC evaluation. Based on emerging safety and PK data, the amount 
of required safety and PK data to be reviewed after a completed cohort might be adjusted. 
Part A: food interaction 
One dose cohort (planned to be cohort A4) will be selected to investigate any potential food 
interaction. The predicted maximum exposure in the food interaction cohort (taking into account a 
possible food interaction effect on the exposure) of the chosen dose level will not exceed the exposure 
tolerated in previously evaluated cohorts. 
Subjects exposed to C106 during fasting conditions in the selected cohort will return to the clinic after 
a wash-out period of at least 5 half-lives (as determined by evaluation of PK data) to receive a second 
dose of C106 under fed conditions. In case of dropouts at the selected dose level, subjects may be 
replaced to guarantee a full cohort size for the food-interaction part of the trial (if considered 
necessary). Any replacers will receive active treatment. The assessments during fed conditions will be 
the same as during fasting conditions except that the subjects will consume a U.S. Food and Drug 
Administration (FDA) recommended high-fat, high calorie breakfast 30 minutes prior to IMP 
administration and no screening visit will be conducted. Potential replacement subjects will come for 
a screening visit and perform one fasting period and one fed period. 
Part B (MAD): 
In Part B, repeated, oral doses of C106 will be administered in 4 sequential dose cohorts. Within each 
cohort, subjects will be randomised to receive C106 (n=6) or placebo (n=2) in a blinded fashion. One 
additional dose cohort can be explored based on emerging safety, tolerability and PK of the drug if 
recommended by the iSRC. The initial dose, dose escalations and dosing schedule will be based on 
emerging safety, tolerability, and PK data observed in the SAD part of the trial (Part A) and on 
emerging data from the MAD part. Each dose level during Part B will be selected such that the 
predicted maximum exposure will not exceed the maximum exposure (based on AUC and Cmax) in 
previously evaluated SAD cohorts. The proposed doses are 40, 100, 180 and 240 mg BID. One (1) 
additional dose cohort can be explored based on emerging safety, tolerability and PK of the drug if 
recommended by the iSRC. The maximum daily oral dose in Part B will not exceed 480 mg C106 
(240 mg BID). Twice daily dosing for 8 days is planned. Based on emerging PK data once daily 
dosing may be applied if recommended by the iSRC. The number of dosing days may be changed 
based on PK data from Part A (SAD), with the aim to reach steady state during the dosing period. The 
treatment duration will, however, not exceed the treatment duration in pre-clinical toxicology studies. 
Subjects will come for 3 visits to the CRU. Screening (Visit 1) will take place within 4 weeks of the 
first dose (Day -28 to Day -1) and will include the subjects signing of the informed consent and an 
eligibility check. At Visit 2, subjects will reside at the CRU from Day -1 (the day before IMP 
administration) until Day 10 for 8 days IMP administration, safety, tolerability, and PK assessments. 
Subjects must fast from 2 hours prior to each IMP administration until 1 hour after. During fasting, 
water, but no other drinks, is allowed as desired. No drinks are allowed for 1 hour before and 1 hour 
after dosing. On Day 8, only the morning dose will be administered. 
The first 2 subjects in each cohort will be dosed in a sentinel fashion, 1 subject will receive C106 and 
the other will receive placebo as randomised. The subjects will be carefully monitored by clinical 
staff during and after dosing. Vital signs and ECG will be checked at regular intervals. There is 
immediate access to equipment, qualified staff and an ICU in case of an acute emergency. To give 


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sufficient time for observation of any reactions there will be at least 24 hours before dosing of the 
remaining 6 subjects, who will be dosed in groups of 3 subjects at least 24 hours apart. A final end- 
of-trial visit (Visit 3) will take place on Day 22 (±2 days) or after early withdrawal. 
For subjects participating in cohort B4, an assessment of endothelial function using EndoPAT will be 
performed before the first IMP administration (on Day -1 or 1), and 30±10 minutes after IMP 
administration on Day 7 (morning or evening). The EndoPAT assessments should be done at 
approximately the same time of the day on both occasions. Subjects must fast for at least 4 hours 
prior to the EndoPAT assessment until end of assessment. During fasting, water, but no other drinks, 
is allowed as desired. No drinks are allowed for 1 hour before and 1 hour after dosing. 
Besides the starting dose and subsequent doses, also time points for safety and PK sampling may be 
adjusted as recommended by the iSRC following evaluation of emerging safety, tolerability, and PK 
data. If needed, one visit for additional safety and PK assessments may be added based on 
recommendations from the iSRC. 
After collection of the last available 10 days data (48 hours after the last dose), there will be at least 
2 weeks between dose escalations. Before initiating a new dose cohort, all subjects in the previous 
cohort must have been treated and all available safety, tolerability, and plasma concentration data up 
until and including 48 hours post dose must have been evaluated by the iSRC. In case of non-replaced 
dropouts, available data for the dropouts will be included in the iSRC evaluation. The iSRC may 
recommend including replacers to be able to make an informed recommendation on the next dose 
level. Based on emerging safety and PK data, the amount of required safety and PK data to be 
reviewed after a completed cohort might be adjusted. 
Investigational Medicinal Product, dosage and mode of administration 
C106 is a potent and selective nonpeptide angiotensin II type 2 receptor (AT2R) agonist developed by 
Vicore Pharma. C106 will be administered as an oral solution. 
Placebo to C106 is a solution for oral administration, manufactured as the drug without the active 
pharmaceutical ingredient. 
The bulk IMP will be provided to the research clinic as: 
• 
C106 solution for oral administration; 1 mg/mL and 10 mg/mL. 
• 
Placebo to C106, solution for oral administration without the active pharmaceutical 
ingredient. 
Part A: planned dosage: 5, 30, 60, 180, 240 and 300 mg. 
Part B: planned dosage: 40, 100, 180 and 240 mg BID. 
Duration of treatment 
Part A: Single doses of C106/placebo oral solution. 
Part B: C106/placebo oral solution for 8 days. In total 15 doses are planned to be administered. 
Duration of each subject’s involvement in the trial 
Part A: Up to 37 days, including a 28-day screening period. 
Part B: Up to 47 days, including a 28-day screening period. 
Subjects who are administered C106 both in the fasted and the fed state in Part A are expected to 
participate in the trial for up to 43 days + at least 5 half-lives of C106 (wash-out between fasting and 
fed IMP administrations). 


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Safety assessments 
AEs, ECGs, vital signs, safety laboratory parameters, physical examinations. 
Pharmacokinetic assessments 
Plasma and urine sampling for C106 concentration analysis and subsequent determination of PK 
parameters. 
Exploratory assessments 
Blood and urine sampling for analysis of C106 metabolites (Part B). Collection of cardiodynamic 
ECG using a Holter device (Part A fasting, except cohort A1). 
Endothelial function will be assessed using EndoPAT (Part B, cohort B4). 
Statistical methods 
No formal sample size calculation has been performed. The proposed sample size is considered 
sufficient to provide adequate information for the trial objectives. A statistical analysis plan (SAP) 
will be prepared and signed prior to database lock. 
All quantitative variables will be summarised by assigned treatment (dose cohort or placebo) and time 
point using standard descriptive statistics. Qualitative variables will be summarised by assigned 
treatment and time point by means of absolute and relative frequencies. 
Assessment of dose proportionality will be performed based on AUCinf and Cmax (Part A) and based 
on AUCtau and Cmax (Part B) using a power model. 
Trial reporting 
After completion of the trial, an International Council for Harmonization of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) E3 compliant clinical trial report (CTR) will be prepared. 


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2 
TABLE OF CONTENTS 
1 
TRIAL SYNOPSIS ................................................................................................... 3 
2 
TABLE OF CONTENTS ......................................................................................... 9 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................... 14 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................................... 17 
4.1 
Medical emergencies contacts ............................................................................... 17 
5 
INVESTIGATOR AND TRIAL ADMINISTRATIVE STRUCTURE ............. 18 
6 
INTRODUCTION .................................................................................................. 20 
6.1 
Background ............................................................................................................. 20 
Idiopathic pulmonary fibrosis ........................................................................... 20 
Product characteristics, mechanism of action and rationale for C106 
treatment of idiopathic pulmonary fibrosis ......................................................................... 21 
Non-clinical pharmacodynamics ....................................................................... 22 
Non-clinical pharmacokinetics and drug metabolism ..................................... 22 
Non-clinical safety pharmacology ..................................................................... 23 
Toxicology ............................................................................................................ 24 
Clinical experience .............................................................................................. 25 
6.2 
Trial rationale ......................................................................................................... 25 
6.3 
Risk/benefit assessment .......................................................................................... 26 
Risk assessment with regards to the COVID-19 pandemic ............................. 28 
7 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................... 30 
7.1 
Objectives and endpoints ....................................................................................... 30 
8 
TRIAL DESIGN ..................................................................................................... 32 
8.1 
Overall trial design and schedule of events .......................................................... 32 
Single Ascending Dose (SAD) part of the trial ................................................. 33 
Multiple Ascending Dose (MAD) part of the trial ........................................... 39 
8.2 
Rationale for trial design ....................................................................................... 46 
8.3 
Selection of starting dose and rationale for planned dose escalation ................. 46 
Selection of starting dose and rationale for dose escalation in Part A for 
cohorts 1 to 4 (completed) ...................................................................................................... 46 
Selection of doses for cohorts 5 and 6 in Part A (SAD) ................................... 49 
Maximum exposure and dose ............................................................................ 50 
From single to multiple dosing and rationale for dose escalation Part B ...... 50 
Stopping criteria for dose escalation ................................................................. 51 
Internal safety review committee ...................................................................... 54 
9 
TRIAL POPULATION .......................................................................................... 56 
9.1 
Recruitment ............................................................................................................. 56 
9.2 
Screening and enrolment log ................................................................................. 56 
9.3 
Number of subjects ................................................................................................. 56 
9.4 
Inclusion criteria ..................................................................................................... 57 
9.5 
Exclusion criteria .................................................................................................... 57 


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9.6 
Restrictions during the trial period .......................................................................58 
General restrictions ............................................................................................. 58 
Prior and concomitant therapy ..........................................................................60 
9.7 
Screen failures .......................................................................................................... 60 
9.8 
Subject withdrawal ..................................................................................................61 
General withdrawal criteria ...............................................................................61 
QTc withdrawal criteria ......................................................................................61 
Liver chemistry withdrawal criteria ..................................................................62 
Procedures for discontinuation of a subject from the trial ..............................62 
Subject replacement ............................................................................................ 62 
9.9 
Randomisation .........................................................................................................63 
9.10 
Blinding ....................................................................................................................63 
9.11 
Emergency unblinding during the trial .................................................................63 
Unblinding for other reasons than emergency ..................................................63 
10 
TREATMENTS .......................................................................................................64 
10.1 
Identity of investigational medicinal products ......................................................64 
10.2 
Manufacturing, packaging, labelling, and release ................................................64 
10.3 
Conditions for storage .............................................................................................64 
10.4 
Preparation and accountability ..............................................................................64 
10.5 
Treatment administration .......................................................................................65 
Treatment administration Part A ......................................................................65 
Treatment administration Part B.......................................................................65 
10.6 
Continuation of treatment with Investigational Medicinal Product ...................65 
10.7 
Treatment compliance .............................................................................................66 
10.8 
Return and destruction of investigational medicinal products ...........................66 
11 
TRIAL ASSESSMENTS .........................................................................................67 
11.1 
Recording of data ....................................................................................................67 
11.2 
Demographics and other baseline characteristics .................................................67 
Informed consent .................................................................................................67 
Eligibility criteria .................................................................................................67 
Demographic information ...................................................................................67 
Weight and height ................................................................................................ 68 
Medical/surgical history ......................................................................................68 
Prior and concomitant medication .....................................................................68 
HIV and Hepatitis B/C ........................................................................................68 
Urine drug screen ................................................................................................68 
Alcohol test ...........................................................................................................68 
11.3 
Assessments related to primary endpoints ............................................................69 
Adverse events ......................................................................................................69 
Electrocardiogram ...............................................................................................74 
Telemetry ..............................................................................................................75 
Vital signs .............................................................................................................75 
Laboratory safety assessments............................................................................75 
Physical examination ...........................................................................................76 
11.4 
Assessments related to secondary endpoints .........................................................76 
Pharmacokinetic blood sampling and analysis .................................................76 
Urine sampling for analysis of C106 ..................................................................77 


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11.5 
Assessments related to exploratory endpoints ..................................................... 77 
Metabolite-In-Safety Testing ............................................................................. 77 
Profile of excreted metabolites in the urine ...................................................... 77 
Cardiodynamic ECG .......................................................................................... 78 
Pharmacodynamic assessment (Part B, cohort B4) ......................................... 78 
11.6 
Appropriateness of measurements ........................................................................ 79 
12 
PROCEDURES FOR BIOLOGICAL SAMPLES .............................................. 80 
12.1 
Sample collection .................................................................................................... 80 
12.2 
Volume of blood ...................................................................................................... 80 
12.3 
Handling, storage and destruction of laboratory samples .................................. 80 
12.4 
Chain of custody of biological samples ................................................................. 81 
12.5 
Withdrawal of informed consent for donated biological samples ...................... 81 
13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .............................................................................................................................. 82 
13.1 
Quality management: critical process, system and data identification ............. 82 
13.2 
Quality assurance and quality control .................................................................. 82 
14 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 83 
14.1 
Ethical conduct of the trial .................................................................................... 83 
14.2 
Ethics and regulatory review ................................................................................. 83 
14.3 
Subject information and consent ........................................................................... 83 
14.4 
Subject participation card ..................................................................................... 84 
14.5 
Subject data protection .......................................................................................... 84 
14.6 
Changes to the approved clinical trial protocol ................................................... 84 
14.7 
Audits and inspections ............................................................................................ 85 
14.8 
Insurance ................................................................................................................. 85 
15 
TRIAL MANAGEMENT ...................................................................................... 86 
15.1 
Training of trial site personnel .............................................................................. 86 
15.2 
Clinical monitoring ................................................................................................. 86 
15.3 
Source data documents .......................................................................................... 87 
15.4 
Trial agreements ..................................................................................................... 87 
15.5 
Trial timetable and end of trial ............................................................................. 87 
15.6 
Termination of the trial .......................................................................................... 87 
15.7 
Reporting and publication ..................................................................................... 88 
Clinical trial report ............................................................................................. 88 
Annual safety report ........................................................................................... 88 
Confidentiality and ownership of trial data ..................................................... 88 
Publication ........................................................................................................... 88 
15.8 
Archiving ................................................................................................................. 88 
16 
DATA MANAGEMENT ........................................................................................ 90 
16.1 
The web-based eCRF .............................................................................................. 90 
16.2 
The entering of data into the eCRF ...................................................................... 90 
16.3 
The query process ................................................................................................... 90 
16.4 
Audit trail ................................................................................................................ 91 
16.5 
External data ........................................................................................................... 91 
16.6 
Medical coding ........................................................................................................ 91 


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16.7 
Database lock ...........................................................................................................91 
17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE . 92 
17.1 
General .....................................................................................................................92 
17.2 
Determination of sample size ..................................................................................92 
17.3 
Analysis data sets .....................................................................................................92 
Full analysis set ....................................................................................................92 
Pharmacokinetic analysis set ..............................................................................92 
17.4 
Description of trial population ...............................................................................93 
Demographics and baseline characteristics .......................................................93 
Medical/surgical history and prior/concomitant medication ...........................93 
Treatment compliance .........................................................................................93 
17.5 
Analysis of primary endpoints................................................................................93 
Adverse events ......................................................................................................93 
12-lead ECG .........................................................................................................93 
Vital signs .............................................................................................................94 
Safety laboratory analyses ..................................................................................94 
Physical examination ...........................................................................................94 
17.6 
Analysis of secondary endpoints ............................................................................94 
Analysis of pharmacokinetics .............................................................................94 
17.7 
Analysis of exploratory endpoints ..........................................................................95 
18 
REFERENCES ........................................................................................................96 
19 
SIGNATURES ....................................................................................................... 100 
19.1 
Principal Investigator statement .......................................................................... 100 
19.2 
Signature page (approval of the clinical trial protocol) ..................................... 101 
 
List of Tables 
Table 4.1-1 Changes to the clinical trial protocol .................................................................. 2 
Table 4.1-1 Medical emergencies contact ............................................................................. 17 
Table 7.1-1 Objectives and endpoints ................................................................................... 30 
Table 8.1-1 Schedule of events, Part A (SAD) ...................................................................... 35 
Table 8.1-2 Detailed schedule of events, Part A (SAD) Day -1 to Day 2 ............................ 37 
Table 8.1-3 Schedule of events, Part B (MAD) .................................................................... 41 
Table 8.1-4 Detailed schedule of events, Part B (MAD) Day -1 to Day 7 .......................... 43 
Table 8.1-5 Detailed schedule of events Part B (MAD) Day 8 to Day 10 ........................... 45 
Table 8.3-1 Predicted human exposure at the starting dose and margins vs the NOAEL 
in rat and dog .......................................................................................................................... 48 
Table 8.3-2 Observed exposure in humans and margin to stopping criteria .................... 49 
Table 8.3-3 Dose escalation and stopping rules in Part A (SAD) ....................................... 52 
Table 8.3-4 Dose escalation and stopping rules in Part B (MAD) ...................................... 53 
Table 11.3-1 Safety laboratory parameters .......................................................................... 75 


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Table 12.2-1 Estimated blood volumes ................................................................................. 80 
List of Figures 
Figure 8.1-1 Overview of the planned cohorts ..................................................................... 32 
Figure 8.1-2 Overview of the trial design ............................................................................. 33 
Figure 8.3-1 Pharmacokinetic mean concentrations for conducted SAD cohorts– 
logarithmic scale C106 (ng/mL) ............................................................................................ 50 


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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or term 
Explanation 
ADL 
Activities of daily living 
AE 
Adverse event 
AI 
Augmentation index 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AT1R 
Angiotensin II type 1 receptor 
AT2R 
Angiotensin II type 2 receptor 
AUC 
Area under the plasma concentration vs. time curve 
AUCinf 
AUC from 0 to infinity 
AUClast 
AUC from 0 to the time of the last quantifiable 
concentration 
AUCtau 
AUC to the end of the dosing period 
BP 
Blood pressure 
bpm 
Beats per minute (unit for pulse measurement) 
BMI 
Body mass index 
C106 
Compound 106 
CA 
Competent authority 
CDC 
Centres for Disease Control and Prevention 
CIOMS 
Council for International Organisations of Medical 
Sciences 
CL/F 
Apparent total body clearance following 
extravascular administration 
Cmax 
Maximum plasma concentration 
CRP 
C-reactive protein 
CTP 
Clinical trial protocol 
CTR 
Clinical trial report 
CTC 
Clinical Trial Consultants AB 
CTCAE 
Common terminology criteria for adverse events 
CTC PV 
CTC’s pharmacovigilance departments 
CV 
Coefficient of variation 
DMP 
Data management plan 
DSUR 
Development safety update report 
ECG 
Electrocardiogram 


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ECM 
Extracellular matrix 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EPQT 
Expert precision QT 
FDA 
U.S. Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GDPR 
General data protection regulation 
GMP 
Good manufacturing practice 
Hb 
Haemoglobin 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for 
Human Use 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IME 
Important medical event 
IMP 
Investigational medicinal product 
IPF 
Idiopathic pulmonary fibrosis 
ISF 
Investigator site file 
iSRC 
Internal safety review committee 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LLOQ 
Lower limit of quantification 
MEC 
Molar extinction coefficient 
MedDRA 
Medical dictionary for regulatory activities 
MIST 
Metabolite In Safety Testing 
MPA 
Medical products agency 
MAD 
Multiple-ascending dose 
NCA 
Non-compartmental analysis 
NIH 
National Institute of Health 
NOAEL 
No observed adverse effect level 


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PCLuS 
Precision cut lung slices 
PII 
Personally Identifiable Information 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PR interval 
(ECG) The time from the onset of the P wave to the 
start of the QRS complex 
PT 
Preferred term 
QA 
Quality assurance 
QC 
Quality control 
QRS interval 
(ECG) The time required for stimulus to spread 
through the heart’s ventricles 
QT interval 
(ECG) The time from the beginning of the QRS 
complex to the end of the T wave 
QTcF 
(ECG) Corrected QT interval by Fredericia 
RAS 
Renin-angiotensin system 
RBC 
Red blood cell 
RHI 
Reactive hyperemia index 
RSI 
Reference safety information 
SAD 
Single-ascending dose 
SAR 
Serious adverse reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SOC 
System organ class 
SOP 
Standard operating procedures 
SPF 
Sun protection factor 
SuHx 
Sugen-hypoxia 
SUSAR 
Suspected unexpected serious adverse reaction 
TMF 
Trial master file 
Tmax 
Time of occurrence of Cmax 
T½(z) 
Plasma half-life associated with the terminal 
elimination phase 
UVA 
Ultraviolet A 
UVB 
Ultraviolet B 
Vz/F 
Apparent volume of distribution following 
extravascular administration 
WBC 
White blood cell 
WHO 
World Health Organisation 


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4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR 
4.1 
Medical emergencies contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the trial. A medical emergency usually 
constitutes a serious adverse event (SAE) and is to be reported as such. Detailed SAE 
reporting procedures are described in Section 11.3.1.13. 
In the case of a medical emergency, the Investigator may (during business hours) contact the 
Medical Monitor (Table 4.1-1). 
Table 4.1-1 Medical emergencies contact 
Name 
Function in the trial 
Telephone number and e-mail 
 
 
 
 


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5 
INVESTIGATOR AND TRIAL ADMINISTRATIVE STRUCTURE 
 
Sponsor 
Vicore Pharma AB 
Kornhamnstorg 53 
SE-111 27 Stockholm, Sweden 
Sponsor’s Medical Representative 
 
 
Sponsor’s Project Manager 
 
 
Clinical conduct 
CTC Clinical Trial Consultants AB (CTC) 
Uppsala University Hospital, 
Entrance 85, 2nd level 
SE-751 85 Uppsala, Sweden 
Principal Investigator 
 
 
Trial management 
CTC 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Clinical Research Manager 
 
 
 
Biostatistician 
 
 
Pharmacokineticist: 
 
Medical writer 
 
 
Medical monitor 
 
 
Laboratories (Safety) 
Clinical Microbiology 
Dag Hammarskjölds väg 38 
SE-752 37 Uppsala, Sweden 
Clinical Chemistry and Pharmacology 
Uppsala University Hospital 
Entrance 61, 2nd level 
SE-751 85 Uppsala, Sweden 


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Laboratory (Bioanalysis) 
Lablytica Life Science AB 
Virdings allé 18 
SE-754 50 Uppsala, Sweden 
Laboratory (Metabolite In Safety 
Testing [MIST]) 
Admescope 
Forskargatan 20J 
SE-151 36 Södertälje, Sweden 
Investigational medicinal product (IMP) 
manufacturing, packaging, labelling, 
and release 
Ardena 
Kleimoer 4 
B-9030 Mariakerke 
Belgium 
Pharmacy 
Apoteket AB 
Clinical Trial Unit 
Dag Hammarskjölds väg 18, Entrance C7 
SE-751 85 Sweden 
Expert precision QT (EPQT) collect & 
store 
Clario 
Peterborough Business Park 
Lynch Wood, Peterborough 
PE2 6FZ, United Kingdom 
Electronic data capture (EDC) system 
provider 
Viedoc Technologies AB 
Stationsgatan 23 
SE-753 40 Uppsala, Sweden 
Signatures are provided in Section 19. 


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6 
INTRODUCTION 
6.1 
Background 
 
 
Idiopathic pulmonary fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and devastating 
interstitial lung disease with no existing cure [1, 2]. IPF is characterised by a progressive 
deposition of extracellular matrix (ECM) proteins and fibrous tissue in the lungs, resulting in 
destruction of lung architecture and reduced lung capacity [3]. The aetiology of IPF is 
unknown. However, several risk factors are reported to be associated with development of IPF 
including cigarette smoking, environmental exposures, microbial pathogens, and genetic 
factors [4]. 
Symptoms of IPF include shortness of breath, fatigue, and a dry intractable cough. IPF is 
usually lethal and death is most commonly caused by acute or subacute respiratory failure due 
to progression of lung fibrosis [5]. Increasing pulmonary vascular pressure often leads to 
pulmonary hypertension and subsequently to heart failure. The prevalence of pulmonary 
hypertension in patients with IPF is between 32 and 85% [6]. The prognosis of IPF is poor, 
with an estimated life expectancy of 3-5 years after diagnosis which is shorter than many 
malignancies [7]. The mortality is on the rise globally [8]. 
Worldwide, approximately 3 million people are living with IPF and it is classified as an 
orphan disease within the EU and the USA. The incidence of IPF is estimated to be 2.8 to 
19 per 100,000 people per year and increases with age. Debilitating symptoms typically 
appear between the ages of 50 and 70 years and, while the disease is most common in men, 
the number of cases in women is increasing [9]. 
IPF is often associated with comorbidities including lung cancer, pulmonary hypertension, 
chronic obstructive pulmonary disease, and ischaemic heart disease [10]. The impact of 
comorbidities on the prognosis of IPF is not well established, however mortality has been 
reported to be higher in patients with the comorbidities mentioned above, and treatment of 
comorbidities may therefore contribute to improved survival and quality of life [10]. 
Currently, there is no cure for IPF and treatment options are limited. Two antifibrotic drugs, 
nintedanib and pirfenidone, are approved by the European Medicines Agency (EMA) and the 
U.S. Food and Drug Administration (FDA) and conditionally recommended for the treatment 
of patients with mild to moderate IPF [10]. Both nintedanib and pirfenidone slow disease 
progression, but they are not curative and cause significant, primarily gastrointestinal, side 
effects [10]. Access to nintedanib and pirfenidone can also be challenging for patients. In the 
UK, nintedanib and pirfenidone are only recommended as an option for treating IPF if the 
patient has a forced vital capacity (FVC) between 50% and 80% of predicted, and treatment is 
stopped if disease progresses (a confirmed decline in percent predicted FVC of 10% or more) 
in any 12-month period [11]. 
Lung transplantation is rare; just 214 lung transplants were carried out for pulmonary fibrosis 
in England in 2017-18 [12], and it is only recommended in a small group of patients with 
moderate to severe IPF. Median post transplantation survival in IPF is estimated to 4.5 years 
[13]. However, patients are often referred late in the course of the disease and may die while 
waiting for a transplant [1]. 


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Thus, a major medical unmet need still exists for finding more safe and efficacious treatment 
for IPF targeting not only disease progression, but also comorbidities including pulmonary 
hypertension. 
 
 
Product characteristics, mechanism of action and rationale for C106 treatment of 
idiopathic pulmonary fibrosis 
Compound 106 (C106) is a low molecular weight, orally available, high affinity angiotensin II 
type 2 receptor (AT2R) agonist, and an analogue to Vicore Pharma’s AT2R agonist C21. 
Angiotensin II (AngII) is the major effector peptide of the renin-angiotensin system (RAS) 
and exerts key roles in multiple physiological processes including regulation of blood 
pressure, fluid homeostasis, cellular growth, differentiation, proliferation, migration, 
apoptosis as well as ECM remodelling and inflammation (reviewed in [14, 15]. 
AngII mediates its effects by binding to angiotensin II type 1 receptors (AT1R) and 
angiotensin II type 2 receptors (AT2R). The AT1R mediates the classical effects of AngII such 
as cellular growth, migration, proliferation, fibrogenesis, inflammation, and vasoconstriction 
and is expressed in many tissues, whereas the AT2R mediates antifibrotic, antiproliferative, 
anti-inflammatory, and vasodilatory effects. The AT2R is abundantly expressed in embryonic 
tissue and, under normal conditions, only at low levels in most tissues in healthy adults [16, 
15]. However, the AT2R is relatively highly expressed in the normal adult human lung, in 
particular by the multifunctional alveolar type 2 cell [17], and can be upregulated in response 
to tissue damage and various diseases including IPF [18, 19, systemic sclerosis [19], vascular 
injury [20] and cardiac fibrosis [21], indicating an inducible tissue-protective role for AT2Rs 
during pathological conditions. 
Several studies suggest that AngII and AT1Rs are involved in the pathogenesis of lung 
fibrosis, including IPF [22, 23, 24]. The role of the AT2R in IPF is not fully established, but a 
protective role is likely considering that the lung AT2R is upregulated in IPF and mediates 
antifibrotic effects such as reducing fibroblast proliferation, cell growth, and ECM synthesis, 
in addition to vasodilatory effects [18, 22, 25]. 
An upregulation of the AT2R was demonstrated in septal and vascular areas [19], in fibrotic 
fibroblasts from human IPF lungs [18], as well as in animal models of lung fibrosis and 
hyperoxia-induced lung injury [18, 26, 27]. In these experiments, the surface expression of 
AT2R on interstitial fibroblasts was increased after lung injury when compared to healthy 
animals, whereas the surface expression of the AT1R was similar in fibrotic and normal 
fibroblasts. Interestingly, AngII-induced proliferation of fibroblasts was mediated primarily 
via the AT1R in healthy fibroblasts whereas AngII induced antiproliferation via an AT2R- 
dependent mechanism in fibrotic fibroblasts, demonstrating a shift in the response to AngII in 
fibrotic lungs, probably due to an upregulation of AT2R [18]. 
Vicore Pharma’s potent and selective AT2R agonist C21 is currently in phase 2 clinical 
development for IPF, and it has previously been demonstrated in 2 different animal models 
that C21 reduces pulmonary fibrosis. In the first study, pulmonary hypertension and fibrosis 
were induced in rats by a monocrotaline injection, and it was found that treatment with C21 
for 2 weeks not only prevented, but also reversed pulmonary interstitial and perivascular 
fibrosis [28]. This effect was associated with significant improvements in right heart function 
and decreased pulmonary vessel wall thickness. In a second study, pulmonary fibrosis and 
associated pulmonary hypertension were induced in rats by bleomycin treatment 
[29]. Treatment with C21 for 2 weeks almost completely prevented the progression of lung 


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fibrosis and, in addition, reduced pulmonary hypertension and muscularisation of the 
pulmonary vessels, and normalised cardiac function. 
Pulmonary hypertension, group III of the international aetiological classification, is a frequent 
and severe complication of interstitial lung diseases, especially IPF [30]. In the Sugen- 
hypoxia (SuHx) model of group I pulmonary arterial hypertension (PAH), but also a useful 
adjunct to group III pulmonary hypertension, C21 caused a robust reduction of the SuHx- 
induced increase in endothelial cell hyperplasia and pulmonary hypertension 
(IPST20200130- 1). 
Thus, C106 is believed to represent a novel treatment of fibrotic diseases such as IPF capable 
of reducing pulmonary inflammation, proliferation, fibrosis, and vasculopathy, like the 
analogue C21. 
 
 
Non-clinical pharmacodynamics 
 
6.1.3.1 Primary pharmacodynamics 
C106 is a selective nonpeptide AT2R agonist with AT2R Ki= 3.3 nM and AT2R IC50=6.5 nM 
(100052430). The binding of C106 to AT1R has been evaluated in several studies and 
inhibition of 18.2% and 48.4% at 1 µM and 86.2% at 10 µM have been demonstrated. In 
comparison, binding of C106 to AT2R was determined to be 97% at 0.1 µM (TW04-0011337) 
and 100% at 1 µM and 10 µM (100052430). 
C106 demonstrated antifibrotic effects in a human ex vivo model of IPF, precision cut lung 
slices (PCLuS), by reducing the secretion of the pro-fibrotic factors’ collagen 1a1 and 
TGF- β1, suggesting that C106 has antifibrotic potential in IPF. 
 
6.1.3.2 Secondary pharmacodynamics 
Upon evaluating binding affinity, C106 did not show any significant binding affinity to the 
75 receptors and ion channels tested or any significant inhibition of the 12 enzyme and uptake 
assays tested, when tested at 1 µM (100059310). 
 
 
Non-clinical pharmacokinetics and drug metabolism 
Pharmacokinetic studies of C106 have been performed in rats following oral and intravenous 
administrations and in dogs after oral administration. The oral route is the intended route of 
administration in the clinical development program. In vitro studies have been conducted to 
evaluate plasma protein binding, metabolic stability, metabolite identification, and 
involvement of enzymes to investigate the potential of metabolic interactions. 
Following intravenous administration in rats, C106 is classified as an intermediate clearance 
compound with an intermediate terminal half-life of about 2 h. 
C106 was absorbed rapidly after single and repeated oral administration with maximum 
plasma concentration Cmax reached within 1-4 h in rats and dogs, followed by a prolonged 
elimination from the plasma and an elimination half-life (t1/2) of 2.9 to 11 h in rats and 1 to 
4.6 h in dogs. No accumulation of C106 was observed following repeated once daily oral 
administration for up to 28 days in rats and dogs, while a trend for a lower systemic exposure 
was seen in rats on Day 28, and at the highest dose in dogs. The oral bioavailability was 
estimated to 30-50% after a single dose of 10 mg/kg in rats. 


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The plasma exposure of C106 following oral administration in both rats and dogs was 
dependent on dose. The exposure in terms of Cmax and area under the plasma concentration vs. 
time curve (AUC) in rats increased more than dose-proportionally following repeated 
administration of doses up to 40 mg/kg. Overall, a trend for higher exposures was seen in 
female rats compared to male rats after a single administration, but not after repeated 
administrations. 
In dogs, the plasma exposure increased more than dose-proportionally following repeated 
administration of doses up to 40 mg/kg, although the supra-proportional increase was less 
pronounced on Day 28 than on Day 1. Overall, there was no significant sex difference in dogs 
in the exposure to C106 with no apparent differences seen in absorption or elimination for 
Day 1 and Day 28. 
The plasma protein binding was high in all species, with dogs having the lowest protein 
binding (on average 97.5% in dog, 99.8% in rat and 99.6% in human), and independent of 
C106 concentration in the range of 0.1-50 µM. 
The metabolism of C106 was slow in human in vitro studies with an intrinsic clearance of 
4.0 µL/min/106 hepatocytes, and with 11 metabolites being formed in vitro. All metabolites 
formed in human hepatocytes were also formed in hepatocytes from the animal species used 
in the safety evaluation (rat and dog), except for a minor metabolite formed by oxidation of 
the imidazole ring and hydrolysis of the methyl formate chain. The main metabolic pathways 
in mouse, rat, dog, monkey, and human included i) oxidation, ii) hydrolysis of methyl 
formate, iii) dehydrogenation, and combination of these pathways. No conjugated metabolites 
were identified in any species. 
 
 
Non-clinical safety pharmacology 
Non-clinical safety pharmacology has been studied in the rat and the dog. 
Overt central and peripheral effects 
Potential side-effects of single doses of C106 on the central and peripheral nervous system (6, 
15, 40 mg/kg; orally by gavage) were investigated in an Irwin test in female Sprague Dawley 
rats (2021-0358). No effects on either general behaviour including home cage observations, 
open field observations and reflexes, or body temperature were observed at any of the doses 
up to 40 mg/kg. Therefore, the no observed adverse effect level (NOAEL) in the study was 
determined to be 40 mg/kg. 
Effects on the cardiovascular system 
Cardiovascular effects of C106 treatment were observed in Beagle dogs. The main findings 
were increased blood pressure and electrocardiogram (ECG) aberrations. Increases in systolic 
and diastolic arterial pressure were observed at doses of 10 to 40 mg/kg in a single dose 
telemetry study. The heart rate showed a slight, yet statistically significant, increase between 
45 and 180 minutes after administration. The ECG intervals RR and QT were decreased at all 
doses tested (10-40 mg/kg), and these changes were compatible with the increase in heart rate. 
In addition, second degree atrioventricular (AV) block was observed as repeated incidences at 
different time-points following administration of 10 to 40 mg/kg. 
No toxicologically relevant changes in body temperature were observed following treatment 
with C106 at any dose tested. 


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In addition, upon evaluating binding affinity to the human potassium channel hERG, C106 
did not show any significant binding at 1 μM. 
Effects on the respiratory system 
The effects of single doses of C106 (6, 15, and 40 mg/kg) on the respiratory system were 
examined by plethysmography in female SD rats (2021-0361). No treatment-related effects on 
respiration (including respiratory rate, tidal volume, and minute volume) or adverse clinical 
signs were observed at any of the doses up to 40 mg/kg during a 4-hour recording period. 
Therefore, the NOAEL in the study was determined to be 40 mg/kg. 
 
 
Toxicology 
The toxicity of C106 has been evaluated in single and repeated dose oral gavage toxicology 
studies of up to 4 weeks duration in rat and dog, as well as in genotoxicity studies. 
In the rat, the main toxicological findings were treatment-related histological changes in the 
heart, the aorta, and the kidney in animals of both sexes. These findings included multifocal 
inflammatory cells infiltration of the myocardium and of the adventitia of aorta after 4 weeks 
of treatment and occurred at 20 and 40 mg/kg/day in males, and at 15 (aorta, only) and 25 
mg/kg/day in females and were in general more pronounced in males than in females. In 4 
males in the high dose group (40 mg/kg/day), a concomitant presence of myocardial fibrosis 
was also observed. In the kidney, changes of cortical tubular basophilia, interstitial 
inflammatory cell infiltration, and tubular dilation were observed in all 3 treatment groups in 
both male (10, 20, and 40 mg/kg/day) and female (6, 15, 25 mg/g/day) animals and occurred 
in a dose-dependent manner in incidence and severity. Treatment-related histological changes 
were also observed in the adrenal glands in 2 male and in 2 female animals administered 40 
and 25 mg/kg/day, respectively, and were considered non-adverse. After the recovery period 
(2 weeks after end of treatment) in the high dose groups, findings in the kidneys and heart 
were still observed, whereas the findings in the aorta and in the adrenal glands were reversible 
and not observed after the recovery period. 
After 7 days of treatment, treatment-related histological changes were also observed in the 
kidneys and the heart. In the kidney, cortical tubular basophilia was observed in animals 
administered 40 mg/kg. Cortical tubular dilatation was observed in control males and in 
female animals in the 40 mg/kg group. In the heart, atrioventricular myocardial necrosis of 
cardiomyocytes with mononuclear inflammatory cell infiltration was observed in animals 
administered 40 mg/kg. 
A minimal to moderate reduction in body weight gain and food consumption was observed 
after 4 weeks of treatment of the high dose in animals of both sexes. 
In the dog, the main toxicological findings were single and repeated incidences of second- 
degree AV-block after single and repeated dosing, respectively. Single episodes of AV block 
were reported in 1 male after a single dose of 30 mg/kg and in 1 male and 1 female after a 
single dose of 90 mg/kg. Repeated incidences of second-degree AV-block were reported in 
1 male dog after 7 days of treatment with 60 mg/kg/day and in 1 male dog after 4 weeks of 
treatment with 40 mg/kg/day. These ECG abnormalities were considered indicative of 
arrhythmias. 
After 4 weeks of treatment in the dog, treatment-related changes were observed in the adrenal 
glands. The findings consisted of a decrease in lipid vacuolation in the cells of the zona 
fasciculata, and an increase in vacuolation of the cells of the zona glomerulosa in both sexes. 


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There are no indications of mutagenic or genotoxic potential of C106. 
 
 
Clinical experience 
This is a first-in-human (FIH) trial, C106 has not yet been studied in humans. 
The safety of activating the AT2R has previously been evaluated with the AT2R agonist C21 
in 3 completed Phase 1 trials (C21-001-16, C21-002-16, and C21-003), in 1 completed 
Phase 2 trial in hospitalised patients with COVID-19 (VP-C21-006) and in 1 completed 
Phase 2 trial in patients with Raynaud’s phenomenon secondary to SSc (VP-C21-004) with a 
total of 146 subjects exposed to at least one oral dose of C21 in these trials. Across the trials, 
C21 was generally well tolerated at daily doses up to 200 mg, whereas doses of 200 mg twice 
daily (in total 400 mg daily) for 8 days resulted in reversible hair loss in 6 out of 6 subjects 
occurring within 2 weeks after end of dosing and improving within 8 weeks (C21-003). In 
addition, there is one ongoing IPF phase 2 trial with C21 (VP-C21-005). After administration 
of 100 mg C21 twice daily, mild to moderate “hair fall or hair loss” has been reported in 5 
subjects in this trial, where 4 out of the 5 cases have resolved and 3 out of 5 subjects 
continued treatment with C21. The observed hair loss was considered related to C21 treatment 
and due to a pharmacological effect of stimulation of the AT2R. This adverse reaction was not 
observed at lower dose levels in any of the completed trials. For additional information, see 
Section 6.3. 
Across the Phase 1 trials, the most commonly observed treatment-emergent adverse event 
(AE) considered related to treatment was headache. C21 is currently in Phase 2 clinical 
development for treatment of IPF and in Phase 3 clinical development for treatment of 
moderate to severe COVID-19. 
In the present trial, 24 subjects have been dosed with C106 in 4 single dose cohorts (5, 30, 60 
and 180 mg). In each cohort, 8 subjects have been administered C106 or placebo in a 3:1 
ratio. The interim PK analysis showed that C106 had a fast absorption with a Tmax at 20- 
40 minutes and a mean terminal half-life (T1/2) of approximately 11 hours. The plasma 
exposure of C106 was lower than expected at all dose cohorts evaluated, and the dose 
proportionality was non-linear. Interim PK analysis of plasma exposure in terms of Cmax and 
AUCinf is presented in Table 8.3-2 in Section 8.3.1. 
C106 has been generally well tolerated, without clinically significant findings regarding AEs, 
ECG, safety laboratory assessments and physical examinations. In total 2 AEs have been 
reported as possibly related to blinded IMP, both were transient and mild in intensity. In 
conclusion, the overall safety and tolerability evaluation has not identified any safety signals 
in the completed cohorts. 
6.2 
Trial rationale 
C106 is being developed for oral treatment of fibrotic diseases, including IPF. C106 is an 
analogue to Vicore Pharma’s AT2R agonist C21, as described in Section 6.1.2, with expected 
lower risk of drug-drug interactions due to cytochrome P450 (CYP) inhibition than C21. It is 
believed to represent a novel treatment capable of reducing pulmonary inflammation, 
proliferation, fibrosis, and vasculopathy. 
This Phase 1 clinical trial (VP-C106-101) is a FIH, double-blind, placebo-controlled, within- 
group, randomised, single-centre trial will be performed to evaluate safety, tolerability, and 
pharmacokinetics (PK) of single and multiple ascending oral doses of C106 in healthy male 


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and female subjects. The results are expected to support the design of further studies, both in 
healthy volunteers and in patients. 
The AT2R agonist C21 has been shown to increase forearm blood flow in healthy subjects 
after intraarterial administration (VP-C21-009) and also to improve blood flow in Raynaud’s 
Phenomenon in patients with severe vasculopathy due to systemic sclerosis (VP-C21-004). 
An exploratory assessment of endothelial function has been added to Part B, cohort B4 to 
evaluate if an improved vasodilator response to reperfusion can be achieved in healthy 
volunteers by stimulating the AT2R with C106. 
The rationale for the trial design is outlined in Section 8.2. 
6.3 
Risk/benefit assessment 
This trial involves the first administration of C106 to humans, and there are no previous data 
on the effects of the drug in humans. It is therefore difficult to make predictions about 
possible adverse reactions. The healthy volunteers in this trial will have no medical benefit 
from participation, and their safety and wellbeing are hence of outmost importance. 
In pre-clinical safety pharmacology and toxicity studies, increased blood pressure and heart 
rate were observed in the dog following administration of single doses of C106 at 10 to 
40 mg/kg. ECG findings comprised a dose-dependent increase in arterial blood pressure 
(systolic, diastolic, and mean) and a slight statistically significant increase in heart rate at all 
doses tested, reduced RR and QT intervals, compatible with the increased heart rate and 
without variation in QTc, but also increases in PR intervals and repeated incidences of 
second-degree AV block, see Section 6.1.5 and Section 6.1.6 for details. Similar 
cardiovascular effects were previously observed with the C106 analogue C21 in toxicity and 
safety pharmacology studies in dogs. C21 has undergone a comprehensive clinical program, 
including Phase 1 and Phase 2 human clinical trials, with extensive cardiovascular 
monitoring. In contrast to the cardiovascular findings in dogs, no clinically significant 
findings related to blood pressure, heart rate or second-degree AV block were observed in 
these C21 human clinical trials or in studies in Cynomolgus monkeys, despite much higher 
exposure of C21 (both in terms of Cmax and AUC) in the human clinical trials compared to the 
exposure inducing the adverse cardiovascular effects in dogs. Altogether, these results 
indicate that the cardiovascular effects observed with C21 in the dog were due to a species- 
specific mechanism. In analogy, the cardiovascular effects observed with C106 are hence 
assumed to be of no relevance to human clinical conditions. However, subjects in this trial 
will be frequently monitored for changes in blood pressure and ECG, including ambulatory 
telemetry monitoring in the Single Ascending Dose (SAD) part, from 30 min pre-dose until 
24 hours post-dose. In addition, subjects with a prolonged QTcF or QRS, or a PR interval 
outside of reference ranges, clinically significant cardiac arrhythmias, or any clinically 
significant abnormalities in the resting ECG at the time of screening will not be included in 
the trial. 
In view of the inflammatory findings observed after administration of C106 in the rat, see 
Section 6.1.6, and not in the dog, it has been demonstrated in several studies that in general, 
the rat seems to be more prone to develop inflammatory cell infiltration in a variety of organs 
than other species (e.g., [31]). In addition, the rat has higher expression of pro-inflammatory 
mediators and lower levels of anti-inflammatory mediators compared to other species [32], 
and the pro-inflammatory response in rats compared to other species including mouse, 
hamster, primate, and human has been characterised as “abnormally high” [33]. In this 
context, even though C106 is characterised as an AT2 receptor agonist, C106 also possesses 


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weak AT1 receptor agonist properties, and the expression of AT1 and AT2 receptors vary 
widely between species and also between various organs within a species [15]. A rat-specific 
altered balance between expression of AT1 versus AT2 receptors may contribute to explain the 
infiltration of inflammatory cells in certain tissues in rats. This assumption is supported by 
quantitative autoradiography studies mapping AT receptor subtypes [34, 35]. 
The absence of infiltration of inflammatory cells in the dog fits also well with the suggestion 
that the dog has been demonstrated to be less prone to pro-inflammatory reactions and 
proliferative changes in various organs as compared to the rat [36]. Altogether, the results 
suggest that the observed infiltration of inflammatory cells in the kidney, heart, and aorta in 
the rat is species-specific to the rat and most likely of no relevance for the current trial. Yet, 
markers of inflammation (C-reactive protein [CRP] and white cell counts with differentials) 
will be monitored throughout both parts of the trial. 
A Phase 1 clinical trial with C21 reported reversible hair loss in 6 healthy subjects exposed to 
200 mg C21 twice daily for 8 days (400 mg per day) (C21-003). The events included hair loss 
on the head and the body and occurred on average 11 (ranging from 8 to 14) days after end of 
dosing. Regrowth of the hair was observed in all subjects within 8 weeks after end of dosing. 
The observed hair loss was considered related to treatment with C21 and was possibly due to 
a pharmacological effect of stimulation of the AT2R. No cases of hair loss have been reported 
at dose levels up to 100 mg C21 twice daily for 7 days or after single doses of 200 mg in any 
of the completed, randomised, controlled clinical trials with C21. 
As described in the current version of the IB (cut-off date 15-Mar-2022), mild to moderate 
“hair fall or hair loss” has been reported in 5 subjects in the ongoing, open-label IPF phase 2 
trial after administration of 100 mg C21 twice daily (VP-C21-005). 4 out of the 5 cases have 
resolved; 3 out of 5 subjects continued treatment with C21. The characteristics and nature of 
the ‘hair fall or hair loss’ reported in this trial appear to be different from the hair loss 
reported in the phase 1 trial, and the relationship to treatment is unclear. 
Although the mechanism for the reversible hair loss is not known, it cannot be excluded that it 
is a potential class effect related to high dose AT2R stimulation. It is therefore a risk that the 
subjects who participate in Part B of the current trial may experience hair loss. Hair loss of 
moderate intensity (i.e., Common Terminology Criteria for Adverse Events [CTCAE] 
grade 2) in 2 subjects assessed as related to the IMP administration has hence been included 
as a stopping criterion for dose escalation, see Section 8.3.5. 
The phototoxicity of C106 has not been investigated but based on the molar extinction 
coefficient (MEC) value obtained from absorbance studies a phototoxic potential cannot be 
excluded. Thus, sun protection, as defined in Section 9.6.1, should be used during the study. 
In both parts, subjects will be admitted to the clinic the day before each residential stay 
(Day -1). In Part A (SAD), subjects will remain in the clinic until 48 hours after the 
administration of the Investigational medicinal product (IMP). In Part B, subjects will be 
admitted to the clinic during the whole dosing period and for 48 hours after the last dose. 
During stays at the clinic, subjects will be closely monitored by medical staff. Sentinel dosing 
will apply for the first subjects in both parts. Visits at the clinic may be prolonged in case the 
Investigator finds it medically warranted for safety reasons. 
The selection of starting-dose and dose-escalation steps represents a careful approach to 
administer the drug for the first time in humans, see Section 8.3. An internal safety review 
committee (iSRC) will monitor emerging safety, tolerability and PK data over the course of 
the trial and will give a recommendation on the next dose level prior to any dose escalation. In 


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Part A, after collection of the last 48 hours data, there will be at least 1 week between dose 
escalations. In Part B (Multiple Ascending Dose [MAD]), after collection of the last available 
10 days data (48 hours after the last dose), there will be at least 2 weeks between dose 
escalations. Any indication of hair loss emerging after the 48-hour data cut off will be 
considered by the iSRC at the iSRC meeting. 
Overdosing is not likely to occur since all IMP will be administered by site personnel under 
medical surveillance. In cases of accidental overdose, standard supportive measures should be 
adopted as required. For further information regarding overdosing, refer to Section 11.3.1.17. 
Each volunteer will be provided with a subject participation card with information about the 
subject participation in a trial, see Section 14.4. 
The Principal Investigator at the research clinic will ascertain that adequate facilities and 
procedures are available to handle emergency situations in case they occur during the trial. 
The medical staff at CTC have extensive experience from early Phase 1 and FIH studies and 
there are adequate procedures in place to handle unexpected and expected adverse reactions in 
the trial subjects. The research clinic is located adjacent to Intensive Care Unit (ICU) at the 
University Hospital in Uppsala. CTC has a separate agreement with the ICU for support in 
case of emergencies. CTC has been regularly inspected by the Swedish Medical Products 
Agency (MPA) and is authorised to conduct FIH studies. 
Besides the risks related to the IMP as described above, there may also be risks related to the 
medical devices used in the trial e.g., indwelling venous catheters. However, these are devices 
that are used in routine medical care and the risk associated with their use is considered low 
and ethically justifiable. EndoPAT is a non-invasive medical device used to assess endothelial 
function. During the assessment, a blood-pressure cuff is used to achieve and maintain arterial 
occlusion for 5 minutes. Inflating the cuff might cause some stress and discomfort to the 
subject. Other trial specific evaluations and sampling procedures, like blood-pressure 
measurements using a blood pressure cuff and frequent blood-sampling, may cause transient 
discomfort but the risk is deemed to be low and ethically justifiable. 
Overall, the combined safety data from the pre-clinical studies have not revealed any safety 
issues that would outweigh the expected benefits of the trial. While keeping the above- 
mentioned risk factors at a minimum level in order to not expose the subjects participating in 
the trial for risks that would not be ethically justifiable it is concluded that the planned trial 
assessments are considered sufficient to meet the scientific and medical goals for the trial. It is 
therefore concluded that the potential benefits from the trial will outweigh the potential risks 
for the treated subjects. 
More detailed information about the known and expected benefits and risks are found in 
current version of the Investigator’s Brochure (IB). 
 
 
Risk assessment with regards to the COVID-19 pandemic 
Current recommendations from the authorities will be considered on a day-to-day basis and a 
continuous risk evaluation will be made to assess how the COVID-19 pandemic is affecting 
the study conduct and the safety of the study subjects. 
Any identified risks in terms of subject safety, trial performance and data quality/integrity will 
be documented in a risk log as part of the Sponsor’s trial master file (TMF). 


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The recommendations from the EMA [37, 38] as well as the Swedish Medical Products 
Agency (MPA) [39] regarding the conduct and management of clinical trials during the 
COVID-19 pandemic will be taken into consideration. 


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7 
TRIAL OBJECTIVES AND ENDPOINTS 
7.1 
Objectives and endpoints 
The objectives, endpoints and assessments are summarised in Table 7.1-1. The exploratory 
endpoints (MIST, urine metabolites and endothelial function) may be reported separately 
from the clinical trial report (CTR). Cardiodynamic ECG data will be stored for potential 
future evaluation and will thus not be included in the CTR. 
Table 7.1-1 Objectives and endpoints 
Objective 
Endpoint 
Assessment(s) 
Primary 
To evaluate the safety 
and tolerability of 
single and multiple oral 
doses of C106 in 
healthy subjects. 
Treatment emergent AEs and SAEs 
AE reporting and questioning 
(Section 11.3.1) 
Clinically significant changes in 12-lead 
electrocardiograms (ECGs), vital signs, laboratory 
safety variables (haematology, coagulation, 
clinical chemistry and urine analysis), and 
physical examinations. 
12-lead ECG (Section 11.3.2), 
Vital signs (Section 11.3.4), 
Blood sampling for clinical 
chemistry and haematology, 
urine sampling for urinalysis 
(Section 11.3.5), 
Physical examination (Section 
11.3.6). 
Secondary 
To characterise the 
pharmacokinetics (PK) 
of single and multiple 
oral doses of C106 in 
plasma and urine of 
healthy subjects. 
Part A 
• AUC from time 0 to infinity (AUCinf) and 
AUC from time 0 to the time of the last 
quantifiable concentration (AUClast,). 
• Plasma half-life associated with the terminal 
elimination phase (T½(z)), Cmax and time to 
Cmax (Tmax). 
Pharmacokinetic sampling and 
analysis (Section 11.4.1 and 
Section 11.4.2). 
• Total clearance of the drug from plasma 
following oral administration (CL/F) and 
apparent volume of distribution associated 
with the terminal elimination phase (Vz/F). 
• Dose proportionality after a single oral dose 
based on AUCinf and Cmax. 
• % of dose excreted unchanged in urine. 
• Renal clearance. 
Part B 
• PK parameters after the first dose: 
o 
AUC over the dosing interval (AUCtau), 
AUCinf, T½(z), Cmax, Tmax, CL/F, Vz/F. 
• PK parameters after the last dose: 
o 
AUC at steady state (AUCtau), T½(z), Cmax, 
Tmax, CL/F, Vz/F . 
• % of dose excreted unchanged in the urine. 
• Renal clearance 


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• Dose proportionality (based on AUCtau and 
Cmax) and accumulation ratios (based on 
AUCtau and Cmax). 
• Observed concentration at the end of a dosing 
interval, immediately before next 
administration (Ctrough). 
To evaluate the effect 
of a high fat meal on 
the single oral dose PK 
of C106 in healthy 
subjects (Part A). 
• 
PK parameters as for Part A. 
• 
Relative bioavailability of C106 in fasted 
versus fed conditions. 
Exploratory 
To evaluate the 
Metabolite In Safety Testing (MIST) analysis of 
MIST (Section 11.5.1). 
metabolite profile of 
the metabolite profile in plasma in comparison 
C106 in plasma of 
with the metabolite profile in plasma from non- 
healthy subjects at 
clinical safety studies. 
steady state (Part B). 
To estimate the 
Profile of excreted metabolites in the urine. 
Urine sampling and analysis 
excreted C106 and its 
(Section 11.5.2). 
metabolites and the 
metabolite profile of 
C106 in urine of 
healthy subjects at 
steady state (Part B). 
To collect and store 
Cardiodynamic ECG parameters. 
EPQT assessment 
ECG data for potential 
(Section 11.5.3). 
future evaluation of the 
effect of C106 on ECG 
parameters, including 
concentration-QTc 
analysis using Expert 
Precision QT (EPQT) 
assessment (Part A). 
To evaluate the 
Change from baseline in reactive hyperemia index 
EndoPAT assessment 
pharmacodynamic 
(RHI) and augmentation index (AI) scores at 
(Section 11.5.4). 
(PD) effect of C106 on 
Day 7 as measured by EndoPAT. 
endothelial function in 
healthy subjects at 
steady state (Part B, 
cohort B4). 


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8 
TRIAL DESIGN 
8.1 
Overall trial design and schedule of events 
This is a FIH, double-blind, placebo-controlled, within-group randomised, trial designed to 
evaluate the safety, tolerability and PK of single and multiple ascending oral doses of C106 in 
healthy females of non-childbearing potential and healthy males. 
The trial will be conducted in 2 parts: 
Part A, SAD including a food interaction cohort: safety, tolerability and PK in healthy males 
and healthy females of non-childbearing potential receiving single ascending doses of C106, 
see Section 8.1.1. 
Part B, MAD: safety, tolerability and PK in healthy males and healthy females of non- 
childbearing potential receiving twice daily multiple ascending doses of C106 for 8 days, see 
Section 8.1.2. 
Subjects included in the SAD part of the present study will not be included in the MAD part 
(regardless of whether 3 months have passed since the SAD participation). 
An overview of the planned cohorts and the trial design is shown in Figure 8.1-1 and 
Figure 8.1-2. 
Figure 8.1-1 Overview of the planned cohorts 
 
The actual doses given in Part A for cohorts 1 to 4 were 5, 30, 60 and 180 mg, corresponding to dose increment of 6, 2 and 3 
times the previous dose. For cohort 5 and 6, the planned doses are 240 mg and 300 mg, corresponding to dose increments of 
1.3 and 1.25 times the previous dose, respectively. The dose given in cohort 6 may be adjusted as recommended by the iSRC 
following evaluation of emerging safety, tolerability, and PK data in cohort 5. Cohorts A7, A8 and B5 are optional. The 
maximum oral dose in Part A and the maximum oral daily dose in Part B will not exceed 480 mg C106 (including the 
optional cohorts). The fed cohort is planned to be cohort A4. The first cohort in Part B (MAD) may be dosed after safety 
evaluation of the SAD cohort A3 if recommended by the iSRC. Each dose level in Part B will be selected such that the 
predicted maximum exposure will not exceed the maximum exposure (based on AUC and Cmax) in previously evaluated SAD 
cohorts. Day 8: only morning dose (i.e., in total 15 doses in Part B). The dosing frequency in Part B is planned to be BID but 
may be changed to QD if recommended by the iSRC. 


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Figure 8.1-2 Overview of the trial design 
 
 
 
 
Single Ascending Dose (SAD) part of the trial 
In Part A, single, oral doses of C106 will be administered in 6 sequential dose cohorts, each of 
8 subjects. Within each cohort, subjects will be randomised to receive either C106 (n=6) or 
placebo (n=2) in the fasted state. The proposed doses are: 5, 30, 60, 180, 240 and 300 mg. The 
rationale for the starting dose and the planned dose escalation is detailed in Section 8.3. Up to 
2 additional dose cohorts can be explored based on the safety, tolerability, and PK of the drug 
if recommended by the iSRC. The maximum oral dose in Part A will not exceed 480 mg 
C106. 
Subjects will come for 3 visits to the Clinical Research Unit (CRU). Screening (Visit 1) will 
take place within 4 weeks of the planned dose (Day -28 to Day -1) and will include the 
subject’s signing of the informed consent and an eligibility check, see Table 8.1-1. At Visit 2, 
subjects will reside at the CRU from Day -1 (the day before IMP administration) until Day 3 
for single dose IMP administration, safety, tolerability, and PK assessments as outlined in 
Table 8.1-1 and detailed in Table 8.1-2. The subjects must fast for at least 10 hours before 
until 4 hours after the anticipated dosing time on Day 1. During fasting, water, but no other 
drinks, is allowed as desired. No drinks are allowed for 1 hour before and 1 hour after dosing. 
The first 2 subjects in each cohort will be dosed in a sentinel fashion, 1 subject will receive 
C106 and the other will receive placebo as randomised. The subjects will be carefully 
monitored by clinical staff during and after dosing. Vital signs and ECG will be checked at 
regular intervals as detailed in Table 8.1-2. Ambulatory ECG telemetry will be used for 
cardiac surveillance up to 24 hours after IMP administration. There is immediate access to 
equipment, qualified staff, and an ICU in case of an acute emergency. To give sufficient time 
for observation of any reactions there will be at least 24 hours before dosing of the remaining 
6 subjects, who will be dosed in groups of 3 subjects at least 24 hours apart. A final end-of- 
trial visit (Visit 3) will take place on Day 7 (±2 days) or after early withdrawal. 
Cardiodynamic ECG assessments (collect and store) will be performed in all cohorts (except 
the first cohort A1) where C106 is given in the fasted state (i.e., not in the fed period of the 


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fasted/fed cohort) and will include serial ECG extractions at baseline (prior to dosing) and at 
the same time points as PK sampling during the first 24 hours post-dose. 
The doses given after the starting dose and time points for safety and PK sampling may be 
adjusted as recommended by the iSRC following evaluation of emerging safety, tolerability, 
and PK data. If needed, one visit for additional safety and PK assessments may be added 
based on recommendations from the iSRC. 
Before initiating a new dose cohort, all subjects in the previous cohort must have been treated 
and all available safety, tolerability and plasma concentration data up until and including 
48 hours post dose must have been evaluated by the iSRC, see Section 8.3.6. After collection 
of the last available 48-hour data, there will be at least one week between dose escalations. In 
case of dropouts, available data for the dropouts will be included in the iSRC evaluation. 
Based on emerging safety and PK data, the amount of required safety and PK data to be 
reviewed after a completed cohort might be adjusted. 
Subjects are expected to participate in Part A for up to 37 days including a 28-day screening 
period. Subjects who are administered C106 both in the fasted and the fed state in Part A are 
expected to participate in the trial for up to 43 days + at least 5 half-lives of C106 (wash-out 
between fasting and fed IMP administrations). 
The schedule of events for Part A is shown in Table 8.1-1 and detailed for Visit 2 in 
Table 8.1-2. 
Trial assessments are described in Section 11. 
 
8.1.1.1 Food interaction 
One dose cohort (planned to be cohort A4) will be selected to investigate any potential food 
interaction. The predicted maximum exposure (taking into account a possible food interaction 
effect on the exposure) of the chosen dose level will not exceed the exposure tolerated in 
previously evaluated cohorts. 
Subjects in the selected cohort will return to the clinic after a wash-out period of at least 
5 half-lives (as determined by evaluation of PK data) to receive a second dose of C106 or 
placebo under fed conditions. In case of dropouts at the selected dose level, subjects may be 
replaced to guarantee a full cohort size for the food-interaction part of the trial (if considered 
necessary). Any replacers will receive active treatment. The assessments during fed 
conditions will be the same as during fasting conditions except that the subjects will consume 
an FDA recommended high-fat, high calorie breakfast 30 minutes prior to IMP administration 
as detailed in Section 10.5.1 and no screening visit will be conducted. Potential replacement 
subjects will come for a screening visit and perform one fasting cohort and one fed cohort. 
The schedule of events for Part A is shown in Table 8.1-1 and detailed for Visit 2 in 
Table 8.1-2. 
Trial assessments are described in Section 11. 


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Table 8.1-1 Schedule of events, Part A (SAD) 
Refer to 
CTP 
section: 
Screening 
Trial intervention and 
observation period 
Follow-up/End-of-trial 
Visit 
Visit 1 
Visit 21,2 
Visit 3 
Assessment 
Day -28 to 
Day -1 
Admission 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 7 (±2)3 
Informed Consent 
14.3 
X 
Inclusion/exclusion 
criteria 
9.4, 
9.5 
X 
X 
Demographics 
11.2 
X 
Medical/surgical 
history 
11.2.5 
X 
HIV, hepatitis B and 
C 
11.2.7 
X 
Alcohol test 
11.2.9 
X 
X 
Weight/height (BMI) 
11.2.4 
X 
Serum FSH4 
11.3.5 
X 
Urine Drug Screen5 
11.2.8 
X 
X 
Physical Examination 
11.3.2 
X 
X6 
X 
Clinical Laboratory 
Profile7 
11.3.5 
X 
X 
X 
X 
X 
Safety urine sampling 
11.3.5 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
11.3.5 
X 
X 
X 
Vital Signs8 
11.3.4 
X 
X 
X 
X 
X 
X 
12-lead safety ECG 
11.3.2 
X 
X 
X 
X 
X 
Telemetry 
11.3.3 
X9 
Randomisation 
X 
IMP administration 
10.5 
X11 
Cardiodynamic 
ECG10 
11.5.3 
X 
X 
PK blood sampling 
11.4.1 
X 
X 
X 
PK urine sampling 
11.4.2 
X 
X 
X 
Breakfast 
X 
X 
High-fat breakfast11 
10.5.1 
X11 
Meals12 
X 
X 
X 
X 
Adverse events 
11.3.1 
------X------ 
Prior and 
concomitant 
medications 
11.2.6 
------X------ 
BMI=Body mass index. CTP=Clinical trial protocol. ECG=Electrocardiogram. FSH=Follicle stimulating hormone. 
HIV=Human immunodeficiency virus. 
1. Details in separate flow chart (Table 8.1-2). 
2. For the food-effect cohort, each subject will participate in 2 trial intervention and observation periods separated by a 
washout period. 
3. Or after early withdrawal. 
4. Females only (questionable cases). 
5. Drug tests may also be performed at 1 to 2 additional random occasions during the trial. 
6. Symptom driven physical examination. 


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7. Clinical chemistry, haematology and coagulation, see Section 11.3.5. 
8. Systolic and diastolic blood pressure, pulse, respiratory rate at all visits indicated. Temperature will be measured on 
Day -1 only (other visits if indicated). For details regarding vital signs, see Section 11.3.4. 
9. Ambulatory telemetry starting 30 min (±10 min) pre-dose and ending 24 hours (±20 min) post-dose. 
10. Cardiodynamic ECG (collect and store) from cohort A2 (i.e., not in cohort A1) and not in the fed part in the food effect 
cohort. 
11. High-fat breakfast only for subjects participating in the fed part in the food effect cohort, see Section 10.5.1. 
12. Day -1 Optional evening snack. Day 1: standardised lunch (at least 4 hours post-dose), optional snack, dinner and 
optional evening snack Day 2: non-standardised breakfast lunch, optional snack, dinner and optional evening snack. 
Day 3: non-standardised breakfast. For timing of meals, refer to Table 8.1-2. 


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Table 8.1-2 Detailed schedule of events, Part A (SAD) Day -1 to Day 2 
Day -1 
Day 1 
Day 2 
Day 3 
Assessment/time-point 
(hh:mm) 
Admission 
Pre- 
dose 
00:00 
00:20 
00:40 
01:00 
01:30 
02:00 
03:00 
04:00 
06:00 
08:00 
10:00 
16:00 
24 h 
48 h 
Inclusion/exclusion criteria 
X 
Urine drug screen 
X 
Alcohol test 
X 
Physical examination 
X 
Clinical Laboratory profile 
X 
X 
X 
Safety urine sampling 
X 
X 
X 
Urinalysis (dipstick) 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead safety ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Telemetry2 
------X------ 
Randomisation 
X 
IMP administration 
X 
Cardiodynamic ECG3 
------X------ 
PK blood sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK urine sampling4 
X 
------X4------ 
Breakfast5 
X 
X 
High-fat breakfast6 
X 
Meals7 
------X------ 
Adverse events 
------X------ 
Prior and concomitant 
medications 
------X------ 


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1. 
Systolic and diastolic blood pressure, pulse, respiratory rate at all time points indicated. Temperature will be measured on Day -1 only (other visits if indicated). For details regarding 
vital signs, see Section 11.3.4. 
2. 
Telemetry: starting 30 min (±10 min) pre-dose and ending 24 hours (±20 min) post-dose. 
3. 
A continuous ECG recording will be performed for 25 hours, starting 1 hour pre-dose on Day 1, in all cohorts in which subjects receive C106 or placebo in the fasted state, except for 
cohort A1. 12-lead ECGs will be extracted at 3 time points within one hour prior to dosing (at -45, -30 and -15 minutes) and subsequently at the same time points as PK blood draws up 
until and including 24-hours post-dose. Subjects will be supinely resting for at least 15 minutes before and 5 minutes after each time point. When ECG extractions coincide with safety 
ECGs, vital signs assessment and blood draws, procedures will be carried out in the order outlined in Section 11.1. 
4. 
PK urine sampling: pre-dose (blank), 0-6 hours, 6-12 hours, 12-24 hours and 24–48 hours post-dose. No urine sampling in the food interaction cohort. 
5. 
Fasting on Day 1. Breakfast on Day 2 and Day 3 after PK blood sampling. 
6. 
High-fat breakfast only for subjects in the fed part in the food effect cohort, see Section 10.5.1. Following an overnight fast of at least 10 hours, subjects should start the meal 30 
minutes prior to administration of the IMP and eat the meal in 30 minutes or less. 
7. 
Day -1: Optional evening snack. Day 1: No breakfast. Standardised lunch at least 4 hours post dose. Standardised snack, dinner and optional evening snack at approximately 7 and 9 
and 11 h post-dose. Day 2: Non-standardised breakfast after 24-hour PK sampling, lunch, snack, dinner and evening snack at approximately 4, 7 and 9 and 11 h post breakfast. Day 3: 
Non-standardised breakfast only. 


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Multiple Ascending Dose (MAD) part of the trial 
In Part B, repeated, oral doses of C106 will be administered in 4 sequential dose cohorts. 
Within each cohort, subjects will be randomised to receive C106 (n=6) or placebo (n=2). The 
initial dose, dose escalations, and dosing schedule will be based on emerging safety, 
tolerability, and PK data observed in the SAD part of the trial (Part A) and on emerging data 
from the MAD part. Each dose level during the Part B will be selected such that the predicted 
maximum exposure will not exceed the maximum exposure (based on AUC and Cmax) in 
previously evaluated SAD cohorts. The proposed doses are 40, 100, 180 and 240 mg BID. 
Twice daily dosing for 8 days is planned. Based on emerging PK data, once daily (QD) 
dosing may be applied if recommended by the iSRC. The number of dosing days may also be 
changed based on PK data from Part A (SAD), with the aim to reach steady state during the 
dosing period. The treatment duration will, however, not exceed the treatment duration in pre- 
clinical toxicology studies i.e., 28 days. One additional dose cohort can be explored based on 
emerging safety, tolerability, and PK of the drug, if recommended by the iSRC. The 
maximum oral daily dose in Part B will not exceed 480 mg C106. 
Subjects will come for 3 visits to the CRU. Screening (Visit 1) will take place within 4 weeks 
of the first dose (Day -28 to Day -1) and will include the subject’s signing of the informed 
consent and an eligibility check, see Table 8.1-3 for details. At Visit 2, subjects will reside at 
the CRU from Day -1 (the day before IMP administration) until Day 10 for 8 days multiple 
dose IMP administration, safety, tolerability and PK assessments, see Table 8.1-3, Table 8.1-4 
(Day -1 to Day ) and Table 8.1-5 (Day 8 to Day 10). Subjects must fast from 2 hours prior to 
each IMP administration until 1 hour after. During fasting, water, but no other drinks, is 
allowed as desired. No drinks are allowed for 1 hour before and 1 hour after dosing. On 
Day 8, only the morning dose will be administered (i.e., in total 15 doses are planned). 
The first 2 subjects in each cohort will be dosed in a sentinel fashion, 1 subject will receive 
C106 and the other will receive placebo as randomised. The subjects will be carefully 
monitored by clinical staff during and after dosing. Vital signs and ECG will be checked at 
regular intervals. There is immediate access to equipment, qualified staff and an ICU in case 
of an acute emergency. To give sufficient time for observation of any reactions there will be 
at least 24 hours before dosing of the remaining 6 subjects, who will be dosed in groups of 3 
subjects at least 24 hours apart. A final end-of-trial visit (Visit 3) will take place on Day 22 
(±2 days) or after early withdrawal. 
For subjects participating in cohort B4, an assessment of endothelial function using EndoPAT 
will be performed before the first IMP administration (on Day -1 or 1), and 30±10 minutes 
after IMP administration on Day 7 (morning or evening). The EndoPAT assessments should 
be done at approximately the same time of the day on both occasions. Subjects must fast for at 
least 4 hours prior to the EndoPAT assessment until end of assessment. During fasting, water, 
but no other drinks, is allowed as desired. No drinks are allowed for 1 hour before and 1 hour 
after dosing. 
Besides the starting dose and subsequent doses, also time points for safety and PK sampling 
may be adjusted as recommended by the iSRC following evaluation of emerging safety, 
tolerability, and PK data. If needed, one visit for additional safety and PK assessments may be 
added based on recommendations from the iSRC. 
After collection of the last available 10 days data (48 hours after the last dose), there will be at 
least 2 weeks between dose escalations. Before initiating a new dose cohort, all subjects in the 


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previous cohort must have been treated and all available safety, tolerability and plasma 
concentration data up until and including 48 hours post last dose must have been evaluated by 
the iSRC. In case of non-replaced dosed dropouts, available data for the dropouts will be 
included in the iSRC evaluation. In case of dropouts, the iSRC may recommend including 
replacers to be able to make an informed recommendation on the next dose level. Based on 
emerging safety and PK data, the amount of required safety and PK data to be reviewed after 
a completed cohort might be adjusted. 
Subjects are expected to participate in Part B for up to 47 days including a 28-day screening 
period. 
The schedule of events for Part B is shown in Table 8.1-3 and is detailed for Visit 2 in 
Table 8.1-4 (Day -1 to Day 7) and Table 8.1-5 (Day 8 to Day 10). 
Trial assessments are described in Section 11. 


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Table 8.1-3 Schedule of events, Part B (MAD) 
Screening 
Trial intervention and observation period 
Follow- 
up/End-of- 
trial 
Visit 
Visit 1 
Visit 21,2 
Visit 3 
Assessment/time- 
point 
Day -28 to 
Day -1 
Admission 
Day -1 
Day 1 
Days 2- 
7 
Day 
8 
Day 
9 
Day 
10 
Day 22 (±2 
days)3 
Informed Consent 
X 
Inclusion/exclusion 
criteria 
X 
X 
Demographics 
X 
Medical/surgical 
history 
X 
HIV, hepatitis B 
and C 
X 
Alcohol test 
X 
X 
Weight/height 
(BMI) 
X 
Serum FSH4 
X 
Urine Drug Screen4 
X 
X 
Physical 
Examination 
X 
X6 
X 
Clinical Laboratory 
Profile7 
X 
X 
X 
X 
X 
X 
Safety urine 
sampling 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
X 
X 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
X 
IMP administration 
X 
X 
X 
Blood sampling for 
PK and metabolite 
profiling9 
X 
X 
X 
X 
X 
Urine sampling for 
PK and metabolite 
profiling9 
X 
X 
PD (EndoPAT) 
assessment10 
X 
X 
Meals11 
X 
X 
X 
X 
X 
X 
Adverse events 
------X------ 
Prior and 
concomitant 
medications 
------X------ 
BMI=Body mass index. CTP=Clinical trial protocol. ECG=Electrocardiogram. FSH=Follicle stimulating hormone. 
1. Details in separate flow charts (Table 8.1-4 and Table 8.1-5). 
2. The duration of the intervention and observation period in Part B may be adjusted (8 days BID dosing duration 
assumed). 
3. Or after early withdrawal. 


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4. Females only (questionable cases). 
5. Drug tests may also be performed at 1 to 2 additional random occasions during the trial. 
6. Symptom driven physical examination 
7. Clinical chemistry, haematology and coagulation, see Section 11.3.5. 
8. Systolic and diastolic blood pressure, pulse, respiratory rate at all visits indicated. Temperature will be measured on 
Day -1 only (other visits if indicated). For details regarding vital signs, see Section 11.3.4. 
9. Metabolite profiling in plasma and urine at steady state only (Day 8 to Day 10). 
10. Cohort B4 only. The EndoPAT assessment will be performed before the first IMP administration (Day -1 or Day 1) and 
30±10 minutes after IMP administration on Day 7 (morning or evening dose). Subjects must fast for at least 4 hours 
prior to the EndoPAT assessment until end of assessment. 
11. Breakfast at least 1-hour post-dose. Day -1 to Day 1 and Day 7 to Day 8: Standardised breakfast, lunch, snack, dinner 
and optional evening snack as applicable. Non-standardised meals Day 2, 3, 4, 5, 6, 9 and 10. For timing of meals, refer 
to Table 8.1-4 and Table 8.1-5. 


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Table 8.1-4 Detailed schedule of events, Part B (MAD) Day -1 to Day 7 
Day 
Day -1 
Day 1 
Day 2 
Day 3 
Days 4 to 7 
Assessment/time- 
point (hh:mm) 
Ad- 
mission 
Pre- 
dose 
00:00 
00:20 
00:40 
01:00 
01:30 
02:00 
03:00 
04:00 
06:00 
08:00 
10:00 
12:00 
24 
h 
36 
h 
48 
h 
60 
h 
D4: 72 h 
D5: 96h 
D6:120 h 
D7:144h 
D4:84h 
D5: 108h 
D6:132 h 
D7: 156 h 
Inclusion/ 
exclusion criteria 
X 
X 
Urine drug screen 
X 
Alcohol test 
X 
Physical 
examination 
X1 
Clinical laboratory. 
Profile 
X 
X2 
X2 
Safety urine 
sampling 
X 
X3 
X3 
Urinalysis 
(dipstick) 
X 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X5 
X5 
X5 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X5 
X5 
X5 
Randomisation 
X 
IMP administration 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X6 
X6 
X6 
Urine sampling for 
PK7 
X 
------X7------ 
PD (EndoPAT) 
assessment8 
X 
X 
Meals9 
X 


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Adverse events 
------X------ 
Prior and 
concomitant meds. 
------X------ 
1. 
Symptom driven physical examination. 
2. 
Clinical laboratory profile Day 3: pre-dose and Day 6: pre-dose. 
3. 
Safety urine sampling Day 3 pre-dose and Day 6 pre-dose. 
4. 
Systolic and diastolic blood pressure, pulse, respiratory rate at all time points indicated. Temperature will be measured on Day -1 only (other visits if indicated). For details regarding 
vital signs, see Section 11.3.4. 
5. 
Vital signs and ECG Day 2 to Day 7: both in association with the morning dose and the evening dose, pre-dose and 1-hour post-dose. 
6. 
Day 1: pre-dose at 12 hours. Day 2: pre-dose at 24 hours. Day 3 to Day 7: trough concentration (Ctrough) pre-morning dose samples, see Section 11.4.1. 
7. 
PK urine sampling pre-dose and 0-12 hours post-dose. 
8. 
Cohort B4 only. The EndoPAT assessment will be performed before the first IMP administration (Day -1 or Day 1) and 30±10 minutes after IMP administration on Day 7 (morning or 
evening dose). Subjects must fast for at least 4 hours prior to the EndoPAT assessment until end of assessment. 
9. 
Standardised meals on Day -1, Day 1, Day 7 and Day 8, non-standardised meals on Day 2 to Day 6. Breakfast at least 1 hour post dose, lunch, snack, dinner and optional evening snack 
at approximately 4, 7 and 9 and 10 h post-dose. Optional evening snack at least 2 hours before or 1 hour after IMP administration. 


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Table 8.1-5 Detailed schedule of events Part B (MAD) Day 8 to Day 10 
Day 
Day 8 
Day 9 
Day 10 
Assessment/time-point 
(hh:mm) 
Pre- 
dose 
00:00 
00:20 
00:40 
01:00 
01:30 
02:00 
03:00 
04:00 
06:00 
08:00 
10:00 
12:00 
16:00 
24 h post 
last dose 
48 h post 
last dose 
Clinical Laboratory 
profile 
X 
X 
Safety urine sampling 
X 
X 
Urinalysis (dipstick) 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
IMP administration 
X 
Blood sampling for PK 
and metabolite profiling 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sampling for PK 
and metabolite 
profiling2 
------X2------- 
Meals3 
-------X------ 
Adverse events 
------X------ 
Prior and concomitant 
medications. 
------X------ 
1. 
Trough (pre-dose) sample on Day 8, see Section 11.4.1. 
2. 
PK urine sampling 0-12 hours post last dose (i.e., morning dose Day 8). 
3. 
Day 8: Standardised breakfast at least 1 hour post dose on Day 8, standardised lunch, snack, dinner and optional evening snack at approximately 4, 7 and 9- and 11-hours post-dose. 
Day 9: Non-standardised breakfast after PK sampling. Lunch, snack, dinner and optional evening snack at approximately 4, 7 and 9 and 11 h post-dose. Day 10: Breakfast only. 


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8.2 
Rationale for trial design 
The EMA guideline on strategies to identify and mitigate risks for FIH and early clinical trials 
with IMPs (EMEA/CHMP/SWP/28367/07 Rev. 1) has been considered. 
The design of the trial is based on the aim to study safety, tolerability, and PK (including 
influence of food) of selected doses of C106 in a limited number of healthy volunteers. The 
design is adaptive, to allow for e.g., flexible dose escalation and involves careful monitoring 
of the subjects’ well-being. The time points for PK blood sampling are selected based on data 
obtained from previous non-clinical studies. 
A placebo control will be used to establish the frequency and magnitude of changes in 
endpoints that may occur in the absence of active treatment. 
Randomisation will be used to minimise bias in the assignment of subjects to dose groups and 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) are evenly balanced across treatment groups. 
Blinded treatment will be used to reduce potential bias during data collection and evaluation 
of endpoints. 
For both Part A (SAD) and Part B (MAD) of the trial, a sequential-cohort, sentinel-dosing, 
ascending-dose design has been chosen for safety reasons as C106 is in early stage of clinical 
development, with Part A of the trial being the first time C106 will be administered to 
humans. Conducting the initial SAD and MAD trial with C106 in healthy subjects mitigates 
the potential confounding effects of the disease state and concomitant medications. 
Oral administration has been chosen for all parts of the trial, as this is the intended clinical 
route of administration. 
A 2-part cross-over design has been chosen for the food-effect evaluation, as a within-subject 
assessment of the influence of food on the PK of C106 increases the power for the given 
number of subjects. 
An exploratory PD assessment will be performed in Part B (MAD), cohort B4 to investigate 
the effect of C106 on endothelial function. This data may support future trials on IPF- 
associated vasculopathy and further use of this PD assessment in early clinical development 
programs. 
Overall, the trial will provide important data to support the design of further studies, both in 
healthy volunteers and in patients. 
8.3 
Selection of starting dose and rationale for planned dose escalation 
 
 
Selection of starting dose and rationale for dose escalation in Part A for cohorts 1 to 
4 (completed) 
The starting dose in the single dose escalation (Part A) in this FIH trial was assessed based on 
the Maximum Recommended Starting Dose (MRSD) as well as the anticipated Minimal 
Anticipated Biological Effect Level (MABEL) approach. 
The MRSD is based on the NOAEL derived from the 28-days repeat dose GLP toxicology 
studies in rat and dog. The NOAEL was determined to 15 (female)/10 (male) mg/kg and 
20 mg/kg in dog. Human equivalent doses (HED) from the rat and dog data were estimated to 
2.4 and 1.6 mg/kg based on the NOAEL in female and male rats, respectively, and 10.8 mg/kg 


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based on the NOAEL in dogs using allometric scaling. Applying a 10-fold safety margin to 
the HEDs, the MRSD based on the most sensitive species (male rat) is 9.7 mg for a 60 kg 
person. If applying a 10-fold safety margin to the HEDs, the MRSD based on the dog is 
65 mg for a 60 kg person. 
The starting dose was also assessed based on the MABEL. An approach of assuming the 
concentration leading to 15% receptor ligation in receptor binding assay was used to estimate 
the MABEL. A concentration of 1 nM C106 resulted in a 15% inhibition of the human AT2R 
expressed in HEK-293 cells. Therefore, the MABEL for C106 (bound + unbound) assuming a 
0.4% unbound fraction, is estimated to 122.4 ng/mL (1 nM *489.66 g/mol /0.004). 
Estimation of human plasma clearance was conducted by an in vitro-in vivo extrapolation 
(IVIVE) approach using human liver hepatocyte stability data. Scaling of human hepatocyte 
intrinsic clearance (Clint) value of 4.0 µL/min/106 cells, according to the well-stirred model 
without correction for binding in plasma and incubations, resulted in an estimated human 
plasma clearance of 5.5 mL/min/kg. A starting dose of 5 mg, assuming 100% bioavailability 
and a plasma CL of 5.5 mL/min/kg, would result in a human plasma AUCinf of 253 h*ng/mL 
for a 60 kg person. The estimated unbound human plasma AUCinf following a 5 mg dose was 
1.0 ng*h/mL (252* fu=0.004). 
Since C106 is an acidic molecule exhibiting high plasma protein binding, the distribution 
volume (Vss) was assumed to be approximately 0.2 L/kg. Predictions of Cmax following a 5 mg 
oral dose of C106 was based on a 1-compartmental model assuming 100% bioavailability, a 
plasma CL of 5.5 mL/min/kg, a Vss of 0.2 L/kg, and an absorption rate constant (Ka) of 1 h-1. 
The prediction, based on these assumptions, resulted in an Cmax of 117 ng/mL. The estimated 
unbound human plasma Cmax following a 5 mg dose was 0.47 ng/mL (117* fu=0.004). 
Based on the PK predictions and assuming maximum oral bioavailability, the dose of C106 
expected to result in a transient minimal measurable pharmacological activity is 5.2 mg (i.e., 
the dose predicted to result in a Cmax of 122.4 ng/mL). 
The proposed starting dose of 5 mg was thus predicted to generate mean Cmax and AUCinf of 
117 ng/mL and 253 ng*h/mL, respectively. These estimates provide a predicted safety margin 
of 19-fold when compared to the Cmax (2190 ng/mL) and 56-fold when compared to the 
AUClast (14200 ng*h/mL) at NOAEL in the most sensitive species (male rat), see Table 8.3-1. 
When compared to the NOAEL of the most sensitive non-rodent species (female dog), these 
estimates provide a predicted safety margin of 75-fold when compared to the Cmax 
(8730 ng/mL) and 63-fold when compared to the AUClast (15900 ng*h/mL), see Table 8.3-1. 


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Table 8.3-1 Predicted human exposure at the starting dose and margins vs the NOAEL in rat and 
dog 
Species 
NOAEL 
(mg/kg) 
Exposure at 
NOAEL 
(Cmax ng/mL) 
Exposure at 
NOAEL 
(AUClast 
h*ng/mL) 
Cmax-based 
margin vs. 
NOAEL 
AUC-based 
margin vs. 
NOAEL 
Rat, 
males 
10 
Tot: 2190 
Unbound*: 4.4 
Total: 14200 
Unbound*: 28.4 
Total: 19 
Unbound*: 9 
Total: 56 
Unbound*: 28 
Rat, 
females 
15 
Total: 2880 
Unbound*: 5.8 
Total: 29300 
Unbound*: 58.6 
Total: 25 
Unbound*: 12 
Total: 116 
Unbound*: 59 
Dog, 
males 
20 
Total: 11000 
Unbound*: 245 
Total: 20500 
Unbound*: 457 
Total: 94 
Unbound*: 522 
Total: 81 
Unbound*: 457 
Dog, 
females 
20 
Total: 8730 
Unbound*: 193 
Total: 15900 
Unbound*: 355 
Total: 75 
Unbound*: 414 
Total: 63 
Unbound*: 355 
Human, 
predicted 
(5 mg) 
Total: 117 
Unbound*: 0.47 
Total: 253 
Unbound*: 1.0 
NA 
NA 
* For plasma protein binding (PPB), see Section 6.1.4. 
There exists a degree of uncertainty associated with the predictions of human Cmax and AUCinf 
for the proposed starting dose. However, the safety of activating the AT2R has previously 
been evaluated with the AT2R agonist C21 in 3 completed Phase 1 trials (C21-001-16, C21- 
002-16, and C21-003), in 1 completed Phase 2 trial in hospitalised patients with COVID-19 
(VP-C21-006) and in 1 completed Phase 2 trial in patients with Raynaud’s phenomenon 
secondary to SSc (VP-C21-004) with a total of 146 subjects exposed to at least one oral dose 
of C21 in these trials. C21 has a similar potency, selectivity and PPB as C106, and a similar 
PK profile in humans is anticipated. Across the trials, C21 has been well tolerated at single 
and daily oral doses up to 200 mg. Following single oral administration of 200 mg C21, the 
mean Cmax was 4605 ng/mL and mean AUCinf was 5619 ng*h/mL (C21-003). 
The starting dose of 5 mg was considered supported by both the estimated MRSD and 
MABEL. The selection of the starting dose was further supported by the clinical data with the 
analogue AT2R agonist C21, which has been shown to be well tolerated at single and daily 
oral doses of up to 200 mg. 
The actual doses given in Part A for cohorts 1 to 4 were 5, 30, 60 and 180 mg, corresponding 
to dose increment of 6, 2 and 3 times the previous dose. For a summary of the observed 
exposures in cohorts 1 to 4, see Table 8.3-2. The plasma exposure of C106 was lower than 
expected at all dose cohorts evaluated and the doses in Part A were adjusted accordingly. 
The start dose in Part A was selected assuming 100% oral bioavailability and linear 
pharmacokinetics up to 200 mg. In case the systemic exposure following the first cohort was 
appreciably smaller than predicted or below the lower limit of quantification (LLOQ), 
multiple, maximum 6-fold, dose escalations were allowed until the exposure is within the 
predicted range of the trial. 
For further details on the prerequisites for the transition from single to multiple dosing, refer 
to Section 8.3.4. 


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Selection of doses for cohorts 5 and 6 in Part A (SAD) 
Based on the interim PK analysis of cohorts 1 to 4 (Table 8.3-2), the planned doses of C106 in 
cohorts 5 and 6 have been adjusted. The results from the interim PK analysis showed that the 
plasma exposure of C106 was lower than expected and that C106 exhibited a non-linear PK. 
The increase in mean Cmax and AUCinf for cohort A:4 (180 mg) in comparison to cohort A:3 
(60 mg) was 13.2-fold and 7.2-fold, respectively (Table 8.3-2). C106 exhibited a fast 
absorption with a Tmax of 20-40 minutes and the mean Cmax and AUCinf were 2590 ng/mL and 
2244 h*ng/mL, respectively, with a mean T1/2 of approximately 11 hours (Figure 8.3-1). The 
mean margin to the exposure stopping criteria for Part A cohort 4 was at least 3.4-fold for 
Cmax. 
For cohorts 5 and 6, the planned doses are 240 mg and 300 mg, corresponding to dose 
increments of 1.3 and 1.25 times the previous dose, respectively. The dose given in cohort 6 
may be adjusted as recommended by the iSRC following evaluation of emerging safety, 
tolerability, and PK data in cohort 5. Up to 2 additional dose cohorts can be explored based on 
the safety, tolerability, and PK of the drug, if recommended by the iSRC. The iSRC 
recommendation, as well as Sponsor’s decision, will be documented in a non-substantial 
amendment to the clinical trial protocol (CTP). For dose escalation and stopping rules in 
Part A, refer to Table 8.3-3. 
Table 8.3-2 Observed exposure in humans and margin to stopping criteria 
Cohort 
Dose 
(mg) 
N 
Observed Cmax 
(ng/mL) 
Mean (Max) 
Observed AUCinf 
(h*ng/mL) 
Mean (Max) 
Stopping criteria 
Margins 
Cmax 
Mean 
Margins 
AUC 
Mean 
Cmax 
(ng/mL) 
AUC 
(h*ng/mL) 
Cohort 
A:1 
5 
6 
1.65 (2.85) 
20.7 (35.0) 
8730 
15900 
5300 
770 
Cohort 
A:2 
30 
6 
82.3 (156) 
114 (142) 
8730 
15900 
106 
139 
Cohort 
A:3 
60 
6 
196 (278) 
312 (501) 
8730 
15900 
44.5 
51.0 
Cohort 
A:4 
180 
6 
2590 (5130) 
2244 (3280) 
8730 
15900 
3.4 
7.1 


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Figure 8.3-1 Pharmacokinetic mean concentrations for conducted SAD cohorts– logarithmic scale 
C106 (ng/mL) 
 
 
 
 
Maximum exposure and dose 
As discussed in detail in Section 6.3, there is considerable evidence in the literature that the 
infiltration of inflammatory cells in some organs in rats (critical finding for setting the 
NOAEL in rats) is species specific and of no human relevance. This suggest that the 
exposures at NOAEL in dogs are more relevant to set a human exposure limit than the 
NOAEL in rats. 
The highest dose of C106 to be tested in this trial (Part A or Part B) shall, thus, not surpass the 
exposure at NOAEL in the female dog, i.e., a mean value of 8730 ng/mL and 
15900 ng*h/mL for Cmax and AUClast, respectively, see Table 8.3-1. 
The maximum oral dose in Part A and the maximum oral daily dose in Part B will not exceed 
480 mg C106. 
 
 
From single to multiple dosing and rationale for dose escalation Part B 
Following completion of cohort A3 of Part A (SAD), the iSRC will evaluate all available 
safety, tolerability, and PK data up until and including at least 48-hour data from SAD cohort 
A3 and, if necessary, suggest adjustments to dose levels, dosing regimens or dosing duration 
for Part B (MAD) in a written recommendation to the Sponsor. If no safety or tolerability 
concerns have been identified, cohort B1 of Part B (MAD) can be initiated approximately in 
parallel with cohort A4 of Part A (SAD), as decided by the Sponsor. 
In Part B, the initial dose, dose escalations and dosing schedule will be based on emerging 
safety, tolerability, and PK data observed in the SAD part of the trial (Part A) and on 
emerging data from the MAD part. 
The planned dose escalation steps are 40 mg BID, 100 mg BID, 180 mg BID and 240 mg 
BID. In Part B, the dose increments between the dose cohorts will be no more than 3-fold. 


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Each dose level during Part B will be selected such that the predicted steady state AUCtau and 
Cmax will not exceed the maximum exposure (based on AUCinf and Cmax) in previously 
evaluated SAD cohorts. 
 
 
Stopping criteria for dose escalation 
The Principal Investigator and the iSRC (Section 8.3.6) will follow the recommendations and 
grading system of CTCAE v5.0 [40], see Section 11.3.1.7 but also take into account the 
recommendations published by Sibille et al. 2010 [41], which is an adaptation to FIH studies 
of the grading systems previously proposed by National Cancer Institute (NCI) [1], World 
Health Organisation (WHO) [42], National Institute of Health (NIH) [43] and the US Food 
and Drug Administration (FDA) [44]. The grade, the frequency of AEs and the blindness will 
be considered. 
A rolling review of emerging safety data will be performed throughout the trial taking into 
account any AEs, the number of subjects in whom they occur, concurrency of more than one 
event within the same subject and any trends. Changes from baseline measurements will also 
be considered and not just absolute cut-off based on upper- or lower limits of normal that 
might apply for healthy volunteers. 
Trends or safety signals, which are not necessarily covered by the stopping criteria in 
Table 8.3-3 and Table 8.3-4 may warrant the scheduling of ad hoc iSRC meetings after which 
the iSRC will make recommendations to the Sponsor on e.g. whether to terminate the trial or 
to stop dosing in individual subjects or a certain cohort. 
Additional withdrawal criteria are summarised in Section 9.8. 


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Table 8.3-3 Dose escalation and stopping rules in Part A (SAD) 
Stop criterion 
Action taken 
At individual and dose group level 
1 
If 1 on active treatment subject 
has an SAE assessed as related to 
IMP administration 
1. Stop dosing of subject with a potential serious adverse reaction 
(SAR). Await dosing of additional subjects until the iSRC’s 
recommendation and the Sponsor’s decision on continuation. 
2. Unblinding of subject with potential SAR. Only voting members 
of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to 
Sponsor. 
4. Sponsor decides how to proceed: 
The subject received active treatment, i.e., met stopping criterion: 
stop further dosing at this dose level for all subjects. Sponsor decides 
if the trial will be terminated or if dosing will resume at a lower dose 
level. 
2 
If 2 subjects on active treatment 
in the same cohort have severe, 
non-serious AEs assessed as 
related to the IMP administration 
(independent of within or not 
within the same System organ 
class [SOC]). 
1. Stop dosing of subjects with severe, non-serious potential adverse 
reactions. Await dosing of additional subjects until the iSRC’s 
recommendation and the Sponsor’s decision on continuation. 
2. Unblinding of the subjects with potential adverse reactions. Only 
voting members of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to 
Sponsor. 
4. Sponsor decides how to proceed: 
Both subjects received active treatment, i.e., met stopping criterion: 
stop further dosing at this dose level for all subjects. Sponsor decides 
if the trial will be terminated or if dosing will resume at a lower dose 
level. 
3 
If the next planned dose level is 
predicted to result in an exposure 
exceeding either an AUCinf of 
15 900 ng*h/mL or a Cmax of 
8730 ng/mL based on the 
NOAEL in the most sensitive 
non-rodent species (female dog).1 
1. Evaluation by iSRC. The iSRC makes recommendation to 
Sponsor. 
2. Sponsor decides if the trial will be terminated or if dosing in the 
next cohort will resume at a lower dose level. 
Final dosing stop and termination of trial 
4 
If 2 subjects on active treatment 
in different cohorts have SAEs 
assessed as related to IMP 
administration 
1. Stop dosing of subjects with potential SAR. Withdrawal of 
subjects. 
2. Unblinding of subjects with potential SARs. Only voting members 
of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to 
Sponsor. 
4. Sponsor decides how to proceed 
Both subjects received active treatment, i.e., met stop criterion: 
Termination of trial. 
One subject (1) received active treatment, i.e., met stop criterion: See 
stop criterion no. 1. 
1. When reviewing emerging data in relation to this criterion, the maximum exposure observed in individual subjects 
within a cohort rather than the mean exposure should be taken into account. The exposure predictions are normally 
based on the highest observed Cmax and AUCinf/AUCtau in the previous conducted SAD cohort assuming linear kinetics. 
If non-linear PK is observed in previously conducted cohorts, this will also be considered. 


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Table 8.3-4 Dose escalation and stopping rules in Part B (MAD) 
Stop criterion 
Action taken 
At individual and dose group level 
If 1 subject on active treatment has 
an SAE assessed as related to IMP 
administration 
1. Stop dosing of subject with a potential serious adverse reaction 
(SAR). Await dosing of additional subjects until the iSRC’s 
recommendation and the Sponsor’s decision on continuation. 
2. Unblinding of subject with potential SAR. Only voting members of 
the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Sponsor decides how to proceed: 
The subject received active treatment, i.e., met stopping criterion: stop 
further dosing at this dose level for all subjects. Sponsor decides if the 
trial will be terminated or if dosing will resume at a lower dose level. 
If 2 subjects on active treatment in 
the same cohort have severe, non- 
serious AEs assessed as related to 
the IMP administration 
(independent of within or not 
within the same System organ class 
[SOC]) 
1. Stop dosing of subjects with severe, non-serious potential adverse 
reactions. Await dosing of additional subjects until the iSRC’s 
recommendation and the Sponsor’s decision on continuation. 
2. Unblinding of the subjects with potential adverse reactions. Only 
voting members of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Sponsor decides how to proceed: 
Both subjects received active treatment, i.e., met stopping criterion: 
stop further dosing at this dose level for all subjects. Sponsor decides if 
the trial will be terminated or if dosing will resume at a lower dose 
level. 
If 2 subjects on active treatment in 
the same cohort have a grade 2 hair 
loss (≥50% normal for that 
individual that is readily apparent to 
others; a wig or hair piece is 
necessary if the patient desires to 
completely camouflage the hair 
loss; associated with psychosocial 
impact) assessed as related to the 
IMP administration. 
1. Stop dosing of subjects with hair loss. Await dosing of additional 
subjects until the iSRC’s recommendation and the Sponsor’s 
decision on continuation. 
2. Unblinding of the subjects with potential adverse reactions. Only 
voting members of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Sponsor decides how to proceed. 
Both subjects received active treatment, i.e., met stopping criterion: 
stop further dosing at this dose level for all subjects. Sponsor decides if 
the trial will be terminated or if dosing will resume at a lower dose 
level. 
If the next planned dose level is 
predicted to result in an exposure 
exceeding either an AUC0-24 of 
15 900 ng*h/mL or a Cmax of 
8730 ng/mL based on the NOAEL 
in the most sensitive non-rodent 
species (female dog).1 
1. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
2. Sponsor decides if the trial will be terminated or if dosing in the next 
cohort should commence at a lower dose level than intended. 
Final dosing stop and termination of trial 
If 2 subjects on active treatment in 
different cohorts have SAEs 
assessed as related to IMP 
administration 
1. Stop dosing of subjects with potential SAR. Withdrawal of subjects. 
2. Unblinding of subjects with potential SARs. Only voting members 
of the iSRC will be unblinded. 
3. Evaluation by iSRC. The iSRC makes recommendation to Sponsor. 
4. Subjects meet stop criterion: Termination of trial. 
1. When reviewing emerging data in relation to this criterion, the maximum exposure observed in individual subjects 
within a cohort rather than the mean exposure should be taken into account. The exposure predictions are normally 


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based on the highest observed Cmax and AUCinf/AUCtau in the previous conducted cohort assuming linear kinetics. If 
non-linear PK is observed in previously conducted cohorts, this will also be considered. 
 
 
Internal safety review committee 
Before initiating a new dose cohort, all subjects in the previous cohort must have been treated 
and all available safety, tolerability, and plasma concentration data up until and including 
48 hours post dose (Part A, SAD) and 48 hours post last dose (Part B, MAD) must have been 
evaluated by the iSRC. After collection of the last available 48-hour data, there will be at least 
one week between dose escalations in Part A (SAD) and 2 weeks in Part B (MAD). Any 
indication of hair loss emerging after the 48-hour data cut off will be considered by the iSRC 
at the iSRC meeting. In case of dropouts, available data for the dropouts will be included in 
the iSRC evaluation. The iSRC may recommend including replacers (Part B, MAD) to be able 
to make an informed recommendation on the next dose level. 
If C106 is considered safe and tolerable, the iSRC will provide the Sponsor with a written 
recommendation on the next dose level (Part A, SAD) or on the starting dose and subsequent 
dose levels (Part B, MAD) based on the predicted exposure. 
Details regarding timing of iSRC review and the data to be reviewed will be provided in a 
separate iSRC charter. Based on emerging safety and PK information, the amount of safety 
and PK data to be reviewed after a completed cohort might be adjusted. 
The voting members of the iSRC will consist of the Principal Investigator or delegate and the 
Sponsor’s Medical Representative or delegate. In addition, the trial clinical research manager 
(CRM), the trial pharmacokineticist and additional Sponsor representatives will be invited as 
appropriate. Further internal or external experts may be invited and consulted by the iSRC as 
appropriate. 
An adaptive dosing strategy will be applied to allow for a flexible and safe dose escalation. 
The planned dose escalation is outlined in Section 8.3. The actual doses given in each cohort 
will be guided by the iSRC recommendations based on available safety, tolerability and PK 
data. Every dose step is thus adjustable and the recommendation to the Sponsor may be to 
continue with a higher or lower dose than the intended dose, repeat the same dose level, 
continue with an intermediate dose level or to stop dosing. The maximal daily dose in the trial 
will not exceed 480 mg. 
The recommendation of the iSRC on the next dose level will be taken in consensus between 
the iSRC members and documented as appropriate. In case there is disagreement between the 
2 voting members, the most conservative approach will be taken. It is not acceptable to repeat 
a dose level where any of the dose escalation stopping rules have been met. 
The duration of the residential periods in each part may be changed following review of data 
from earlier cohorts. An additional visit for safety and PK sampling may be added if 
considered necessary by the iSRC. Should the duration of any residential period change, 
subsequent changes to the timing of safety and PK assessments will be done as necessary. A 
significantly longer T½ than expected may require a change in the dosing interval, i.e., once 
daily dosing rather than twice daily as currently planned. Should the dosing interval change, 
subsequent changes to the timing of safety and PK assessments will be done as necessary. 
Two optional cohorts may be added in Part A (SAD) and 1 optional cohort may be added in 
Part B (MAD), if recommended by the iSRC. Such changes to the CTP will be documented in 
non-substantial amendments. 


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The treatment code may be broken by the iSRC during the assessment process (partial un- 
blinding) in accordance with stopping criteria described in Section 8.3.6. The medical staff 
and the subjects will still be blinded for the treatments (active drug or placebo) to be 
administered in the subsequent dose groups/cohorts in order to minimise bias. If unblinding 
was considered necessary, the iSRC meeting may consist of a closed part and an open part. 
Only voting members will be unblinded. 


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9 
TRIAL POPULATION 
Prospective approval of protocol deviations to eligibility criteria, also known as protocol 
waivers or exemptions, is not permitted. 
9.1 
Recruitment 
The subjects will be recruited from CTC’s database of healthy volunteers and patients, as well 
as from strategic marketing campaigns. Advertisements in social media and other media 
(newspapers, internet, radio, local distribution of flyers etc.) will be used to reach the target 
audience. The advertisement texts approved by the independent ethics committee (IEC) will 
be used to create all the digital, radio and print material for recruitment. 
9.2 
Screening and enrolment log 
Investigators must keep a record of all screened subjects even if they were not subsequently 
included in the trial. This information is necessary to verify that subjects were selected 
without bias. The reason for screen failure should be stated for all subjects screened but not 
included. The reason for withdrawal should be stated for all subjects included but not 
completed. 
A screening number will be allocated to each subject in connection to the informed consent 
process at the Screening visit. The screening number is generated automatically in the 
electronic case report form (eCRF). The screening number will allow identification of 
subjects irrespective of their possible eligibility for the trial. 
Subjects included and randomised will be assigned a randomisation number (1101, 1102 etc. 
in Part A (SAD), cohort A1 and so on and 2101, 2102 etc. in Part B (MAD), cohort B1 and so 
on). The first digit will correspond to the trial part, the second digit will correspond to the 
cohort and the 3rd and 4th digits correspond to the subject number. 
If a subject cannot receive the planned dose of IMP within 28 days after screening (i.e., the 
time interval between signing informed consent until dose administration) the subject should 
be rescreened before proceeding in the trial. 
9.3 
Number of subjects 
Approximately 160 subjects will be screened (approximately 96 for Part A and 64 for Part B) 
to achieve a total of 80 randomised and dosed subjects. The number may increase if additional 
dose cohorts need to be investigated and/or if recommended by the iSRC. 
Part A: 48 subjects will be randomised and dosed in 6 cohorts (Cohorts A1 to A6, each of 
8 subjects with 6 subjects receiving C106 and 2 subjects receiving placebo). 
Part B: 32 subjects will be randomised and dosed in 4 cohorts (Cohorts B1 to B4, each of 
8 subjects with 6 subjects receiving C106 and 2 subjects receiving placebo). 
If indicated by emerging data and recommended by the iSRC, 2 cohorts (8+8 subjects) may 
be added to Part A and 1 cohort (8 subjects) may be added to Part B. In such cases, and to 
account for potential dropouts, additional subjects might be included in the trial. 
For replacements of subjects who discontinue from the trial, see Section 9.8. 


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9.4 
Inclusion criteria 
For inclusion in the trial, subjects must fulfil the following criteria: 
1. Willing and able to give written informed consent for participation in the trial. The 
signed informed consent should be obtained before initiation of any trial related 
procedures. 
2. Healthy males and healthy females of non-childbearing potential aged 18-65 years 
inclusive. 
3. Body Mass Index (BMI) ≥ 18.5 and ≤ 30.0 kg/m2. 
4. Clinically normal medical history, physical findings, vital signs, ECG, and laboratory 
values at the time of screening, as judged by the Investigator. 
5. Women of non-childbearing potential, defined as pre-menopausal females who are 
sterilized (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females 
who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal 
defined as 12 months of amenorrhea (in questionable cases a blood sample with 
simultaneous detection of follicle stimulating hormone [FSH] ≥ 25 IU/L is 
confirmatory). 
Male subjects must be willing to use condom or be vasectomised or practice sexual 
abstinence to prevent pregnancy and drug exposure of a partner and refrain from 
donating sperm from the date of dosing until 3 months after (last) dosing with the IMP. 
Their female partner of child-bearing potential must use highly effective contraceptive 
methods with a failure rate of < 1% to prevent pregnancy (combined [oestrogen and 
progestogen containing] hormonal contraception associated with inhibition of ovulation 
[oral, intravaginal, transdermal], progestogen-only hormonal contraception associated 
with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD]or 
intrauterine hormone-releasing system [IUS]) from at least 4 weeks prior to dose to 
3 months after last dose. 
9.5 
Exclusion criteria 
Subjects must not enter the trial if any of the following exclusion criteria are fulfilled: 
1. History of any clinically significant disease or disorder which, in the opinion of the 
Investigator, may either put the subject at risk because of participation in the trial, or 
influence the results or the subject’s ability to participate in the trial. 
2. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks 
of the first administration of IMP. 
3. Malignancy within the past 5 years except for in situ removal of basal cell carcinoma. 
4. Any planned major surgery within the duration of the trial. 
5. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C 
antibody and Human Immunodeficiency Virus (HIV). 


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6. After 10 minutes supine rest at the time of screening, any vital signs values outside the 
following ranges: 
• Systolic blood pressure <90 or >140 mmHg, or 
• Diastolic blood pressure <50 or >90 mmHg, or 
• Pulse <40 or >90 bpm 
7. Prolonged QTcF (>450 ms), PR interval < 120 ms or > 240 ms, QRS>115 ms, clinically 
significant cardiac arrhythmias or any clinically significant abnormalities in the resting 
ECG at the time of screening, as judged by the Investigator. 
8. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged 
by the Investigator, or history of hypersensitivity to drugs with a similar chemical 
structure or class to C106. 
9. Regular use of any prescribed or non-prescribed medication including antacids, 
analgesics, herbal remedies, vitamins and minerals within 2 weeks prior to the (first) 
administration of IMP, at the discretion of the Investigator. 
10. Planned treatment or treatment with another investigational drug within 3 months prior 
to Day -1. Subjects consented and screened but not dosed in previous clinical trials are 
not excluded. 
11. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, 
snuffing, chewing tobacco) less than three times per week is allowed before screening 
visit. 
12. Positive screen for drugs of abuse or alcohol at screening or on admission to the unit 
prior to administration of the IMP. 
13. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator. 
14. Presence or history of drug abuse, as judged by the Investigator. 
15. History of, or current use of, anabolic steroids. 
16. Excessive caffeine consumption defined by a daily intake of >5 cups of caffeine 
containing beverages. 
17. Plasma donation within one month of screening or blood donation (or corresponding 
blood loss) during the three months prior to screening. 
18. Investigator considers the subject unlikely to comply with trial procedures, restrictions, 
and requirements. 
9.6 
Restrictions during the trial period 
 
 
General restrictions 
The subjects must be willing to comply to the below restrictions during the entire trial 
duration i.e., from screening to the end-of-trial visit (or longer if specified). 
• Contraception Requirements: The male volunteers are expected to use condom to 
prevent pregnancy and drug exposure of a partners and refrain from donating sperm 
from the date of dosing until 3 months after last dosing of the IMP. Fertile female 
partners are expected to use highly effective contraceptive methods with a failure rate of 


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< 1% to prevent pregnancy from at least 4 weeks prior to dose to 3 months after last 
dose (for details regarding contraceptive methods, refer to inclusion criterion No 5). 
• Meals and Dietary Restrictions: Standardised meals will be served on Day -1 and Day 1 
in Part A (SAD) and on Day -1, Day 1, Day 7 and Day 8 in Part B (MAD). Non- 
standardised meals will be served on the other days. Lunch will be served at least 
4 hours post-dose. Snack, dinner, and optional evening snack will be served 
approximately 7-, 9- and 11-hours post-dose, respectively. 
For details on IMP administration in fasted and fed state, refer to Section 10.5.1. 
Standardised meals: A menu option decided by CTC. The meal selection is standardised 
in the sense that the nutritional content of the meals should be similar at each time point 
of each treatment day. 
• Fasting: In Part A (SAD), the subjects should be fasting overnight (10 hours) before 
Day 1 and until 4 hours post-dose (except in the fed cohort). In Part B (MAD), subjects 
must fast from 2 hours prior to each IMP administration until 1-hour post-dose. Water is 
allowed ad libitum at the clinic except 1 hour before dose and 1 hour after dose. The 
IMP will be taken with water (approximately 240 mL, including the volume of the 
IMP). Subjects participating in Part B, cohort B4 must fast for at least 4 hours prior to 
the EndoPAT assessment until end of assessment. 
• Sun protection: Protection from the sun is required from each C106 administration until 
3 days post dose in Part A and from the first until 3 days after the last C106 
administration in Part B. Study subjects are required to follow the recommendations 
given by Centres for Disease Control and Prevention (CDC, see [45]): 
o Stay in the shade, especially during sun peak hours of 10 AM to 4 PM. 
o Wear clothing that covers arms and legs. 
o Use a hat or cap that shades the face, head, ears, and neck. 
o Wear sunglasses that block both ultraviolet A (UVA) and ultraviolet B (UVB) 
rays 
o Proper use of a broad-spectrum sunscreen with a sun protection factor (SPF) of 
15 or higher. 
o Abstain from use of tanning beds. 
• Alcohol: Consumption of alcohol is not allowed within 48 hours prior to the screening 
visit and all subsequent visits to the clinic including the end-of-trial visit of each part. In 
addition, consumption of alcohol is disallowed during all visits to the clinic. 
• Drugs of abuse: Use of drugs of abuse is not allowed within 48 hours prior to the 
screening visit and during the entire trial duration i.e., from screening to the end-of-trial 
visit. 
• Coffee: Consumption of up to 5 cups of coffee per day will be allowed from screening 
to the end-of-trial visit of each part. 
• Xanthine or taurine containing products/beverages: Energy drinks (e.g., Red Bull) are 
not allowed from screening to the end-of-trial visit of each part. 
• Nicotine: Smoking or use of nicotine-containing products is not allowed from screening 
to the end-of-trial visit of each part. 


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• Grapefruit and grapefruit containing products: Consumption of grapefruit and/or 
grapefruit containing products, Seville oranges is not allowed from screening to the end- 
of-trial visit of each part. 
• Exercise: The subjects must refrain from strenuous exercise for 72 hours before and 
during any visit to the clinic. 
• Blood donation: The subjects must not donate blood or plasma during the trial until 
3 months after the final medical examination at the end-of-trial visit of each part. 
• Participation in other clinical trials: The subjects are not allowed to participate in any 
other interventional clinical trial from screening to the end-of-trial visit of each part. 
• Trial intervention and observation periods: The subjects are not allowed to leave the 
research clinic during residential stays at the research clinic (Visit 2 in both Part A and 
Part B), unless authorised by the trial personnel. 
 
 
Prior and concomitant therapy 
Prohibited medication 
Regular use of any prescribed or non-prescribed medication including antacids, analgesics, 
herbal remedies, vitamin supplements and minerals from 2 weeks prior to the (first) 
administration of IMP at the discretion of the investigator. 
Any use of prescribed or non-prescribed medication including antacids, analgesics, herbal 
remedies, vitamin supplements and minerals from the (first) administration of IMP until the 
end-of trial visit of each part is not allowed except as detailed below. 
Allowed medication 
• Paracetamol in doses up to 2000 mg/day for a maximum of 3 consecutive days. If this 
amount of paracetamol is not sufficient for treatment of the subjects, withdrawal 
should be considered. 
• Nasal decongestants without cortisone, antihistamine or anticholinergics for a 
maximum of 10 days. 
• Hormone replacement therapy. 
Other medications considered necessary for the subject’s safety and wellbeing may be given 
at the discretion of the Investigator during the residential period. Following consultation with 
the Sponsor, the Investigator will determine whether or not the subject should continue in the 
trial. 
9.7 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but do 
not fulfil all eligibility criteria and are not subsequently randomised in the trial. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
subjects. Minimal information includes documentation of signed and dated informed consent 
form (ICF) and reason(s) for screening failure. 


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Re-screening can be performed if any of the following were reasons for screening failure or 
non-randomisation (as judged by the Investigator): 
• Practical reasons. 
• Non-significant medical conditions (e.g., influenza, nasopharyngitis). 
• Reserve subject in previous cohort. 
• Plasma or blood donation outside allowed time windows. 
For subjects who are re-screened, a new screening number will be assigned and a new, signed 
ICF will be collected. 
9.8 
Subject withdrawal 
 
 
General withdrawal criteria 
Subjects are free to discontinue their participation in the trial at any time and for whatever 
reason without affecting their right to an appropriate follow-up investigation or their future 
care. If possible, the reason for withdrawal of consent should be documented. 
Subjects may be withdrawn from the trial at any time at the discretion of the Investigator. 
Reasons for withdrawal include: 
• Subject decision 
• Severe non-compliance to trial protocol procedures, as judged by the Investigator 
and/or Sponsor 
• Subject is lost to follow-up 
• Significant AEs posing a risk for the subject, as judged by the Investigator and/or 
Sponsor 
• Withdrawal of informed consent to the use of biological samples 
• Pregnancy 
• Death 
• Meeting of an exclusion criterion during the trial, which, in the opinion of the 
Investigator, may pose a risk for the subject 
• Use of prohibited medication 
 
 
QTc withdrawal criteria 
A subject meeting the criteria below will be withdrawn from the trial. The same QT 
correction formula will be used to determine discontinuation throughout the trial. 
• QTcF > 500 msec 
• Change from baseline: QTcF > 60 ms 
Withdrawal decisions will be based on an average QTc value of triplicate ECGs. If an ECG 
demonstrated a prolonged QT interval, two more ECGs will be obtained over a brief period 


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and the averaged QTc values of the three ECGs used to determine whether the subject should 
be discontinued from the trial. 
 
 
Liver chemistry withdrawal criteria 
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event aetiology. Trial treatment will be stopped for the individual subject if any 
of the following liver chemistry stopping criteria, defined in the FDA Guidance on Drug- 
Induced Liver Injury [46], is met: 
• Alanine aminotransferase (ALT) 3 x Upper Limit of Normal (ULN) and total bilirubin 
≥ 2xULN (>35% direct bilirubin); or ALT 3xULN and INR > 1.5. 
NOTE: plasma bilirubin fractionation will be performed. 
• ALT 5xULN. 
• ALT 3xULN if associated with symptoms (new or worsening) believed to be related to 
hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness or 
jaundice) or believed to be related to hypersensitivity (such as fever, rash, or 
eosinophilia). 
 
 
Procedures for discontinuation of a subject from the trial 
A subject who prematurely discontinues participation in the trial will always be asked about 
the reason(s) for discontinuation and the presence of any AEs. If a subject withdraws consent, 
the Investigator must ask the subject if he/she is willing, as soon as possible, to be assessed 
according to the procedures scheduled for the end-of-trial visit in each part. Any ongoing AEs 
will be followed as described in Section 11.3.1.15. 
The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final drug accountability must be performed. If the primary reason is an AE, the AE must be 
specified. 
 
 
Subject replacement 
Subjects who are prematurely withdrawn from the trial for any reason except the occurrence 
of AEs assessed as possibly or probably related to trial treatment may be replaced during the 
course of the trial. 
Part A (SAD): subjects who are randomised but not dosed will be replaced. Subjects who are 
dosed will not be replaced. 
In the event of dropouts in the fed cohort, subjects may be replaced to guarantee a full cohort 
size for the food-interaction part of the trial. Any replacers will receive active treatment both 
in the fasted and fed state. 
Part B (MAD): Subjects who are randomised but not dosed will be replaced. Subjects who 
were prematurely withdrawn from the trial for any reason except the occurrence of AEs 
assessed at least possibly related to the IMP may be replaced. 


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9.9 
Randomisation 
On Day 1 of each part, subjects in each cohort will be randomised to receive either C106 
(n=6) or placebo (n=2). Subjects will be randomised in 2 blocks. The first 2 subjects in a 
cohort will be randomised to C106 (n=1) or placebo (n=1). The next subjects will be 
randomised in a 5:1 ratio to receive C106 (n=5) or placebo (n=1). A computer-generated 
randomisation list will be created using SAS Proc Plan, SAS Version 9.4. The randomisation 
list will contain subject number and treatment and will be kept by the randomiser in a sealed 
envelope until database lock. A copy of the randomisation list will be kept by an unblinded 
IMP preparation staff member at the site. 
Sealed individual, treatment code envelopes will be kept at the clinic and at CTC’s 
Pharmacovigilance department (CTC PV) in locked and restricted areas if needed for 
emergency unblinding. 
9.10 Blinding 
This is a double-blind trial, and the allocation of treatments will not be disclosed until clean 
file has been declared and the database has been locked. 
The IMP, i.e., the C106 and the placebo oral solutions, are identical in appearance. Both 
solutions are colourless to yellow. Hence, it is expected that the subjects, Investigator and 
other site personnel will remain unaware of treatment allocation. 
9.11 Emergency unblinding during the trial 
The treatment code may only be broken by the Principal Investigator or delegate in case of 
emergency when knowledge of the treatment received is necessary for the proper medical 
management of the subject. The code breaking procedure should be carefully documented. 
 
 Unblinding for other reasons than emergency 
The treatment code may be broken by the iSRC during the assessment process (partial 
unblinding) to enable their decision on continued dosing of further cohorts or to stop the dose 
escalation. The medical staff and the subjects will still be blinded for the treatments (active 
drug or placebo) to be administered in the subsequent cohorts in order to minimise bias, see 
Section 8.3.6. 
For unblinding procedures in case of a potential suspected unexpected serious adverse 
reaction (SUSAR), see Section 11.3.1.14. 


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10 TREATMENTS 
10.1 Identity of investigational medicinal products 
C106 is a potent and selective nonpeptide AT2R agonist developed by Vicore Pharma. C106 
will be administered as an oral solution. 
The bulk drug product will be provided to the research clinic as: 
• C106 solution for oral administration; 1 mg/mL (25 mL solution in 30 mL amber 
vials) and 10 mg/mL (50 mL solution in 50 mL amber vials). Expressed as salt; 
equivalent to 0.955 mg/mL and 9.55 mg/mL of the free form. 
• Placebo to C106 is a solution for oral administration, manufactured as the drug 
without the active pharmaceutical ingredient. Placebo will be provided in volumes of 
50 mL (50 mL amber vials). 
10.2 Manufacturing, packaging, labelling, and release 
The IMP, including placebo, is manufactured, packaged, labelled, and released by Ardena, 
Ghent, Belgium. 
Trained, unblinded clinical staff will prepare and label the IMP according to the 
randomisation schedule. 
Labels will comply with applicable Good Manufacturing Practice (GMP), with Annex 13 of 
the European Union Good Manufacturing Practice regulations and local regulatory 
requirements. 
The bulk IMP will be shipped to the research clinic (CTC). 
10.3 Conditions for storage 
The bulk drug product will be stored refrigerated at 2 to 8°C in an access-controlled storage 
area at CTC. The finally prepared in-use IMP can be stored at 2 to 8°C for a maximum of 
24 hours. 
Temperature logs will be kept for the area where the IMP is stored. The temperature should be 
noted on a daily basis (working days only unless automatic temperature readings are 
available). 
The drug product must be protected from light. 
10.4 Preparation and accountability 
IMP preparation will be done by trained personnel, i.e., a site pharmacist or a registered nurse, 
in a dedicated room at CTC. There will be two unblinded persons working together, one 
person will handle the IMP and perform the preparation according to the randomisation list 
and the other person will supervise the process. The personnel preparing the IMP will not be 
involved in any other trial activities. 
CTC and the Investigator will maintain a Storage and Accountability Log as well as a Drug 
Dispensing Log detailing the dates and quantities of IMP received, prepared for and used by 
each subject and IMP returned or destroyed at the end of the trial. Any discrepancies between 
prepared and returned IMP must be explained and documented. Products deliberately and/or 
accidentally destroyed by the site or the subject must be accounted for. 


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10.5 Treatment administration 
 
 Treatment administration Part A 
Subjects in Part A (SAD) will be administered a single oral dose of either C106 or placebo as 
randomised. The proposed doses are 5, 30, 60, 180, 240 and 300 mg C106. 
Subjects who participate in the food interaction part will be administered a second single dose 
of either C106 or placebo. Any replacers in the food interaction part will receive C106 and 
will participate in both a fasting and a fed period. 
Part A fasting conditions 
Following an overnight fast of at least 10 hours, subjects will be administered the IMP with 
approximately 240 mL of water (including the volume of the IMP). No food is allowed for at 
least 4 hours post dose. During fasting, water, but no other drinks, is allowed as desired. 
Water is allowed ad libitum at the clinic except 1 hour before dose and 1 hour after dose. The 
IMP will be taken with water (approximately 240 mL, including the volume of the IMP). 
Part A fed conditions (one cohort) 
Following an overnight fast of at least 10 hours, subjects will start a high-fat, high-calorie 
meal 30 minutes prior to administration of the IMP (for details on the breakfast, see below). 
The subjects should eat this meal in 30 minutes or less, however, the IMP should be 
administered 30 minutes after start of the meal. No food is allowed for at least 4 hours post- 
dose. During fasting, water, but no other drinks, is allowed as desired. Water is allowed ad 
libitum at the clinic except 1 hour before dose and 1 hour after dose. The IMP will be taken 
with water (approximately 240 mL, including the volume of the IMP). 
The high-fat, high-calorie breakfast will consist of the following (or equivalent): 2 eggs fried 
in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes 
(118 mL) and 8 ounces (236 mL) of whole milk. Substitutions in this meal can be made as 
long as the meal provides a similar number of calories from protein, carbohydrate, and fat and 
has comparable meal volume and viscosity. The test meal should derive approximately 150, 
250, and 500-600 calories from protein, carbohydrate, and fat, respectively. 
 
 Treatment administration Part B 
Subjects in Part B (MAD) will be administered oral doses of C106, or placebo as randomised 
for 8 consecutive days. The proposed doses are 40, 100, 180 and 240 mg BID for 8 days. 
Subjects will be administered the IMP with approximately 240 mL of water (including the 
volume of the IMP) by clinical staff from Day 1 to 8, i.e., at all dosing occasions. 
The first IMP dose should be taken prior to breakfast and the second dose after 12 hours, on 
all treatment days. On Day 8, only the morning dose will be administered. Fasting is required 
2 hours before and 1 hour after both the morning and evening dose. 
10.6 Continuation of treatment with Investigational Medicinal Product 
This is a Phase 1 trial in healthy volunteers who will have no medical benefit from the 
treatment and thus there will be no treatment with C106 after end of trial participation. 


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10.7 Treatment compliance 
In both Part A and Part B, all IMP will be administered at the research clinic under medical 
supervision to ensure compliance. 
10.8 Return and destruction of investigational medicinal products 
Any unused trial medication and all empty containers will be destructed at the site upon 
confirmation from the Sponsor. The Monitor will perform final IMP accountability 
reconciliation at the trial end to verify that all unused IMP is adequately destroyed and 
documented. 


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11 TRIAL ASSESSMENTS 
The trial assessments are described in the sections below and the timing of these assessments 
are detailed in the schedule of events (Table 8.1-1 and Table 8.1-2 for Part A and Table 8.1-3, 
Table 8.1-4 and Table 8.1-5 for Part B). 
11.1 Recording of data 
The Principal Investigator will provide the Sponsor with all data produced during the trial 
from the scheduled trial assessments. The PI ensures the accuracy, completeness, legibility, 
and timeliness of the data reported to Sponsor in the eCRF and in all required reports. 
It is important that Cardiodynamic ECG and PK blood sampling occurs as close as possible to 
scheduled time. In order to achieve this, the timing priority order at a particular time point is: 
Part A (SAD): 
1. Cardiodynamic ECG/Blood samples for PK 
2. Safety laboratory samples 
3. Safety 12-lead ECG 
4. Vital signs 
Part B (MAD): 
1. Blood samples for PK 
2. PD assessment (cohort B4 only) 
3. Safety laboratory samples 
4. Safety 12-lead ECG 
5. Vital signs 
Time points for PK blood sampling, PD assessment (cohort B4 only), safety laboratory 
samples, 12-lead ECG, and vital signs are outlined in Table 8.1-1 and Table 8.1-2 for Part A 
and in Table 8.1-3, Table 8.1-4 and Table 8.1-5 for Part B. 
For allowed time windows for PK samples, see Section 11.4.1. 
11.2 Demographics and other baseline characteristics 
 
 Informed consent 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 14.3. 
 
 Eligibility criteria 
Eligibility criteria should be checked during screening and verified before randomisation. The 
criteria are specified in Sections 9.4 and 9.5. 
 
 Demographic information 
The following demographic data will be recorded: gender, age, ethnicity, and race. 


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 Weight and height 
Weight and height will be measured without shoes. BMI will be calculated, with one decimal, 
from the height and weight recorded. 
 
 Medical/surgical history 
Medical/surgical history will be obtained by subject interview in order to verify that the 
eligibility criteria are met. 
The medical/surgical history should include all relevant diseases and surgeries prior to 
screening as judged by the Investigator. 
 
 Prior and concomitant medication 
Prior medications taken within 2 weeks will be obtained by subject interview in order to 
verify that the eligibility criteria are met (see also Section 9.6.2). 
Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose) and as concomitant if ongoing on the day of the first dose 
administration, stopped after the first dose administration or started after the first dose 
administration. To distinguish between prior and concomitant medications on Day 1 in each 
part (i.e., the first dosing day), the start time of any newly introduced medication or the stop 
time of any previously ongoing medication must be recorded in the eCRF. 
Any use of concomitant medication from screening until the last end-of-trial visit must be 
documented appropriately in the subject’s eCRF. Relevant information (i.e., name of 
medication, dose, dose form, unit, route, frequency, start and stop dates, reason for use) must 
be recorded. All changes in medication should be noted in the eCRF. 
 
 HIV and Hepatitis B/C 
Subjects will be tested for HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen, hepatitis B 
virus surface antigen and hepatitis C virus antibodies prior to inclusion into the trial. Any 
positive result will exclude the subject from participating in the trial. 
 
 Urine drug screen 
Urine will be screened for drugs of abuse at time points outlined in the schedule of events 
(Table 8.1-1 for Part A and Table 8.1-3 for Part B) using the Drug Screen Multi-12/15 Dip 
Test (Nal von minden) or equivalent. Additional random tests can be performed during the 
trial period. 
 
 Alcohol test 
An alcohol test will be performed at time points outlined in the schedule of events 
(Table 8.1-1 for Part A and Table 8.1-3 for Part B). Additional random tests can be performed 
during the trial period. 


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11.3 Assessments related to primary endpoints 
 
 Adverse events 
The Principal Investigator is responsible for ensuring that all medical staff involved in the 
trial is familiar with the content of this section and the content of the CTC standard operating 
procedures (SOPs) regarding emergencies and FIH studies. 
 
11.3.1.1 Definition of adverse event 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
 
11.3.1.2 Definition of serious adverse event 
An SAE is any AE which: 
• results in death 
• is life-threatening (this refers to a reaction in which the subject was at risk of death 
at the time of the reaction; it does not refer to a reaction that hypothetically might 
had led to death if the reaction was more severe) 
• requires in-subject hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event (IME) (this refers to a reaction that may not be 
immediately life-threatening or result in death or hospitalisation, but may jeopardise 
the subject or may require intervention to prevent any of the other outcomes defined 
above) 
Examples of IMEs are intensive treatment in an emergency room for allergic bronchospasm 
or blood dyscrasias, convulsions that do not result in hospitalisation, development of drug 
dependency, and drug abuse. 
Planned hospitalisations or surgical interventions for a condition that existed before the 
subject signed the ICF and that did not change in intensity are not SAEs. 
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE. 
 
11.3.1.3 Definition of adverse drug reaction 
The term adverse reaction is to be used for all untoward and unintended responses to the IMP 
assessed as related to any dose administered. 
 
11.3.1.4 Definition of serious adverse drug reaction 
The term serious adverse reaction (SAR) is to be used whenever either the Investigator or 
Sponsor or designee assessed the SAE as related to the IMP. 


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11.3.1.5 Definition of suspected unexpected serious adverse reaction 
A SUSAR is any SAE that has a suspected causal relationship with the IMP (assessed as 
related by the Sponsor or Investigator), but the nature of which is not consistent with the 
applicable product information (i.e., the IB). 
 
11.3.1.6 Time period and frequency for collecting adverse events 
All AEs (including SAEs) will be collected from the signing of informed consent until the 
end-of-trial visit of each part. 
Any AE with start date on the day of IMP administration must be recorded with start time. 
At the end-of-trial visit, information on new AEs or SAEs, if any, and stop dates for ongoing 
events must be recorded as applicable. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the trial 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the trial, and he/she considers the event to be 
reasonably related to the trial intervention or trial participation, the Investigator must 
promptly notify the Sponsor. 
 
11.3.1.7 Assessment of intensity 
The grading of the intensity of AEs will follow the CTCAE v5.0 [40]. Grade refers to the 
severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline. 
The Investigator must assess the intensity of an AE using the following definitions, and record 
it on the AE Log in the eCRF: 
 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self- care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self- care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 


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11.3.1.8 
Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and the IMP using the 
definitions below and record it the AE Log of the eCRF: 
 
Related 
There is a reasonable possibility that the AE was caused by the drug. There is a 
reasonable time relationship to drug intake. The AE cannot be explained by 
disease or other drugs. There may or may not be information about de- 
challenge or re-challenge. Disappearance of the AE upon de-challenge 
supports this category. Reappearance upon re-challenge is strongly supportive. 
Not 
related 
There is no reasonable possibility that the event was caused by the IMP. The 
temporal relationship to drug administration makes a causal relationship 
improbable or other drugs or underlying disease or conditions provide 
plausible explanations. 
Not 
applicable 
This assessment can be used e.g., in cases where the subject did not 
receive any treatment with IMP. 
 
11.3.1.9 Assessment of outcome 
The Investigator must assess the outcome of an AE using the definitions below and record 
it on the AE Log of the eCRF: 
 
Recovered/resolved 
The subject has recovered completely, and no symptoms remain. 
Recovering/resolving The subject’s condition is improving, but symptoms still remain. 
Recovered/resolved 
with sequelae 
The subject has recovered, but some symptoms remain (for 
example, the subject had a stroke and is functioning normally but 
has some motor impairment). 
Not recovered/not 
resolved 
The subject’s condition has not improved, and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic). 
Fatal 
Unknown 
 
11.3.1.10 Reporting of action taken with trial treatment 
The Investigator must report the action taken with trial treatment using the definitions 
below and record it on the AE Log of the eCRF: 
 
Dose increased 
Not applicable for the present trial 
Dose not changed 
Dose rate reduced 
Not applicable for the present trial 
Dose reduced 
Not applicable for the present trial 
Drug interrupted 
Not applicable for the present trial 
Drug withdrawn 
Not applicable 
Unknown 
Not applicable for the present trial 


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11.3.1.11 Collecting adverse events 
AEs identified using any of the following methods will be recorded: 
• AEs spontaneously reported by the subject 
• AEs observed by the Investigator or medical personnel 
• AEs elicited based on non-leading questions from the Investigator or medical 
personnel 
 
11.3.1.12 Recording adverse events 
AEs must be recorded in the AE Log of the eCRF. The Investigator must provide 
information on the AE, preferably with a diagnosis or at least with signs and symptoms; 
start and stop dates, start and stop time; intensity; causal relationship to IMP; action taken, 
and outcome. 
If the AE is serious, this must be indicated in the eCRF. 
AEs, including out-of-range clinically significant clinical safety laboratory values, must be 
recorded individually, except when considered manifestations of the same medical condition 
or disease state; in such cases, they must be recorded under a single diagnosis. 
 
11.3.1.13 
Reporting of serious adverse events 
SAE reporting should be performed by the Investigator within 24 hours of awareness via the 
eCRF. All available information regarding the SAE should be entered in the eCRF SAE form 
(i.e., term, intensity, causality, outcome, SAE criteria, action taken, narrative including 
rational for causality assessment). for the specific subject. By saving the event as “serious” in 
the eCRF and once the Investigator has signed-off of the event, an e-mail alert is 
automatically sent to predefined recipients to highlight that an SAE has been registered. The 
same information is automatically sent to: sae@ctc-ab.se. 
The SAE report is reviewed by a designated person at CTC’s Pharmacovigilance (CTC PV) 
department to ensure that the report is valid and correct. For fatal or life-threatening SAEs 
where important or relevant information is missing, immediate follow-up is undertaken and 
queries to the site are raised. Investigators or other site personnel should inform CTC PV of 
any follow-up information (including rational for changes, e.g., changes in causality 
assessment and intensity, that should be described in the SAE narrative) on a previously 
reported SAE immediately but no later than within 24 hours of awareness. 
If the SAE report in the eCRF is updated and signed by the Investigator, a new e-mail alert 
will be sent. 
If any additional documentation is required (e.g., autopsy report), CTC PV will request this 
information from the trial site. 
In case the eCRF cannot be accessed, the SAE should be reported by manual completion of 
the paper SAE Form, provided in the Investigator Site File (ISF). The completed, signed and 
dated paper SAE Form should, within 24 hours, be scanned and delivered via encrypted e- 
mail secure file transfer to CTC’s SAE inbox at sae@ctc-ab.se. 
A copy of the paper SAE form must also be e-mailed to CTC at: sae@ctc-ab.se. 


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The trial site should notify the site Monitor via phone or e-mail about the submission of the 
SAE report. As soon as the site personnel have access to the eCRF, the SAE should be 
reported electronically as well. 
The Sponsor has delegated to CTC the responsibility to report SAEs to the competent 
authority (CA) and IEC in accordance with local regulations. 
 
11.3.1.14 Reporting of SUSARs to EudraVigilance, local CA and IEC 
The term SAR is used whenever either the Investigator or Medical Monitor deems a blinded 
SAE as related to IMP. If a SAR is assessed as unexpected based on the reference safety 
information (RSI)/IB, it is a potential SUSAR and under such circumstances an 
EudraVigilance reporter will be unblinded. In case the event is regarded as a SUSAR the 
EudraVigilance reporter will report the SUSAR to the CA, via the EudraVigilance database, 
and to the IEC in accordance with local regulations and CTC SOPs within the following 
timelines: 
• 7 calendar days if fatal or life-threatening 
• 15 calendar days if non-fatal and non-life-threatening 
The clock for expedited initial reporting (Day 0 = Di 0) starts as soon as the information 
containing the minimum reporting criteria has been received by the Sponsor. The date should 
be documented on an acknowledgement receipt. 
The Medical Monitor is responsible for medical review of the SAE narrative in the Council 
for International Organisations of Medical Sciences (CIOMS) form (or equivalent) prior to 
expedited reporting. The CIOMS form will be reviewed and approved by the Sponsor’s 
Medical Representative, including expectedness and causality assessment. 
The Sponsor has delegated to CTC the responsibility to inform the Investigators concerned of 
relevant information about SUSARs that could adversely affect the safety of subjects. 
The Sponsor or delegate is responsible for, once a year throughout the clinical trial (or on 
request), submitting a safety report to the CA and the IEC taking into account all new 
available safety information received during the reporting period. 
 
11.3.1.15 Treatment and follow-up of adverse events 
Subjects with AEs that occur during the trial must be treated according to daily clinical 
practice at the discretion of the Investigator. 
AEs must be followed up until they have reached a “final outcome” (recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving, not recovered/not resolved/ongoing, 
fatal, or unknown) or the subjects’ participation in the trial ends, whichever comes first. At 
the end-of-trial visit, information on new AEs, if any, and stop dates for previously reported 
AEs must be recorded (if known). AEs assessed as stable by the Investigator at the end-of- 
trial visit will not have to be followed up until resolution. 
It is the responsibility of the Investigator to follow up on all SAEs until the subject has 
reached a “final outcome” or the subjects’ participation in the trial ends, whichever comes 
first. 
SAEs and severe, non-serious AEs assessed as “Related” to IMP, still ongoing after the trial 
participation has ended, should be followed on a regular basis according to the Investigator’s 


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clinical judgment until a “final outcome” has been established and to report to the Sponsor all 
relevant new information using the same procedures and timelines as those for the initial 
report. Relevant information includes discharge summaries, autopsy reports, and medical 
consultation. 
 
11.3.1.16 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy of any female partners of male 
subjects, the outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth or congenital abnormality) must be followed up and documented even after the 
end of the subject’s trial participation. Pregnancy itself is not regarded as an AE unless there 
is a suspicion that the IMP may have interfered with the effectiveness of the contraceptive 
medication. 
All events of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages 
should also be reported and handled as AEs. All outcomes of pregnancy must be reported to 
the Sponsor and the Principal Investigator on the pregnancy outcomes report form. 
 
11.3.1.17 Treatment of overdose 
An overdose is a dose in excess of the dose specified for each cohort in this CTP. 
Over-dosing is not likely to occur in this trial since all IMP will be administered by site 
personnel under medical surveillance. In cases of accidental overdose, standard supportive 
measures should be adopted as required. 
An overdose should be documented as follows: 
• An overdose with associated AE is recorded as the AE diagnosis/symptoms in the AE 
Log of the eCRF. 
• 
An overdose without associated symptoms is reported in the subject’s medical records. 
In addition, any overdose will be recorded as a protocol deviation. 
No known antidote is available. 
 
 Electrocardiogram 
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG 
machine. Heart rate (HR) and PR, QRS, QT and QTcF intervals will be recorded. 
Safety ECGs will be reviewed and interpreted on-site by the Investigator. 
Any abnormalities will be specified and documented as clinically significant or not clinically 
significant. Abnormal post-dose findings assessed by the Investigator as clinically significant 
will be reported as AEs. 
For timing of assessments, refer to Table 8.1-1to Table 8.1-5. 


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 Telemetry 
Ambulatory ECG telemetry will be used for cardiac surveillance up to 24 hours after IMP 
administration in Part A (SAD). 
Telemetry will be reviewed on-site by the Investigator and judged as normal, abnormal not 
clinically significant or abnormal, clinically significant. If judged as abnormal, clinically 
significant, a print-out will be saved for documentation. Abnormal post-dose findings 
assessed by the Investigator as clinically significant will be reported as AEs. 
 
 Vital signs 
At visits and time points outlined in Table 8.1-1 and Table 8.1-2 (Part I) and in Table 8.1-3, 
Table 8.1-4 and Table 8.1-5 (Part II), systolic and diastolic blood pressure (BP) and pulse will 
be measured in supine position after 10 minutes of rest. Respiratory rate will be assessed. 
Body temperature will be measured using a digital thermometer on Day -1 of each part. 
Any vital signs outside the normal ranges will be judged as not clinically significant or 
clinically significant. The assessment will be recorded in the eCRF. Abnormal post-dose 
findings assessed by the Investigator as clinically significant will be reported as AEs. 
 
 Laboratory safety assessments 
Blood samples for analysis of clinical chemistry, haematology, and coagulation parameters 
will be collected through venepuncture or an indwelling venous catheter and sent to the 
certified clinical chemistry laboratory at Uppsala University Hospital and analysed by routine 
analytical methods. 
Urinalysis will be performed at the research clinic using dipsticks. The assessments will be 
performed at visits specified in (Table 8.1-1 for Part A and Table 8.1-3 for Part B). In 
addition, urine sampling for analysis of the albumin/creatinine ratio will be performed at all 
visits where blood sampling for safety laboratory analysis is planned. 
The safety laboratory parameters are defined in Table 11.3-1 and will be assessed at time- 
points detailed in (Table 8.1-2 for Part A and Table 8.1-4 and Table 8.1-5 for Part B). 
Any lab values outside the normal ranges will be judged as not clinically significant or 
clinically significant. The assessment will be recorded in the eCRF. Abnormal post-dose 
findings assessed by the Investigator as clinically significant will be reported as AEs. 
Table 11.3-1 Safety laboratory parameters 
Category 
Parameter 
Clinical chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Aldosterone 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bilirubin (total and conjugated) 
Calcium 
C-reactive protein (CRP) 
Creatinine (eGFR included) 


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Category 
Parameter 
Glucose 
Phosphate 
Potassium 
Sodium 
Urea (nitrogen) 
Haematology 
Haematocrit 
Haemoglobin (Hb) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential count 
Coagulation 
Activated Partial Thromboplastin Time (APTT) 
Prothrombin Complex International Normalised Ratio (PK[INR]) 
Urinalysis (dipstick) 
Erythrocytes 
Glucose 
Ketones 
Leucocytes 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Urinalysis (safety urine 
sample) 
Albumin/creatinine ratio 
FSH-test (at screening, 
postmenopausal 
females, questionable 
cases only) 
Follicle stimulating hormone (FSH) 
 
 Physical examination 
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, neurological, lungs, cardiovascular, and abdomen. 
Any abnormalities will be specified and documented as clinically significant or not clinically 
significant. Abnormal post-dose findings assessed by the Investigator as clinically significant 
will be reported as AEs. 
11.4 Assessments related to secondary endpoints 
 
 Pharmacokinetic blood sampling and analysis 
Venous blood samples (approximately 5 mL) for the determination of plasma concentrations 
of C106 after administration of the IMP, will be collected through an indwelling venous 
catheter at the pre-specified time-points Table 8.1-2 for Part A and Table 8.1-4 and 


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Table 8.1-5 for Part B). Actual time for blood PK sampling must not deviate more than ±10% 
from the planned time except as detailed below. 
Pre-dose sampling before the first dose in any Part, may be performed within 60 minutes prior 
to dosing. 
The 24-hour and 48-hour samples in Part A should be taken within ±2 hours of the planned 
sampling time point. 
Pre-morning dose sampling on Days 2 to 8 in Part B (MAD) must be performed immediately 
(within 5 minutes) before dosing. 
The date and time of collection of each sample will be recorded in the eCRF. 
Samples for determination of plasma concentrations of C106, will be analysed by Lablytica 
Life Science AB, Uppsala by means of a validated bioanalytical method. The details of the 
analytical method used will be described in a separate bioanalytical report. 
Details on sample collection and handling will be provided in a separate laboratory manual. 
 
 Urine sampling for analysis of C106 
Urine collection for the determination of C106 will be performed in Part A and in Part B 
(Day 1 and Day 8). In Part A, urine will be collected at visits and time intervals presented in 
Table 8.1-2. In Part B, urine will be collected at visits and time intervals presented in 
Table 8.1-4 and Table 8.1-5. 
The volume of urine will be determined by total weight and documented in the eCRF. The 
date and time interval of each collection (start and stop time) will be recorded in the eCRF. 
Three urine aliquots (5 mL) from each collection interval and pre-dose samples will be 
transferred to pre-labelled polypropylene cryotubes and will thereafter immediately be frozen 
at -70°C until analysed. 
Samples for determination of urine concentrations of C106, will be analysed by Lablytica Life 
Science AB, Uppsala by means of a qualified bioanalytical method. The details of the 
analytical method used will be described in a separate bioanalytical report. 
Details on sample collection and handling will be provided in a separate laboratory manual. 
11.5 Assessments related to exploratory endpoints 
 
 Metabolite-In-Safety Testing 
Blood sampling for future analysis of C106 metabolites will be performed at steady state in 
Part B (MAD), i.e., from Day 8. The collection of these samples is described in 
Section 11.4.1. The same samples constitute an aliquot of separated plasma (750 µL) 
generated from each PK sample. Metabolite sampling will be performed at visits presented in 
Table 8.1-4 and Table 8.1-5. 
Details on sample collection and handling will be provided in a separate laboratory manual. 
 
 Profile of excreted metabolites in the urine 
Urine sampling (an aliquot of 5 mL urine taken from the PK urine samples) for future analysis 
of excreted C106 metabolites in the urine will be performed at steady state in Part B (MAD), 


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i.e., Day 8. The collection and handling of these samples are described in section 11.4.2 at 
visits presented in Table 8.1-3. 
Details on sample collection and handling will be provided in a separate laboratory manual. 
 
 Cardiodynamic ECG 
Twelve (12)-lead ECGs will be extracted from continuous recordings prior to and serially 
after dosing at time points presented in the schedule of events for Part A of the trial 
(Table 8.1-3). Continuous ECG recordings will be performed for 25 hours, starting 1 hour 
prior to dose administration and baseline ECGs will be extracted at 3 time points before 
dosing (-45, -30 and -15 minutes). Subjects will be supinely resting for at least 15 minutes 
prior to each time point for PK sampling. 
The 12-lead Holter and ECG equipment will be supplied and supported by Clario. All ECG 
data will be collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG 
continuous 12 lead digital recorder. The continuous 12-lead digital ECG data will be stored 
onto SD memory cards. ECGs to be used in the analyses will be selected by pre-determined 
time points 5 minutes before each PK sample is drawn as defined in the schedule of events 
(Table 8.1-3) and may be read centrally by Clario. 
If a decision is made to analyse data at the Clario core laboratory, a specific analysis protocol 
will be developed in accordance with accepted standards for EPQT. 
 
 Pharmacodynamic assessment (Part B, cohort B4) 
The PD effect on endothelial function will be assessed by EndoPAT at visits and time points 
specified in the schedule of events for Part B of the trial (Table 8.1-3 and Table 8.1-4) 
according to the manufacturer’s instructions. The EndoPAT assessments should be done at 
approximately the same time of the day on both occasions. 
The EndoPAT assessment will be conducted in a quiet and relaxed atmosphere. Before 
initiating the assessment, the subject will be supine for at least 15 minutes. The subjects will 
be instructed to remain as still as possible during the assessment period. EndoPAT bio sensors 
will be placed on the subjects right and left index fingers. If this finger is unsuitable (e.g., 
finger is cut or injured), a different finger may be used as long as the same finger is used on 
both hands. The same finger should preferably be used at both assessments. A cuff will be 
placed on the nondominant upper arm for occlusion of the brachial artery. 
Each recording will consist of a 5-minute baseline assessment, a 5-minute occlusion 
assessment, and 5-minute post-occlusion assessment. During the post-occlusion period, blood 
flow is restored causing an endothelium-dependent vasodilation. 
The EndoPAT software, provided with the device, will calculate the RHI and AI scores using 
a computerised automated algorithm as outlined below. The results will be recorded in the 
eCRF. 
• RHI score: post-to-pre occlusion pulse amplitude tonometry signal ratio in the 
occluded arm relative to the same ratio in the control arm, and corrected for baseline 
vascular tone. RHI is a measure of endothelial function. 


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• AI: calculated from pulse amplitude tonometry pulses at the baseline period. AI is a 
measurement of vascular stiffness and reflects the structural nature and basal tonus of 
the vessel. 
The time points of the initiation and completion of the EndoPAT assessment, the arm 
occluded, the fingers assessed and any significant deviations from the instructions for use will 
be recorded in the eCRF. 
11.6 Appropriateness of measurements 
The stopping rules for dose escalation used (see Section 8.3.4) follows the recommendations 
and grading system of CTCAE v5.0 [40] but also take into account the recommendations 
published by Sibille et al 2010 [41], which is an adaptation to FIH studies of the grading 
systems previously proposed by NCI [1], WHO [42], NIH [43] and FDA [44]. 
EndoPAT is an FDA-cleared, non-invasive device commonly used to assess endothelial 
function. 
All other methods used for safety assessments are commonly used in standard medical care 
and in Phase 1 clinical trials. Non-compartmental analysis (NCA) of PK parameters is 
standard for Phase 1 clinical trials. 


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12 PROCEDURES FOR BIOLOGICAL SAMPLES 
12.1 Sample collection 
The sample collection procedure for PK analysis is described in Section 11.4.1. 
Safety laboratory samples are collected according to standard procedures. 
12.2 Volume of blood 
The anticipated volume of blood samples collected during the trial from each subject will not 
exceed 450 mL (i.e., less than the volume drawn during a regular blood donation). 
Estimated blood volumes to be collected are presented in Table 12.2-1. 
Table 12.2-1 Estimated blood volumes 
Category 
Estimated 
number of 
sampling 
occasions 
Estimated volume 
per occasion 
Estimated 
total 
volume 
Part A 
Clinical chemistry, haematology, coagulation1 
5 
14 mL 
70 mL 
Aldosterone 
5 
4 mL 
20 mL 
HIV, Hepatitis B/C 
1 
4 mL 
4 mL 
PK sampling 
14 
5 mL 
70 mL 
Total: 
164 mL 
Part B 
Clinical chemistry, haematology, coagulation 
7 
14 mL 
98 mL 
Aldosterone 
7 
4 mL 
28 mL 
HIV, Hepatitis B/C 
1 
4 mL 
4 mL 
PK sampling 
32 
5 mL 
160 mL 
Total: 
290 mL 
1. FSH test in females only (questionable cases), estimated volume: 4 mL. 
 
12.3 Handling, storage and destruction of laboratory samples 
All biological samples will be stored in a biobank at CTC (Biobank #893). 
Any remains from the safety laboratory samples will be disposed of after analyses. 
The samples for analyses of PK (blood and urine) and metabolites will be stored at <-70°C 
until analysed. The PK samples will be disposed of after the CTR has been finalised. The 
samples for MIST analysis will be sent to Admescope, Södertälje, Sweden. The MIST 
samples will be disposed once analysed but may be stored for a maximum of 10 years prior to 
analysis. 


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12.4 Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
CTC keeps full traceability of collected biological samples from the subjects while in storage 
at the research clinic until shipment and keeps documentation of receipt of arrival. 
The sample receiver (the analytical laboratory) keeps full traceability of the samples while in 
their storage and during use until used or disposed of. 
The Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring 
of trial sites, and auditing of external laboratory providers. 
12.5 Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of biological samples donated, the samples will be 
disposed of/destroyed, if not already analysed and documented. 
The Principal Investigator will ensure that: 
• Subject withdrawal of informed consent is notified immediately to Sponsor. 
• Biological samples from the subject if stored at the research clinic, are immediately 
identified, disposed of/destroyed and the action is documented. 
The Sponsor has to ensure that the laboratory holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed or returned to the 
research clinic and the action is documented. 


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13 QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL 
13.1 Quality management: critical process, system and data identification 
During CTP development, the Sponsor will identify those processes, systems (facilities, 
computerised systems), and data that are critical to ensure human subject protection and the 
reliability of trial results according to applicable SOPs and International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 R2. 
Identified risks, including risks associated with the COVID-19 (coronavirus disease 2019) 
pandemic, will be categorised separately from the CTP. 
In relation to the COVID-19 pandemic, trial conduct/procedures including e.g., monitoring, 
AE reporting, safety monitoring, changes in investigators and key trial team staff and quality 
assurance (QA) activities may need to be reassessed and temporary, alternative proportionate 
mechanisms of trial conduct/procedures may be required. All changes to the original plan will 
be documented. 
13.2 Quality assurance and quality control 
The Sponsor is responsible for implementing and maintaining QA and quality control (QC) 
systems with written SOPs with regards to management of identified risks, CTP compliance, 
good clinical practice (GCP) compliance and applicable regulatory requirements. 
The Sponsor is responsible for securing agreements with involved subcontractors and to 
perform regular subcontractor oversight to ensure CTP compliance, GCP compliance, and 
compliance with applicable regulatory requirements. 
The Sponsor is responsible for implementing a risk-based validated electronic data capture 
system and maintain SOPs for the whole life cycle of the system. 
QC should be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly. 
The Sponsor has delegated the responsibilities outlined above to CTC whilst maintaining 
overall trial oversight. 


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14 ETHICAL AND REGULATORY REQUIREMENTS 
14.1 Ethical conduct of the trial 
The trial will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [47] and are consistent with the ICH E6 (R2) guideline for GCP [48], 
the EU Clinical Trials Directive 2001/20/EC [49], and applicable local regulatory 
requirements. 
14.2 Ethics and regulatory review 
The Principal Investigator is responsible for submission of the CTP, the subject information 
and ICF, any other written information to be provided to the subjects, and any advertisements 
used for recruitment of subjects to applicable IEC for approval. 
The Sponsor is responsible for submission of trial documents to the applicable Competent 
Authorities (CAs) according to local regulatory requirements. 
Approval must be obtained in writing from both IEC and CA before the first subject can be 
recruited. 
The Sponsor will provide the CA, IEC, and Principal Investigators with safety updates/reports 
according to local requirements. Progress reports and notifications of SUSARs will be 
provided to the IEC according to local regulations and guidelines. 
14.3 Subject information and consent 
It is the responsibility of the Investigator or an authorised associate to give each potential trial 
subject adequate verbal and written information before any trial specific assessments are 
performed. 
The information will include the objectives and the procedures of the trial as well as any risks 
or inconvenience involved. It will be emphasized that participation in the trial is voluntary and 
that the subject may withdraw from participation at any time and for any reason, without any 
prejudice. All subjects will be given the opportunity to ask questions about the trial and will 
be given sufficient time to consider participation before signing the ICF. 
Before performing any trial-related procedures the ICF must be signed and personally dated 
by the subject by the Investigator. A copy of the subject information including the signed ICF 
will be provided to the subject. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the eCRF. The subject information sheet and the signed ICF 
should be filed by the Investigator for possible future audits and/or inspections. 
The final approved version of the subject information and ICF must not be changed without 
approval from the Sponsor and the applicable IEC. 


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14.4 Subject participation card 
The subject will be provided with a Subject participation card including the following 
information: 
• That he/she is participating in a clinical trial 
• Subject trial ID 
• That he/she is treated with the IMP 
• The name and phone number of the Investigator 
• Name and address of the Sponsor 
14.5 Subject data protection 
The ICF includes information that data will be recorded, collected and processed and may be 
transferred to European Economic Area (EEA) or non-EEA countries. In accordance with the 
European Union general data protection regulation (GDPR), Regulation (EU) 2016/679 [50] 
the data will not identify any persons taking part in the trial. 
The potential trial subject should be informed that by signing the ICF he/she approves that 
authorized representatives from Sponsor and CTC, the concerned IEC and CA have direct 
access to his/her medical records for verification of clinical trial procedures. For further 
details on the subject information and ICF process, refer to Section 14.3. 
The subject has the right to request access to his/her personal data and the right to request 
rectification of any data that is not correct and/or complete in accordance with the GDPR 
(EU) 2016/679 and the request will be raised to the Principal Investigator. 
The Investigator must file a Subject Identification List which includes sufficient information 
to link records, i.e., the eCRF and clinical records. This list should be preserved for possible 
future inspections/audits but must not be made available to the Sponsor except for monitoring 
or auditing purposes. 
Personal data that are collected in the trial such as health information and ethnicity are 
considered as sensitive personal data. This data will be pseudonymised, i.e., personally 
identifiable information (PII) will be removed and replaced by a unique subject ID and will be 
processed by the Sponsor and other involved parties during the trial. 
For this trial, the Sponsor is the data controller of all data processed during the trial (e.g., Trial 
Master File [TMF], trial reports) and CTC AB is the data processor. Any subcontractors used 
in the trial, are also data processors. 
For data that are processed at the clinic(s) (e.g., medical records and ISF), CTC AB is the data 
controller. 
14.6 Changes to the approved clinical trial protocol 
Any proposed change to the approved final CTP (including appendices) will be documented 
in a written and numbered clinical protocol amendment. All substantial amendments to the 
protocol must be approved by the appropriate IEC and/or CA before implementation 
according to applicable regulations. 


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14.7 Audits and inspections 
Authorised representatives of Sponsor, a CA, or an IEC may perform audits or inspections at 
the research clinic, including source data verification (SDV). The purpose of an audit or 
inspection is to systematically and independently examine all trial-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, ICH-GCP guidelines and any 
applicable regulatory requirements. The Investigator will contact the Sponsor immediately if 
contacted by a CA about an inspection at the centre. The Investigator will provide direct 
access to source data and documents in case of audits and inspections. 
14.8 Insurance 
Subjects will be covered under a liability insurance policy through the Swedish 
Pharmaceutical Insurance (Läkemedelsförsäkringen). The certificate of insurance and an 
information leaflet containing essential information about the insurance coverage can be 
provided upon request. The participating subjects are also protected in accordance with 
national regulations, as applicable. CTC has a company insurance covering services 
performed by CTC. 


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15 TRIAL MANAGEMENT 
15.1 Training of trial site personnel 
Before enrolment of the first trial subject a Sponsor representative or delegate will perform a 
site initiation visit at the research clinic. The requirements of the CTP and related documents 
will be reviewed and discussed, and the investigational staff will be trained in any trial 
specific procedures and system(s) utilised. 
It is the responsibility of the Investigator to ensure that all personnel involved in the trial are 
fully informed of all relevant aspects of the trial and have a detailed knowledge of and 
training in the procedures that are to be executed by them. Any new information of relevance 
to the performance of this trial must be forwarded to the staff involved in a timely manner. 
The Investigator will keep a list of all personnel involved in the trial together with their 
function and trial related duties delegated. A Curriculum Vitae will be available for all staff to 
whom trial-specific duties are delegated. 
15.2 Clinical monitoring 
The Sponsor is responsible for securing agreement from all involved parties to ensure direct 
access to all trial related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities. The Investigator will permit trial related monitoring providing direct access to 
source data and documents. 
As defined in the risk-based monitoring (RBM) plan, approved by the Sponsor and provided 
separately, the responsible Monitor will periodically visit the trial site at times agreed upon by 
the Investigator and the Monitor. Adaptations related to the on-site monitoring plan, when it is 
impossible or inappropriate to follow due to the COVID-19 pandemic, may be required such 
as supplementation with (additional/increased) centralised monitoring and central review of 
data if considered possible and meaningful. Results of adjusted monitoring/review measures 
should be reported to the Sponsor in monitoring reports and in the CTR. At the time of each 
monitoring visit, the role of the Monitor is (but not limited to) to: 
• provide information and support to the investigational team. 
• confirm that facilities and resources remain acceptable. 
• confirm that the investigational team is adhering to the CTP, applicable SOPs, 
guidelines, manuals and regulatory requirements. 
• verify that the correct informed consent procedure has been adhered to for participating 
subjects 
• verify that data are being accurately and timely recorded in the eCRFs and that IMP 
accountability checks are being performed. 
• verify that data in the eCRF are consistent with the clinical records (SDV) in 
accordance with the RBM plan. 
• ensure that withdrawal of informed consent to the use of the subject’s biological 
samples will be reported and biological samples are identified and disposed 
of/destructed accordingly, and that this action is documented and reported to the 
subject. 


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• verify that AEs are recorded and reported in a timely manner and according to the CTP. 
• raise and escalate any serious quality issues, serious GCP breach, and any data privacy 
breach to the Sponsor. 
Centralised monitoring will also be performed continuously by trial team members at CTC in 
accordance with the RBM plan. 
When the trial has been completed and all queries have been resolved and the database has 
been locked, the Monitor will perform a close-out visit. 
15.3 Source data documents 
A separate Origin of Source Data List will be generated for each site before start of 
enrolment, specifying the location of the source of derived information appearing in the 
eCRF. This document must be signed by the Principal Investigator and the Monitor to confirm 
agreement before start of recruitment. 
Source documents are all documents used by the Investigator or hospital that relate to the 
subject’s medical history, that verifies the existence of the subject, the inclusion and exclusion 
criteria, and all records covering the subject’s participation in the trial. They include 
laboratory notes, memoranda, material dispensing records, subject files, etc. The eCRF may 
constitute source data if clearly defined in the Origin of Source Data List. 
The Investigator should guarantee access to source documents to the Monitor, CAs, and the 
IECs, if required. 
15.4 Trial agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Trial Agreement for this trial. 
Agreements between Sponsor and CTC must be in place before any trial-related procedures 
can take place, or subjects be enrolled. 
15.5 Trial timetable and end of trial 
The trial is expected to start in Q2 2022 and to be completed by Q3 2023. 
A subject is considered to have completed the trial if he/she has completed all visits in the 
trial including the end-of-trial-visit. 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
15.6 Termination of the trial 
The Investigator or the Sponsor may terminate this trial prematurely for any reasonable cause. 
The IEC and CA should be informed promptly. Conditions that may warrant trial termination 
include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the trial or potential trial subjects; or 
• A decision by the Sponsor to suspend or discontinue development of the IMP. 
• If the CA obtains information that raises doubts about the safety or scientific validity 
of the clinical trial, the CA can suspend or prohibit the trial. Before the CA reaches its 
decision, it shall, except where there is imminent risk, ask the Sponsor and/or the 


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Investigator for their opinion, to be delivered within 1 week (Directive 2001/20/EC, 
Article 12, Section 1). 
If the trial is prematurely terminated or suspended for any reason, the Investigator/institution 
should promptly inform the trial subjects and should assure appropriate follow-up for the 
subjects. 
15.7 Reporting and publication 
 
 Clinical trial report 
A summarising report must be submitted to the applicable CA and IEC within 12 months after 
completion of the trial (in accordance with LVFS 2011:19, Chapter 9). 
A CTR in compliance with ICH-E3, describing the conduct of the trial, any statistical 
analyses performed and the results obtained, will be prepared by CTC. The report will be 
reviewed and approved by, as a minimum, the Principal Investigator, the Statistician and the 
Sponsor. The trial results will be reported in the EudraCT database per applicable regulations 
within 12 months after completion of the trial. 
All data obtained from any exploratory analyses will be reported separately. 
 
 Annual safety report 
If the trial duration exceeds one year, the Sponsor must submit development safety update 
report (DSUR) to the CA and to the IEC. The report shall summarise all pertinent safety 
information collected during the reporting period and contain an update of the risk-benefit 
evaluation if there has been any change since the approval of the clinical trial. 
 
 Confidentiality and ownership of trial data 
Any confidential information relating to the IMP or the trial, including any data and results 
from the trial, will be the exclusive property of the Sponsor. The Investigator and any other 
persons involved in the trial are responsible for protecting the confidentiality of this 
proprietary information belonging to the Sponsor. 
 
 Publication 
The results from this trial may be submitted for publication at the discretion of the Sponsor. 
15.8 Archiving 
The Principal Investigator is responsible for maintaining essential documents, (as defined in 
ICH E6 GCP, Section 8) for 25 years after finalisation of the CTR. This includes any original 
source documents related to the trial, the Subject Identification List (providing the sole link 
between named subject source records and anonymous eCRF data), the original signed ICFs 
and detailed records of disposition of IMP. 
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
The Sponsor will archive the TMF in accordance with ICH E6 GCP, Section 8 and applicable 
regulatory requirements. 


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The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the clinic and 
filed in the Investigator Trial File for archiving for 25 years after finalisation of the CTR. 
The completed eCRFs are the sole property of the Sponsor and should not be made available 
in any form to third parties, except for authorised representatives of appropriate 
Health/Regulatory Authorities, without written permission from the Sponsor. 


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16 DATA MANAGEMENT 
The data management routines include procedures for handling of the eCRF, database set-up 
and management, data entry and verification, data validation, QC of the database, and 
documentation of the performed activities including information of discrepancies in the 
process. The database, data entry screens, and program will be designed in accordance with 
the CTP. 
Data validation/data cleaning procedures are designed to assure validity and accuracy of 
clinical data. These procedures consist of computerised online edit checks identifying e.g., 
data values that are outside the allowed range and SAS-programmed batch checks on data 
exports. All trial-specific and standard data validation programming will be tested in a 
separate testing environment prior to use on production data. 
Detailed information on data management will be described in a trial-specific Data 
Management Plan (DMP). 
16.1 The web-based eCRF 
Clinical data will be entered into a 21 CFR Part 11-compliant eCRF (Viedoc™) provided by 
Viedoc Technologies AB. The eCRF includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents or at bedside 
(if the eCRF data constitutes source data). Source data are to be defined at the site before 
inclusion of the first subject (Section 15.3). 
Authorised site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorised trial site personnel prior to the trial being initiated and any data being entered into 
the system for any trial subject. 
16.2 The entering of data into the eCRF 
All entries, corrections, and alterations are to be made by the Investigator or designee. Neither 
the Monitor nor any other trial team member besides site staff can enter data in the eCRF. All 
data should be entered in English. The eCRFs should be completed as soon as possible 
(within 24 hours in case of an SAE) during or after the subject’s visit. The Investigator must 
verify that all data entries in the eCRFs are accurate and correct. If some assessments are not 
done, or if certain information is not available, not applicable or unknown, the Investigator or 
assigned clinical staff should record such information in the eCRF. The Investigator will be 
required to electronically sign off the clinical data. This will be performed by means of the 
Investigator’s unique User ID and password; date and time stamps will be added 
automatically at time of electronic signature. 
16.3 The query process 
The Monitor will review the eCRFs and evaluate them for completeness and consistency. 
Data in the eCRF will be compared with the respective source documents to ensure that there 
are no discrepancies for critical data as described in the RBM plan. All entries, corrections, 
and alterations are to be made by the Investigator or designee. 
If corrections are needed, queries will be raised within the eCRF, either as a result of built-in 
edit checks or manually raised by the monitor. An appropriate member of the site staff will 


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answer the queries in the eCRF either by correcting the data or by entering a response to the 
query. The monitor will either approve the answer/correction or re-issue the query. 
16.4 Audit trail 
All entries in the eCRF will be fully recorded in a protected audit trail. Once clinical data 
have been saved, corrections to the data fields will be audit trailed, meaning that the reason 
for change, the name of the person who made the change, together with time and date will be 
logged. 
16.5 External data 
External data consists of data that are not recorded in the eCRF. Data will be received in 
electronic format. Key variables are defined in order to uniquely identify each sample record. 
File and data formats are agreed with the external data provider. 
External data in the present trial are safety laboratory data, cardiodynamic ECG data and 
plasma and urine concentration data, and EndoPAT data. 
16.6 Medical coding 
Medical coding will be performed by trained personnel at CTC. AEs and medical/surgical 
history verbatim terms will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA; latest version available at start of coding). Prior and concomitant medications will 
be coded according to the World Health Organization (WHO) Anatomic Therapeutic 
Chemical (ATC) classification system. All coding will be approved by Sponsor prior to 
database lock. 
16.7 Database lock 
When all data have been entered, all external data have been received and discrepancies 
solved, clean file will be declared, the database will be locked, the randomisation code will be 
broken and the data will be analysed. 


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17 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
The principal features of the statistical analysis to be performed are described in this section. 
A more technical and detailed elaboration of the principal features will be presented in a 
separate Statistical Analysis Plan (SAP), which will be signed and approved prior to database 
lock. 
Analyses of the primary and secondary endpoints will be performed by CTC. 
17.1 General 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic 
mean, SD, median, minimum and maximum value. 
Categorical data will be presented as counts and percentages and by means of absolute and 
relative frequencies where applicable. 
All descriptive statistics will be presented by part, assigned treatment (dose cohort or placebo) 
and by assessment time where applicable. 
Individual subject data will be listed by part, treatment, subject number, and, where 
applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or 
later (SAS Institute, Inc., Cary, NC). 
The baseline measurement will be defined as the latest measurement prior to the first 
administration of the IMP. 
No imputation of missing data will be performed. 
17.2 Determination of sample size 
No formal sample size calculation has been performed for this trial. The proposed sample size 
is considered sufficient to provide adequate information for the trial objectives. 
Approximately 144 subjects will be screened to achieve a total of 72 randomised and dosed 
subjects. The number may increase if additional dose cohorts need to be investigated and/or if 
recommended by the iSRC. 
17.3 Analysis data sets 
 
 Full analysis set 
The Full Analysis Set (FAS) will consist of all subjects who have been randomised and 
received at least one dose of IMP and who has at least one post-baseline assessment of data. 
The FAS will be used for all safety and PD evaluations. 
 
 Pharmacokinetic analysis set 
The Pharmacokinetic analysis set (PKAS) will consist of all subjects who received at least 
one dose of the trial drug and provided an plasma concentration data and who have no AEs or 


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protocol deviations judged to affect the PK analysis. Individual PK values may be excluded 
from the analysis as specified in the SAP. 
17.4 Description of trial population 
 
 Demographics and baseline characteristics 
Descriptive statistics for demographics, weight, height and BMI, will be presented by 
treatment and cohort. All data will be listed by part, treatment and subject. 
 
 Medical/surgical history and prior/concomitant medication 
Medical/surgical history will be presented by SOC and preferred term (PT). Prior/concomitant 
medications will be presented by ATC level 3 and 5. All data will be listed by part, treatment 
and subject. 
 
 Treatment compliance 
Individual dose(s) will be listed by part, treatment and subject. 
17.5 Analysis of primary endpoints 
 
 Adverse events 
An overview of all AEs, including SAEs, intensity, and relationship to IMP will be presented. 
Incidence of AEs and SAEs will be summarised by SOC and PT by part, cohort, treatment 
and overall. An overview of any related AEs will be summarised by SOC and PT if 
considered appropriate. 
All AE data will be listed by part, treatment, and subject and include the verbatim term 
entered by the Investigator. 
 
 12-lead ECG 
All ECGs will be categorised as” normal”, ”abnormal”, “not clinically significant”, or 
”abnormal, clinically significant” (as judged by the Investigator) and summarised by 
treatment and cohort using frequency tables. Changes over time will be presented using shift 
tables, if considered appropriate. All data will be listed by part, cohort, treatment, and subject. 


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 Vital signs 
Vital signs (systolic/diastolic BP, pulse and respiratory rate) will be summarised by part, 
treatment, and cohort. Data will be presented with absolute change from baseline. All data 
will be listed by part, cohort, treatment, and subject. 
 
 Safety laboratory analyses 
Safety laboratory data will be summarised by treatment and cohort with absolute change from 
baseline at each visit. Abnormal, clinically significant values will be summarised separately, 
if considered appropriate. All data will be listed by part, cohort, treatment, and subject. 
 
 Physical examination 
Clinically significant and non-clinically significant abnormal findings will be specified and 
presented by subject and summarised by treatment and cohort. Changes over time will be 
presented using shift tables, if considered appropriate. All data will be listed by part, cohort, 
treatment, and subject. 
17.6 Analysis of secondary endpoints 
 
 Analysis of pharmacokinetics 
The PK analysis will be based on the PK analysis set and performed by CTC. The PK 
parameters will be calculated by non-compartmental analysis (NCA) using the software 
Phoenix WinNonlin® version 8.1 or later (Certara, U.S.A.). 
Part A, SAD: 
• The following non-compartmental PK parameters will be assessed: 
o AUCinf 
o AUC0-last 
o Cmax 
o Tmax 
o T½(z) 
o CL/F 
o Vz/F 
o Relative bioavailability for fasted versus fed cohort. 
In addition, dose proportionality after a single dose, based on AUCinf and Cmax will be 
analysed. Assessment of dose proportionality will be performed by a power model. 
All PK parameters will be calculated both for the fasted and the fed cohort. 


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Part B, MAD: 
The following non-compartmental PK parameters will be assessed: 
• PK parameters after first dose: 
o AUCtau 
o AUCinf 
o Cmax 
o Tmax 
o T½(z) 
o CL/F 
o Vz/F 
• PK parameters after last dose: 
o AUCtau 
o Cmax 
o Tmax 
o T½(z) 
o CL/F 
o Vz/F 
In addition, dose proportionality based on AUCtau and Cmax and accumulation ratios based on 
AUCtau and Cmax will be analysed. Assessment of dose proportionality will be performed by a 
power model using 90% power. 
Observed concentration at the end of a dosing interval, immediately before next 
administration (Ctrough from Days 2 to 8, pre-morning dose samples) will also be calculated to 
assess steady state. 
Urine excretion (evaluated in Part A and in Part B part at steady state): 
• % of dose and absolute amount excreted unchanged in the urine 
• Renal clearance. 
Summary statistics for the PK parameters will be presented by treatment and cohort with 
number of measurements, arithmetic mean, standard deviation (SD), coefficient of variation 
(CV), median, minimum, maximum, geometric mean and geometric CV (CV%). 
All data will be listed by part, cohort, treatment, and subject. 
Additional PK parameters may be calculated if considered appropriate. 
17.7 Analysis of exploratory endpoints 
The exploratory endpoints (MIST, urine metabolites and endothelial function) may be 
reported separately from the CTR. Cardiodynamic ECG data will be stored for potential 
future evaluation and will thus not be included in the CTR. 
Details of the analyses will be given in the SAP, if applicable. 


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19 SIGNATURES 
19.1 Principal Investigator statement 
I have read and understood this CTP and agree to conduct the trial accordingly and to comply 
with the Investigator obligations stated in this CTP, GCP and applicable regulatory 
requirements. 
 
Principal Investigator 
 


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19.2 Signature page (approval of the clinical trial protocol) 
Sponsor signatories