Clinical trial NCT05830799
Conditions: Drug Interaction
Sponsor: Vicore Pharma AB
Start date: 2023-03-29; Completion date: 2023-05-11
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-centre, open-label, fixed-sequence trial to evaluate the impact of C21 on the exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy volunteers.

Detailed description:
This is a single-centre, open-label, fixed-sequence trial to evaluate the influence of C21 on the exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy male and female volunteers.

The trial consists of a screening phase (Day -28 to Day -1), an open-label intervention phase (Day -1 to Day 19), and a follow-up phase (Day 20 to Day 25 \[±2 days\]). Subjects will remain at the trial site from the afternoon of Day -1 to the morning of Day 6, and again from the afternoon of Day 16 to the morning of Day 19.

The intervention phase consists of 3 periods: in period 1 (Day -1 to Day 3), the pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2 (Day 4 to Day 6), a potential inhibitory effect of C21 on the substrates be evaluated, and in period 3 (Day 17 to Day 19), the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated.

Subjects will be expected to attend a total of 4 visits to the trial site, including a screening visit (Visit 1), 2 intervention visits (Visits 2 and 3) and a follow-up visit (Visit 4).

Each subject is expected to participate in the trial for approximately 55 days, including an up to 28-day screening period, 19-day intervention period and a 4- to 8-day follow-up period.

Arms: arm 1: C21, single dose, oral administration twice daily, for 15 days
Interventions: intervention 1: Drug Drug Interaction
Intervention descriptions: intervention 1: The intervention phase consists of 3 periods: in period 1, the pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2, a potential inhibitory effect of C21 on the substrates be evaluated, and in period 3, the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated

Protocol documents:
Prot_SAP_000.pdf: 
 
Clinical Trial Protocol VP-C21-012, Final v2.0 
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Clinical Trial Protocol 
EudraCT no. 
2022-003822-29 
Investigational medicinal product Compound 21 (C21) 
Trial code 
VP-C21-012 
Protocol version and date 
Final v2.0; 28FEB2023 
 
A single-centre, open-label, fixed-sequence trial to evaluate the 
impact of C21 on the exposure of CYP1A2, CYP2C9, CYP3A4 
and P-gp substrates in healthy volunteers 
Phase 
Phase 1, Human pharmacology 
Indication 
N/A 
Test product 
C21 
CYP1A2 substrate 
Caffeine 
CYP2C9 substrate 
Tolbutamide 
CYP3A4 substrate 
Midazolam 
P-gp substrate 
Nintedanib 
Sponsor signatories 
 
 
 
 
 
 
Principal Investigator 
 
 
Clinical trial conduct and management 
Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
 
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. 


 
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1 
TRIAL SYNOPSIS 
Trial title 
A single-centre, open-label, fixed-sequence trial to evaluate the impact of C21 on the exposure of 
CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy volunteers. 
Trial code 
VP-C21-012 
EudraCT no. 
2022-003822-29 
Planned trial period 
Q1 to Q2 2023 
Phase of development 
Phase 1, Human pharmacology 
Principal Investigator 
 
 
Trial design 
This is a single-centre, open-label, fixed-sequence trial to evaluate the influence of C21 on the 
exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy volunteers. 
Objectives 
Primary objective 
• 
To evaluate the impact of C21 on the pharmacokinetics (PK) of caffeine, tolbutamide, 
midazolam, nintedanib, and their main metabolites. 
Secondary objectives 
• 
To evaluate the PK of C21 and its main metabolite M1. 
• 
To evaluate the safety of C21. 
Exploratory objectives 
• 
To explore the impact of C21 on endogenous biomarkers of transporter inhibition and/or 
induction, e.g., coproporphyrin I (biomarker for OATP1B1 inhibition). 
• 
To evaluate the metabolite profile of C21 at steady state in plasma of healthy subjects. 
• 
To evaluate how genetic factors may influence the PK of C21. 
Exploratory endpoints related to the biomarker coproporphyrin I will be reported in the clinical trial 
report (CTR). Other exploratory endpoints will not be reported in the CTR but may be included in 
separate reports. 
Endpoints 
Primary endpoint 
• 
PK variables (Cmax, Tmax, AUC0-last and AUCinf) for caffeine, tolbutamide, midazolam, 
nintedanib, and their metabolites paraxanthine, 4-hydroxy-tolbutamide, carboxy-tolbutamide, 
1-hydroxy-midazolam, and BIBF 1202. 
Secondary endpoints 
• 
PK variables (Cmax, Tmax, AUC0-last and AUCtau) for C21 and M1. 
• 
Frequency, seriousness and intensity of adverse events (AEs). 
• 
Clinically significant changes in vital signs, electrocardiogram (ECG) and clinical laboratory 
measurements (haematology, clinical chemistry, coagulation). 


 
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Exploratory endpoints 
• 
Plasma concentration profiles of selected endogenous biomarkers of transporter inhibition 
and/or induction. 
• 
Metabolite in safety testing (MIST) in plasma at steady state. 
• 
Genotyping of genes encoding enzymes and/or transporters of relevance for investigational 
medicinal product (IMP) metabolism and/or transport. 
Number of subjects planned 
Approximately, 30 subjects are planned to be screened to achieve 18 included subjects and at least 16 
treated and fully evaluable subjects, i.e., subjects that complete the trial up until at least the end of 
Day 19. 
Diagnosis and eligibility criteria 
Healthy male or female volunteers, 18 to 60 years (inclusive) with a body mass index (BMI) of 18.5 
to 30.0 kg/m2 and who are willing and able to give written informed consent are considered eligible 
for participation in the trial. 
Only women of non-childbearing potential and male subjects will be eligible for participation. Male 
subjects with female partners of child-bearing potential must agree to use a highly effective method 
of contraception. Subjects with a history of or present medical condition that may interfere with the 
conduct of the trial or may put the subject at risk because of participation in the trial will be 
excluded. 
Methodology 
The trial consists of a screening phase (Day -28 to Day -1), an open-label intervention phase (Day -1 
to Day 19), and a follow-up phase (Day 20 to Day 25 [±2 days]). Subjects will remain at the trial site 
from the afternoon of Day -1 to the morning of Day 6, and again from the afternoon of Day 16 to the 
morning of Day 19. 
The intervention phase consists of 3 periods: in period 1 (Day 1 to Day 3), the pharmacokinetics 
(PK) of all substrates will be evaluated in the absence of C21, in period 2 (Day 4 to Day 6), a 
potential inhibitory effect of C21 on the substrates be evaluated, and in period 3 (Day 17 to Day 19), 
the net effect of potential C21-mediated induction and inhibition on the substrates will be evaluated. 
Subjects will be expected to attend a total of 4 visits to the trial site, including a screening visit (Visit 
1), 2 intervention visits (Visits 2 and 3) and a follow-up visit (Visit 4). 
An overview of the trial dosing schedule is shown below. 


 
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IMP, dosage and mode of administration 
IMP 
Type 
Formulation  
Strength 
Dose and no. of doses 
C21 
Test/perpetrator drug Oral capsules 50 mg 
100 mg BID Day 4 to Day 18. 
Caffeine 
CYP1A2 substrate 
Oral tablets 100 mg 
Single dose 100 mg on Days 2, 5 and 18. 
Tolbutamide 
CYP2C9 substrate 
Oral tablets 500 mg 
Single dose 500 mg on Days 2, 5 and 18. 
Midazolam 
CYP3A4 substrate 
Oral solution 1 mg/mL Single dose 2 mg on Days 2, 5 and 18. 
Nintedanib 
P-gp substrate 
Oral soft capsules 
150 mg 
Single dose 150 mg on Days 1, 4 and 17. 
Duration of IMP administration 
The participating subjects will receive 3 single doses of nintedanib, on Days 1, 4, and 17 of the trial, 
as well as 3 single doses of the CYP substrate cocktail (caffeine, tolbutamide and midazolam) on 
Days 2, 5, and 18 of the trial. In total, participating subjects will receive 30 doses of C21, 
administered BID, over 15 days (Day 4 to Day 18).  
Duration of each subject’s involvement in the trial 
Each subject is expected to participate in the trial for approximately 55 days, including an up to 
28-day screening period, 19-day intervention period and a 4- to 8-day follow-up period. 
Pharmacokinetic assessments 
Blood samples for the determination of plasma concentrations and PK characterisation of caffeine, 
tolbutamide, midazolam, nintedanib and their metabolites (paraxanthine, 4-hydroxy-tolbutamide, 
carboxy-tolbutamide, 1-hydroxy-midazolam, and BIBF 1202), as well C21 and its main metabolite 
M1. 
Safety assessments 
AE reporting, vital signs (blood pressure and pulse rate), resting 12 lead ECG, blood sampling for the 
analysis of clinical chemistry, haematology and coagulation parameters, and physical examinations. 
Exploratory assessments 
Plasma concentration profiles of endogenous biomarkers of transporter inhibition and/or induction, 
e.g., coproporphyrin I. 
MIST analysis of C21 in plasma at steady state. 
Genotyping of genes encoding enzymes and/or transporters of relevance for C21 and substrate 
metabolism and/or transport (optional). 
Statistical methods 
No formal sample size calculation has been performed for this trial. The proposed sample size is 
considered sufficient to provide adequate information to meet the trial objectives. 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic mean, 
standard deviation (SD), median, minimum and maximum value.  
Categorical data will be presented as counts and percentages. When applicable, summary data will be 
presented by treatment, and by assessment time. Individual subject data will be listed by subject 
number, treatment, 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 PK parameters will be calculated by non-compartmental 
analysis (NCA) using the software Phoenix WinNonlin® version 8.3 or later (Certara, U.S.A.). 


 
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Baseline will be defined as the last non-missing data collection point prior to the first administration 
of IMP. All hypothesis testing will use a significance level of 5 %. No imputation of missing data 
will be performed. 
PK parameters will be calculated by standard non-compartmental analysis (NCA). PK data will be 
presented by substance using summary statistics with number of measurements, arithmetic mean, 
SD, as well as median, minimum and maximum values. For AUC and Cmax parameters, the geometric 
mean and geometric CV% will be presented. Cmax and AUC ratios will be analysed using a paired 
t-test and summarised by substance using geometric means and their 90% confidence intervals. 
Safety data will be summarised using descriptive statistics as appropriate. 
Trial reporting 
After completion of the trial, an International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) E3 guideline-compliant CTR will be prepared. 


 
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2 
TABLE OF CONTENTS 
1 
TRIAL SYNOPSIS ....................................................................................................... 2 
2 
TABLE OF CONTENTS ............................................................................................. 6 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................... 11 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ....................................................................................................... 15 
4.1 
Medical emergencies contact ..................................................................................... 15 
5 
INVESTIGATOR AND TRIAL ADMINISTRATIVE STRUCTURE ................. 16 
6 
INTRODUCTION ...................................................................................................... 19 
6.1 
Background ................................................................................................................. 19 
6.1.1 
Non-clinical data ...................................................................................................... 19 
6.1.2 
Clinical experience ................................................................................................... 20 
6.2 
Trial rationale ............................................................................................................. 21 
6.3 
Risk/benefit assessment .............................................................................................. 22 
6.3.1 
General risk/benefit assessment ............................................................................... 22 
7 
TRIAL OBJECTIVES AND ENDPOINTS ............................................................. 24 
8 
TRIAL DESIGN ......................................................................................................... 25 
8.1 
Overall trial design and schedule of events .............................................................. 25 
8.1.1 
Visit 1 – Screening ................................................................................................... 25 
8.1.2 
Visit 2 – First intervention visit ................................................................................ 25 
8.1.3 
At-home self-administration of C21 ........................................................................ 26 
8.1.4 
Visit 3 – Second intervention visit ........................................................................... 26 
8.2 
Rationale for trial design ........................................................................................... 36 
9 
TRIAL POPULATION .............................................................................................. 38 
9.1 
Recruitment ................................................................................................................ 38 
9.2 
Screening and enrolment log ..................................................................................... 38 
9.3 
Number of subjects ..................................................................................................... 38 
9.4 
Inclusion criteria ........................................................................................................ 38 
9.5 
Exclusion criteria ........................................................................................................ 39 
9.6 
Restrictions during the trial ...................................................................................... 40 
9.6.1 
General restrictions .................................................................................................. 40 
9.6.2 
Prior and concomitant therapy ................................................................................. 42 
9.7 
Screen failures ............................................................................................................ 42 
9.8 
Subject withdrawal .................................................................................................... 42 
9.8.1 
General withdrawal criteria ...................................................................................... 42 
9.8.2 
Electrocardiogram withdrawal criteria ..................................................................... 43 
9.8.3 
Liver chemistry withdrawal criteria ......................................................................... 43 


 
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9.8.4 
Renal function withdrawal criterion ......................................................................... 43 
9.8.5 
Procedures for discontinuation of a subject from the trial ....................................... 44 
9.8.6 
Subject replacement ................................................................................................. 44 
9.9 
Randomisation ............................................................................................................ 44 
9.10 
Blinding ....................................................................................................................... 44 
9.11 
Emergency unblinding during the trial .................................................................... 44 
10 
TRIAL TREATMENTS ............................................................................................ 45 
10.1 
Identity of investigational medicinal products ........................................................ 45 
10.2 
Identity of auxiliary medicinal products .................................................................. 45 
10.3 
Manufacturing, packaging, labelling and release ................................................... 45 
10.4 
Conditions for storage ................................................................................................ 45 
10.5 
Preparation and accountability ................................................................................. 45 
10.6 
Administration of investigational medicinal products ............................................ 47 
10.7 
Continued administration of investigational medicinal product ........................... 47 
10.8 
Administration compliance ....................................................................................... 47 
10.9 
Return and destruction of investigational medicinal product ............................... 47 
11 
TRIAL ASSESSMENTS ............................................................................................ 48 
11.1 
Recording of data ....................................................................................................... 48 
11.2 
Demographics and other baseline characteristics ................................................... 48 
11.2.1 
Informed consent ...................................................................................................... 48 
11.2.2 
Eligibility criteria ..................................................................................................... 48 
11.2.3 
Demographic information ........................................................................................ 48 
11.2.4 
Height, weight and body mass index ....................................................................... 48 
11.2.5 
Medical/surgical history ........................................................................................... 49 
11.2.6 
HIV and hepatitis B/C .............................................................................................. 49 
11.2.7 
Urine drug screen and alcohol tests .......................................................................... 49 
11.2.8 
Physical examinations .............................................................................................. 49 
11.2.9 
Blood sampling for CYP2C9 genotyping ................................................................ 49 
11.2.10 Prior and concomitant medication ............................................................................ 50 
11.3 
Blood sampling for pharmacokinetics, biomarker analysis and metabolites in 
safety testing ............................................................................................................................ 50 
11.4 
Assessments related to pharmacokinetic endpoints ................................................ 51 
11.4.1 
Pharmacokinetic analysis ......................................................................................... 51 
11.5 
Assessments related to safety endpoints ................................................................... 51 
11.5.1 
Adverse events ......................................................................................................... 51 
11.5.2 
Vital signs ................................................................................................................. 58 
11.5.3 
Safety electrocardiogram .......................................................................................... 58 


 
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11.5.4 
Clinical laboratory assessments ............................................................................... 58 
11.6 
Assessments related to exploratory endpoints ......................................................... 59 
11.6.1 
Biomarker analysis ................................................................................................... 59 
11.6.2 
Metabolites in safety testing ..................................................................................... 60 
11.6.3 
Exploratory genetic blood sampling ........................................................................ 60 
11.7 
Appropriateness of measurements ........................................................................... 60 
12 
PROCEDURES FOR BIOLOGICAL SAMPLES .................................................. 61 
12.1 
Sample collection ........................................................................................................ 61 
12.2 
Volume of blood .......................................................................................................... 61 
12.3 
Handling, storage and destruction of laboratory samples ...................................... 61 
12.4 
Chain of custody of biological samples ..................................................................... 61 
12.5 
Withdrawal of informed consent for donated biological samples ......................... 62 
13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .................................................................................................................. 63 
13.1 
Quality management: critical process, system and data identification ................. 63 
13.2 
Quality assurance and quality control ..................................................................... 63 
14 
ETHICAL AND REGULATORY REQUIREMENTS .......................................... 64 
14.1 
Ethical conduct of the trial ........................................................................................ 64 
14.2 
Ethics and regulatory review .................................................................................... 64 
14.3 
Subject information and consent .............................................................................. 64 
14.4 
Subject information card ........................................................................................... 64 
14.5 
Subject privacy and data protection ......................................................................... 65 
14.6 
Changes to the approved clinical trial protocol ....................................................... 65 
14.7 
Audits and inspections ............................................................................................... 66 
14.8 
Insurance ..................................................................................................................... 66 
15 
TRIAL MANAGEMENT .......................................................................................... 67 
15.1 
Training of trial site personnel .................................................................................. 67 
15.2 
Clinical monitoring .................................................................................................... 67 
15.3 
Source data documents .............................................................................................. 68 
15.4 
Trial agreements ......................................................................................................... 68 
15.5 
Trial timetable and end of trial ................................................................................. 68 
15.6 
Termination of the trial ............................................................................................. 68 
15.7 
Reporting and publication ......................................................................................... 69 
15.7.1 
Clinical trial report ................................................................................................... 69 
15.7.2 
Annual safety report ................................................................................................. 69 
15.7.3 
Confidentiality and ownership of trial data .............................................................. 69 
15.7.4 
Publication ................................................................................................................ 69 


 
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15.8 
Archiving ..................................................................................................................... 69 
16 
DATA MANAGEMENT ........................................................................................... 70 
16.1 
The web-based eCRF ................................................................................................. 70 
16.2 
The entering of data into the eCRF .......................................................................... 70 
16.3 
The query process ....................................................................................................... 70 
16.4 
Audit trail .................................................................................................................... 71 
16.5 
External data .............................................................................................................. 71 
16.6 
Medical coding ............................................................................................................ 71 
16.7 
Database lock .............................................................................................................. 71 
17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ..... 72 
17.1 
General ........................................................................................................................ 72 
17.2 
Determination of sample size .................................................................................... 72 
17.3 
Analysis data sets ........................................................................................................ 72 
17.4 
Description of trial population .................................................................................. 73 
17.4.1 
Demographics and baseline characteristics .............................................................. 73 
17.4.2 
Medical/surgical history and prior/concomitant medication .................................... 73 
17.4.3 
Administration compliance ...................................................................................... 73 
17.5 
Analysis of primary endpoints .................................................................................. 73 
17.5.1 
Analysis of pharmacokinetics .................................................................................. 73 
17.6 
Analysis of secondary endpoints ............................................................................... 73 
17.6.1 
Secondary pharmacokinetic endpoints ..................................................................... 73 
17.6.2 
Adverse events ......................................................................................................... 74 
17.6.3 
Vital signs ................................................................................................................. 74 
17.6.4 
Electrocardiogram .................................................................................................... 74 
17.6.5 
Clinical laboratory .................................................................................................... 74 
17.7 
Analysis of exploratory objectives ............................................................................ 74 
18 
REFERENCES ........................................................................................................... 75 
19 
SIGNATURES ............................................................................................................ 78 
19.1 
Principal Investigator statement ............................................................................... 78 
19.2 
Approval of the clinical trial protocol ...................................................................... 79 
 
List of tables 
Table 1 
Medical emergencies contact 
15 
Table 2 
Trial objectives and endpoints 
24 
Table 3 
Overall schedule of events 
28 
Table 4 
Detailed schedule of events for Visit 2, Day -1 to Day 1 
30 
Table 5 
Detailed schedule of events for Visit 2, Day 2 to Day 3 
31 


 
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Table 6 
Detailed schedule of events for Visit 2, Day 4 
32 
Table 7 
Detailed schedule of events for Visit 2, Day 5 to Day 6 
33 
Table 8 
Detailed schedule of events for Visit 3, Day 16 to Day 17 
34 
Table 9 
Detailed schedule of events for Visit 2, Day 18 to Day 19 
35 
Table 10 
Investigational medicinal products 
46 
Table 11 
Blood sampling schedule 
51 
Table 12 
Laboratory parameters 
59 
Table 13 
Estimated blood volumes 
61 
Table 14 
Definitions of analysis sets 
72 
 
List of figures 
Figure 1 
Overview of the trial dosing schedule 
25 
 


 
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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Explanation 
ATC 
Anatomical therapeutic chemical  
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMP 
Auxiliary medicinal product 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin clotting time 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
AT2R 
Angiotensin II type 2 receptor 
ATRAG 
Angiotensin II type 2 receptor agonist 
AUC 
Area under the plasma concentration vs. time curve 
AUC0-last 
AUC from 0 to time of last measurable plasma 
concentration 
AUCinf 
AUC from 0 to infinity 
AUCtau 
AUC from 0 to the end of the dosing interval 
BCRP 
Breast cancer resistance protein 
B-EVF 
Blood erythrocyte volume fraction (haematocrit) 
BID 
Twice daily (lat. bis in die) 
BMI 
Body mass index 
CA 
Competent authority 
CIOMS 
Council for International Organisations of Medical Sciences 
Cmax 
Maximum observed concentration 
COVID-19 
Coronavirus disease 2019 
CRP 
C-reactive protein 
CTC 
Clinical Trial Consultants AB 
CTCAE 
Common terminology criteria for adverse events 
CTP 
Clinical trial protocol 
CTR 
Clinical trial report 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 enzymes 
DDI 
Drug-drug interaction 


 
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Abbreviation 
Explanation 
DMP 
Data management plan 
DSUR 
Development safety update report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
GDPR 
General data protection regulation 
GMP 
Good manufacturing practice 
Hb 
Haemoglobin 
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 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IPF 
Idiopathic pulmonary fibrosis 
ISF 
Investigator site file 
MCH 
Mean corpuscular haemoglobin 
MCV 
Mean corpuscular volume 
MDR1 
Multi-drug resistance protein 1 
MedDRA 
Medical dictionary for regulatory activities 
MIST 
Metabolites in safety testing 
NCA 
Non-compartmental analysis 
NSAID 
Non-steroidal anti-inflammatory drug 


 
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Abbreviation 
Explanation 
OAT3 
Organic anion transporter 3 
OATP1B1 
Organic anion transporting polypeptide 1B. 
PI 
Principal Investigator 
PII 
Personally identifiable information 
PK 
Pharmacokinetics 
PK(INR) 
Prothrombin complex international normalised ratio 
PKAS 
PK analysis set 
PKRAS 
PK ratio analysis set 
PPE 
Personal protective equipment 
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 
QP 
Qualified person 
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 
QTcR 
(ECG) Corrected QT interval by Rautaharju 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SD 
Standard deviation 
SDV 
Source data verification 
SLC 
Solute carrier 
SMP 
Safety management plan 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SOP 
Standard operating procedures 
SSc 
Systemic sclerosis 
SuHx 
Sugen-Hypoxia 
SUSAR 
Suspected unexpected serious adverse reaction 
Tmax 
Time of occurrence of Cmax 


 
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Abbreviation 
Explanation 
TMF 
Trial master file 
WHO 
World Health Organization 
WHODrug 
WHO Drug Dictionary 
 


 
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4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR 
4.1 
Medical emergencies contact 
The Principal Investigator (PI) 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 11.5.1.14. 
In the case of a medical emergency, the Investigator may, during office hours, contact the 
Medical Monitor (Table 1). 
Table 1 
Medical emergencies contact 
Name 
Function in the trial 
Telephone number 
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 signatories 
  
 
 
 
 
 
 
 
  
 
 
 
Sponsor’s project manager 
 
 
 
Sponsor’s trial physician 
 
 
 
Clinical conduct (trial site) 
Clinical Trial Consultants AB 
CTC Oscar, 
Dag Hammarskjölds väg 10C 
SE-752 37 Uppsala, Sweden 
Principal Investigator 
 
 
 
Trial management 
Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Clinical research manager 
 
  
 
Biostatistician 
 
 
 


 
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Pharmacokineticist 
 
 
 
Medical Writer (Author of the clinical trial 
protocol [CTP]) 
 
 
 
Medical Monitor 
 
 
 
Pharmacovigilance services 
PrimeVigilance  
1 Occam Court 
Surrey Research Park 
Guildford, Surrey 
GU2 7HJ 
Laboratory (HIV and hepatitis) 
Clinical Microbiology 
Uppsala University Hospital 
Dag Hammarskjölds väg 38 
SE-752 37 Uppsala, Sweden 
Laboratory (safety parameters,  
CYP2C9 genotyping) 
Clinical Chemistry and Pharmacology 
Uppsala University Hospital 
Entrance 61, 2nd level 
SE-751 85 Uppsala, Sweden 
Laboratory (bioanalysis) 
Lablytica Life Science AB 
Virdings Allé 16 
SE-754 50 Uppsala, Sweden 
Laboratory (MIST) 
MetaSafe Sweden AB 
Biovation Park B215 
Forskargatan 20J 
SE-151 36 Södertälje, Sweden 
Manufacturing, packaging, labelling, 
and release of test product (C21) 
Ardena Gent NV 
Kleimoer 4 
B-9030 Mariakerke (Gent), Belgium 
Import of CYP2C9 substrate 
(tolbutamide) 
ClinStorage AB 
Banvaktsvägen 22 
SE-171 48 Solna, Sweden 
Trial pharmacy 
Apoteket AB Nationella Enheten Uppsala 
Clinical Trial Unit 
Södra Depågatan 2 
SE-754 54 Uppsala, Sweden 


 
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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 
Vicore Pharma's Compound 21 (C21), 3-[4-(1H-imidazol-1-ylmethyl)phenyl]-5-(2-
methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulphonamide] sodium salt, is a potent 
and selective nonpeptide angiotensin II type 2 receptor (AT2R) agonist, in clinical 
development for oral treatment of coronavirus disease 2019 (COVID-19) and rare lung 
diseases including idiopathic pulmonary fibrosis (IPF). C21 has been granted orphan drug 
designation in IPF by the European Medicines Agency (EMA) and the United Stated Food 
and Drug Administration (FDA). 
6.1.1 
Non-clinical data 
C21 exerts antifibrotic effects in several in vivo and in vitro models of fibrosis. In both the 
bleomycin -and monocrotaline-induced rat models of pulmonary fibrosis, C21 attenuated 
pulmonary fibrosis and within the monocrotaline model, C21 also reversed it. In addition, 
C21 restored cardiac function and reduced pulmonary vascular remodelling and pulmonary 
hypertension. The antifibrotic effects were in several studies accompanied by 
anti-inflammatory as well as antiproliferative effects. In the Sugen-Hypoxia (SuHx) model of 
pulmonary hypertension, C21 caused a robust reduction of the SuHx-induced increase in 
endothelial cell hyperplasia and pulmonary hypertension.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


 
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More detailed information is found in the current version of the C21 investigator’s brochure 
(IB). 
6.1.2 
Clinical experience 
C21 is being developed for oral treatment of COVID-19 and rare lung diseases, including IPF. 
It represents a novel treatment capable of reducing pulmonary inflammation, proliferation, 
fibrosis, and vasculopathy. 
The safety and pharmacokinetics of C21 have been investigated in 3 phase 1 trials in healthy 
or obese subjects (VP-C21-001-16, VP-C21-002-16, and C21-003), a mechanistic phase 1 
trial investigating the effect of intra-arterial infusions on forearm blood flow (VP-C21-009) 
and 2 phase 2 trials in subjects with COVID-19 (VP-C21-006, the Angiotensin II Type Two 
Receptor Agonist COVID-19 Trial [ATTRACT]) and in subjects with Raynaud’s 
phenomenon (RP) secondary to systemic sclerosis (SSc) (VP-C21-004). In total, 151 subjects 
have been exposed to at least 1 dose of C21 in the completed trials. Overall, C21 has been 
well-tolerated at doses up to 100 mg twice daily (BID) administered for up to 8 days. 
The safety and efficacy of C21 in subjects with COVID-19 have been investigated in a 
multicentre, randomised, placebo-controlled, double-blind phase 2 trial (VP-C21-006). The 
trial included 106 adult subjects hospitalised with COVID-19, having a C-reactive protein 
(CRP) concentration of 50-150 mg/L, and not in need of mechanical ventilation. The subjects 
were randomised to receive oral treatment with C21 (100 mg twice daily, n=51) or placebo 
(n=55) for 7 days on top of SoC. C21 was well tolerated with a good safety profile and 
decreased the need for supplemental oxygen therapy compared with placebo in subjects with 
COVID-19. A phase 3 trial to confirm the efficacy and safety of C21 in hospitalised subjects 
with COVID-19 has been clinically completed and the final report is pending (VP-C21-008). 
The trial was a randomised, double blind, placebo-controlled, parallel-group, two-arm, 
multicentre trial investigating the efficacy and safety of C21 versus placebo as add-on therapy 
to local SoC in 272 subjects with COVID-19. 
One phase 2 trial is currently ongoing. This is a multicentre, open-label, single-arm trial 
investigating the safety, tolerability, pharmacokinetics, and efficacy of C21 in subjects with 
IPF (VP-C21-005). Approximately 60 subjects are planned to be administered 100 mg C21 
orally twice daily for a maximum of 36 weeks. 
 
 
 
 
 
  


 
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6.2 
Trial rationale 
C21 is a first-in-class, low molecular weight, orally available, potent and selective angiotensin 
II type 2 receptor agonist (ATRAG) in clinical development for treatment of rare lung 
diseases, including IPF. 
 
 
 
 
 
 
 
 
  
The purpose of this trial is to investigate the impact of C21 on the metabolic capabilities of 
CYP1A2, CYP2C9 and CYP3A4 using the following substrates administrated as a cocktail: 
caffeine (CYP1A2), tolbutamide (CYP2C9) and midazolam (CYP3A4). Furthermore, the 
influence of C21 on intestinal P-gp will be evaluated using nintedanib. Nintedanib is 
frequently used as standard of care in IPF, and thus has co-administration potential with C21. 
The selected substrates have been used in DDI trials previously and can be found in several 
publications (see Section 8.2).  
The duration of C21 administration was selected based on the turnover of the enzymes to be 
investigated (i.e., sufficient to capture a potential induction). 


 
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6.3 
Risk/benefit assessment 
6.3.1 
General risk/benefit assessment 
As the healthy volunteers in this trial will have no medical benefit from participation, their 
safety and wellbeing are of utmost importance.  
 
 
 
 
 
 
 
  
 
 
 Overall, based on the available clinical experience, the risks associated 
with short-term administration of C21 100 mg BID in healthy volunteers are considered low. 
C21 100 mg BID has been shown to exert beneficial effects in the lungs, as evidenced by the 
effect on the FVC in the ongoing phase 2 trial in IPF (VP-C21-005) and the effects on the 
requirement for oxygen supplementation in the completed phase 2 trial in COVID-19 
(VP-C21-006). 
The substrates used in the trial, i.e., caffeine, tolbutamide, midazolam, and nintedanib are well 
known substances and the proposed single dose administration of these substrates is 
considered safe. 
Subjects will remain at the trial site for at least 24 hours after co-administration of C21 and 
any of the substrates, and will be closely monitored by medical staff. Site visits may be 
prolonged in the event that the Investigator finds it medically warranted for safety reasons.  
In cases of accidental overdose, subjects will be monitored appropriately, and standard 
supportive measures will be adopted as required. For further information regarding 
overdosing, refer to Section 11.5.1.18.  
Each volunteer will be provided with a subject information card with information about the 
subject’s participation in a trial, see Section 14.4.  
The PI at the trial site will ascertain that adequate facilities and procedures are available to 
handle emergency situations should they occur during the trial. The medical staff at the trial 
site have extensive experience from phase 1 and first-in-human (FIH) studies, and there are 
adequate procedures in place to handle unexpected and expected adverse reactions in the trial 
subjects.  
Aside from the risks related to C21 and the substrates used in the trial, as detailed above, there 
may also be risks related to the medical devices used in the trial (e.g., indwelling venous 
catheters). However, these devices are used in routine medical care and the risk associated 
with their use is considered low and ethically justifiable. Trial-specific evaluations and 
sampling procedures, such as 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 previous pre-clinical and clinical 
studies have not revealed any safety issues that would outweigh the expected benefits of the 
trial.  


 
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While keeping the above-mentioned risk factors at a minimum level in order to not expose the 
subjects participating in the trial to 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 and reasonably 
expected adverse reactions (ARs) is found in the current version of the C21 IB. For detailed 
information, including safety information, on the CYP and P-gp substrate investigational 
medicinal products (IMPs) (caffeine, tolbutamide, midazolam, and nintedanib, see Table 10), 
refer to the corresponding summaries of product characteristics (SmPC) [3-6]. 


 
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7 
TRIAL OBJECTIVES AND ENDPOINTS 
Table 2 
Trial objectives and endpoints 
Primary objective 
Endpoints 
Assessments 
Analysis 
To evaluate the impact of 
C21 on the 
pharmacokinetics (PK) of 
caffeine, tolbutamide, 
midazolam, nintedanib, 
and their main 
metabolites. 
PK variables (Cmax, Tmax, 
AUC0-last and AUCinf) for 
caffeine, tolbutamide, 
midazolam, nintedanib, 
and their metabolites 
paraxanthine, 
4-hydroxy-tolbutamide, 
carboxy-tolbutamide, 
1-hydroxy-midazolam, 
and BIBF 1202. 
Plasma sampling for PK 
analysis (Sections 11.3 
and 11.4.1). 
Section 17.5.1 
Secondary objectives 
Endpoints 
Assessments 
Analysis 
To evaluate the PK of C21 
and its main metabolite 
M1. 
Pharmacokinetic variables 
(Cmax, Tmax, AUC0-last and 
AUCtau) for C21 and M1. 
Plasma sampling for PK 
analysis (Section 11.3 and 
11.4.1). 
Section 17.5.1 
To evaluate the safety of 
C21. 
Frequency, seriousness 
and intensity of adverse 
events (AEs). 
AE reporting 
(Section 11.5.1). 
Section 17.6.1 
Clinically significant 
changes in vital signs, 
ECG and clinical 
laboratory measurements 
(haematology, clinical 
chemistry, coagulation). 
Vital signs 
(Section 11.5.2). 
Section 17.6.3 
Safety ECG 
(Section 11.5.3). 
Section 17.6.4 
Clinical laboratory 
assessments 
(Section 11.5.4). 
Section 17.6.5 
Exploratory objective 
Endpoints 
Assessments 
Analysis 
To explore the impact of 
C21 on endogenous 
biomarkers of transporter 
inhibition and/or 
induction, e.g., 
coproporphyrin I 
(biomarker for OATP1B1 
inhibition). 
Plasma concentration 
profiles of selected 
endogenous biomarkers of 
transporter inhibition 
and/or induction. 
Plasma sampling for 
biomarker analysis 
(Sections 11.3 and 
11.6.1). 
Section 17.7. 
To evaluate the metabolite 
profile of C21 at steady 
state in plasma of healthy 
subjects. 
Metabolite in safety 
testing (MIST) in plasma 
at steady state. 
MIST (Section 11.6.2). 
Section 17.7. 
To evaluate how genetic 
factors may influence the 
PK of C21 
Genotyping of genes 
encoding enzymes and/or 
transporters of relevance 
for C21 and substrate 
metabolism and/or 
transport. 
Plasma sampling for 
analysis of genetic factors 
(Section 11.6.3). 
Section 17.7. 
IMP=investigational medicinal product, OATP1B1=organic anion transporting polypeptide 1B, PK=pharmacokinetic(s). 
Exploratory endpoints related to the biomarker coproporphyrin I will be reported in the 
clinical trial report (CTR). Other exploratory endpoints will not be reported in the CTR but 
may be included in separate reports. 


 
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8 
TRIAL DESIGN 
8.1 
Overall trial design and schedule of events 
This is a single-centre, open-label, fixed-sequence trial to evaluate the influence of C21 on the 
exposure of CYP1A2, CYP2C9, CYP3A4 and P-gp substrates in healthy male and female 
volunteers. 
The trial consists of a screening phase (Day -28 to Day -1), an open-label intervention phase 
(Day -1 to Day 19), and a follow-up phase (Day 20 to Day 25 [±2 days]). Subjects will remain 
at the trial site from the afternoon of Day -1 to the morning of Day 6, and again from the 
afternoon of Day 16 to the morning of Day 19. 
The intervention phase consists of 3 periods: in period 1 (Day -1 to Day 3), the 
pharmacokinetics (PK) of all substrates will be evaluated in the absence of C21, in period 2 
(Day 4 to Day 6), a potential inhibitory effect of C21 on the substrates be evaluated, and in 
period 3 (Day 17 to Day 19), the net effect of potential C21-mediated induction and inhibition 
on the substrates will be evaluated (Table 3). 
Subjects will be expected to attend a total of 4 visits to the trial site, including a screening 
visit (Visit 1), 2 intervention visits (Visits 2 and 3) and a follow-up visit (Visit 4). 
Each subject is expected to participate in the trial for approximately 55 days, including an up 
to 28-day screening period, 19-day intervention period and a 4- to 8-day follow-up period.  
The overall schedule of events is presented in Table 3 while an overview of the trial dosing 
schedule is shown in Figure 1. Trial assessments are described in Section 11. 
Figure 1 
Overview of the trial dosing schedule 
 
8.1.1 
Visit 1 – Screening 
Screening (Visit 1) will take place from Day -28 to Day -1 and will include an eligibility 
check, a general health assessment (see Table 3 for details) and signing of the informed 
consent form (ICF). Eligible subjects will also be sampled to identify CYP2C9 variant 
genotypes (refer to exclusion criterion no. 9). Adverse events (AEs) will be collected from the 
subject’s signing of the ICF. 
8.1.2 
Visit 2 – First intervention visit 
At Visit 2, the subjects will be admitted to the trial site in the afternoon/evening of Day -1 and 
will remain at the trial site until the morning of Day 5. Visit 2 encompasses period 1 and 
period 2. 


 
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On Day 1, after pre-dose assessments, the subjects will be administered a P-gp substrate 
(nintedanib 150 mg) in a fasted state, followed by blood sampling for PK and biomarker 
analyses, as well as safety assessments. The PK profile of nintedanib and its metabolites, e.g., 
BIBF 1202, in the absence of C21 will be assessed until 48 hours post-dose. The plasma 
profile of biomarkers of transporter inhibition and/or induction, e.g., coproporphyrin I, will be 
assessed until 12 hours post-dose. 
A detailed schedule of events of Day -1 to Day 1 is presented in Table 4. 
On Day 2, after pre-dose assessments, the subjects will be administered a cocktail of CYP 
enzyme substrates (caffeine 100 mg, tolbutamide 500 mg and midazolam 2 mg) in a fasted 
state, followed by PK sampling and safety assessments. The PK profile of caffeine, 
tolbutamide, midazolam, and their metabolites (paraxanthine, 4-hydroxy-tolbutamide, 
carboxy-tolbutamide, and 1-hydroxy-midazolam) in the absence of C21 will be assessed until 
24 hours post-dose.  
A detailed schedule of events of Day 2 to Day 3 is presented in Table 5. 
On Day 4, after pre-dose assessments, the subjects will be administered nintedanib (150 mg) 
together with the first scheduled dose of C21 100 mg (2x50 mg capsules) in a fasted state, 
followed by PK sampling and safety assessments. The PK profile of nintedanib and its 
metabolites in the presence of C21 will be assessed until 48 hours post-dose. The 
administration of C21 100 mg BID will continue for the subsequent 15 days (Day 4 to 
Day 18). A detailed schedule of events for Day 4 is presented in Table 6. 
On Day 5, after pre-dose assessments, the subjects will be administered a cocktail of caffeine 
(100 mg), tolbutamide (500 mg), and midazolam (2 mg) together with the scheduled morning 
dose of C21 100 mg in a fasted state, followed by PK sampling and safety assessments. The 
PK profile of caffeine, tolbutamide, midazolam, and their metabolites in the presence of C21 
will be assessed until 24 hours post-dose. On Day 6, the subjects will leave the trial site in the 
morning after PK sampling at 24 hours post-dose, the scheduled morning C21 dose and safety 
assessments.  
A detailed schedule of events of Day 5 to Day 6 is presented in Table 7. 
8.1.3 
At-home self-administration of C21 
From the evening of Day 6 until the morning of Day 16, subjects will self-administer C21 at 
home BID (morning and evening, a total of 20 doses) in a fasted state. Two remote check-ups 
for the collection of AEs and the use of concomitant medications, as well as verbal 
confirmation of C21 self-administration, will take place via telephone on Day 9 (±1 day) and 
Day 13 (±1 day).  
8.1.4 
Visit 3 – Second intervention visit 
At Visit 3, the subjects will be admitted to the trial site in the afternoon/evening of Day 16 
and will remain at the trial site until the morning of Day 19. 
On Day 17, after pre-dose assessments, the subjects will be administered nintedanib (150 mg), 
together with the scheduled dose of C21 100 mg in a fasted state, followed by PK sampling 
and safety assessments. The PK profile of C21 and its main metabolite M1 at steady state will 
be assessed until 12-hours post-dose. The PK profile of nintedanib and its metabolites in the 
presence of C21 will be assessed until 48 hours post-dose. The plasma profile of biomarkers 
of transporter inhibition and/or induction will be assessed until 12 hours post-dose. Plasma 
samples from Day 17 will also be used for metabolites in safety testing (MIST). 


 
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A detailed schedule of events of Day 16 to Day 17 is presented in Table 8. 
On Day 18, after pre-dose assessments, the subjects will be administered a cocktail of caffeine 
(100 mg), tolbutamide (500 mg) and midazolam (2 mg) together with the scheduled morning 
dose of C21 100 mg in a fasted state, followed by PK sampling and safety assessments. The 
PK profile of caffeine, tolbutamide, and midazolam in the presence of C21 will be assessed 
until 24 hours post-dose.  
The last C21 dose will be given in the evening of Day 18. On Day 19, the subjects will leave 
the trial site in the morning after the 24-hour post-dose PK sampling and safety assessments.  
A detailed schedule of events of Day 18 to Day 19 is presented in Table 9. 
 


















 
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8.2 
Rationale for trial design 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) guideline M12 on drug interaction studies (EMA guideline 
EMEA/CHMP/ICH/652460/2022, draft 21 July 2022) [7] was considered when designing this 
trial. 
The proposed dose of C21 for the present trial is 100 mg BID, which is the highest intended 
therapeutic dose. The C21 dose is based on results from multiple preclinical studies, clinical 
safety and efficacy data of C21 from completed clinical trials in healthy or obese subjects and 
in subjects with COVID-19, as well as preliminary safety and efficacy data from the ongoing 
phase 2 trial in subjects with IPF (VP-C21-005). 
 
 
 
 
 
 
 
 
  
To start exploring the clinical DDI characteristics of C21 as a perpetrator, a DDI cocktail 
containing the index substrates caffeine (CYP1A2 substrate), tolbutamide (CYP2C9 
substrate) and midazolam (CYP3A4 substrate) has been selected. The intended doses for the 
index substrates are 100 mg for caffeine, 500 mg for tolbutamide and 2 mg for midazolam. 
This cocktail of index substrates has previously been used in clinical DDI studies at similar or 
at higher doses [8, 9]. The PK profiles of caffeine, tolbutamide, midazolam, and their main 
metabolites, will be studied on Day 2 (baseline), Day 5 (potential inhibitory effects including 
time-dependent inhibition) and Day 18 (potential net effect of inhibition and induction). To 
maximize the potential DDI effects of C21 as perpetrator, a C21 dose of 100 mg BID for 15 
consecutive days was selected. The duration of C21 administration (Day 4 to Day 18) was 
selected to allow for potential steady state conditions in respect to CYP induction. 
In addition to the CYP index substrates, the P-gp substrate nintedanib will be included in the 
trial. Nintedanib is frequently used as standard of care in IPF, and therefore any impact of 
C21 on nintedanib is important to identify. Nintedanib was also selected based on previously 
demonstrated interactions with P-gp perpetrators and the co-administration potential with C21 
for the treatment of IPF. Nintedanib is only metabolized by CYP enzymes to a minor extent 
[10, 11]. Thus, it is expected to be a useful index drug for the assessment of C21 influence of 
P-gp. Nintedanib exhibits a low DDI risk as a perpetrator [10, 11] but has not been evaluated 
together with caffeine, tolbutamide and midazolam in a cocktail approach. Consequently, a 
staggered dosing schedule of nintedanib will be used, it will be administered the day before 
the CYP substrate cocktail, i.e., on Day 1, Day 4 and Day 17. The intended dose for 
nintedanib is 150 mg, which a commonly used therapeutic dose that previously has been 
evaluated in DDI studies with nintedanib as a victim drug [12, 13]. 


 
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The exploratory biomarker for OATP1B activity coproporphyrin I has also been included in 
the trial to evaluate the influence of C21 on OATP1B transport activity. The lipid-lowering 
3-hydroxy-3-metaglutaryl coenzyme A reductase inhibitors, or statins, are substrates of 
OATPB1B and are commonly used in patients with IPF, as cardiovascular co-morbidities are 
frequent. There is thus a co-administration potential with C21. Since it has been demonstrated 
that nintedanib neither inhibits OATP1B1 nor OATP1B3 [10] the interaction potential 
between nintedanib and coproporphyrin I is considered very low. Thus, it is considered 
appropriate to investigate the plasma profile of coproporphyrin I on the same days as 
nintedanib. 


 
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9 
TRIAL POPULATION 
Prospective approval of deviations from the eligibility criteria, also known as protocol 
waivers or exemptions, is not permitted. 
9.1 
Recruitment 
Subjects will be recruited from CTC’s database of healthy volunteers, 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 materials (digital, radio and/or print) 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 screening failure should be stated for all subjects screened but 
not included and treated. The reason for withdrawal should be stated for all subjects that were 
included but did not complete the trial. 
A screening number generated automatically in the electronic case report form (eCRF) will be 
allocated to each subject in connection to the informed consent process at the screening visit 
(Visit 1). The screening number will allow identification of subjects irrespective of their 
possible eligibility for the trial. 
Eligible subjects will be assigned a 3-digit randomisation number (i.e., 101-118) prior to the 
first IMP administration. 
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 first administration of IMP), the subject 
should be rescreened before proceeding in the trial. 
9.3 
Number of subjects 
Approximately, 30 subjects are planned to be screened to achieve 18 included subjects and at 
least 16 treated and fully evaluable subjects, i.e., subjects that complete the trial up until at 
least Day 19. 
For the replacement of subjects who discontinue the trial, see Section 9.8.6. 
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. 
2. Healthy male, or healthy female subject of non-childbearing potential, aged 18 to 
60 years, inclusive. 
3. Body mass index ≥ 18.5 and ≤ 30.0 kg/m2 at the time of the screening visit. 
4. Medically healthy subject without abnormal clinically significant medical history, 
physical findings, vital signs, ECG and laboratory values at the time of the screening visit, 
as judged by the Investigator. 


 
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5. Women of non-childbearing potential, i.e. pre-menopausal females who have undergone 
any of the following surgical procedures; hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy, or who are post-menopausal defined as 12 months of amenorrhea 
(in questionable cases a blood sample with detection of follicle stimulating hormone 
[FSH] >25 IU/L is confirmatory). 
6. Male subjects who are vasectomised, who are willing to use condoms or to practice sexual 
abstinence from heterosexual intercourse (only allowed when this is the preferred and 
usual lifestyle of the subject) to prevent pregnancy and drug exposure of a partner. Male 
subjects must also refrain from donating sperm from the first administration of IMP until 
3 months after the last administration of IMP. Any female partner of a non-vasectomised 
male subject who is of child-bearing potential must use contraceptive methods with a 
failure rate of < 1% (see inclusion criterion no. 5) to prevent pregnancy from at least 
2 weeks prior to the first administration of IMP to 4 weeks after the last administration of 
IMP. 
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, with the exception of in situ removal of basal cell 
carcinoma. 
4. Any planned major surgery within the duration of the trial. 
5. Subjects who are pregnant, currently breastfeeding, or intend to become pregnant during 
the course of the trial. 
6. Any positive result at the screening visit for serum hepatitis B surface antigen, hepatitis C 
antibodies and/or human immunodeficiency virus (HIV). 
7. After 10 minutes supine rest at the screening visit, 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 
8. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant 
abnormalities in the resting ECG at the screening visit, as judged by the Investigator. 
9. CYP2C9 genotype hetero- or homozygous for CYP2C9*2 (Arg144Cys) and/or CYP2C9*3 
(Ile359Leu) variant alleles associated with altered CYP2C9 activity and tolbutamide 
metabolism [14], sampled at the screening visit. 
10. 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 any of the IMPs. 


 
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11. Regular use of any prescribed or non-prescribed medications, including antacids, 
analgesics, herbal remedies, e.g. St. John’s wort, vitamins and minerals, within 2 weeks 
prior to the first administration of IMP, except occasional intake of paracetamol 
(maximum 2000 mg/day and not exceeding 3000 mg/week), as well as nasal 
decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10 
days, at the discretion of the Investigator. 
12. Planned treatment or treatment with another investigational drug within 3 months prior to 
Day -1. Subjects consented and screened but not dosed in previous phase 1 studies are not 
to be excluded. 
13. Regular current smokers or users of nicotine products. Irregular use of nicotine (e.g., 
smoking, snuffing, chewing tobacco) less than 3 times/week is allowed before the 
screening visit. 
14. Positive screening result for drugs of abuse or alcohol at the screening visit or on 
admission to the trial site prior to the first administration of the IMP. 
15. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator. 
16. Presence or history of drug abuse, as judged by the Investigator. 
17. History of, or current use of anabolic steroids, as judged by the Investigator. 
18. Excessive caffeine consumption defined by a daily intake of > 5 cups (1 cup = 
approximately 240 mL) of caffeine containing beverages, as judged by the Investigator. 
19. Plasma donation within one month of screening or blood donation (or corresponding 
blood loss) during the last three months prior to screening. 
20. The Investigator considers the subject unlikely to comply with trial procedures, 
restrictions and requirements. 
9.6 
Restrictions during the trial 
Subjects must be willing to comply with the restrictions as outlined in 9.6.1 and 9.6.2. 
9.6.1 
General restrictions 
1. Contraception requirements: See inclusion criterion #5.  
2. Fasting: Subjects must fast overnight (at least 10 hours) prior to the anticipated morning 
IMP administrations on Day 1, Day 2, Day 4, Day 5, Day 17, and Day 18, and until 
4 hours post-dose. C21 should always be taken in a fasted state, i.e., no food intake for at 
least 2 hours before and 1 hour after C21 intake. The latter applies to evening 
administrations of C21 in-clinic and to all at-home administrations. Water will be allowed 
ad libitum at the trial site except from 1 hour pre-dose to 1 hour post-dose. 


 
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3. Meals and dietary restrictions: At the trial site: The IMP will be administered under 
fasting conditions and swallowed with approximately 240 mL of tap water on days 
detailed in the schedule of events (Table 3 to Table 9). Standardised meals will be served 
while the subjects are in the trial site. The meal selection is standardised in the sense that 
the nutritional content of the meals is similar at each timepoint of each treatment day at 
the trial site. Lunch is served approximately 4 hours post-dose. A mid-day snack, dinner, 
and an evening snack is served approximately 6 hours, 9 hours, and 12 hours after the 
morning IMP administration, respectively. Breakfast will be served on days where no IMP 
is administered. Water will be allowed ad libitum at the trial site except from 1 hour 
pre-dose to 1 hour post-dose. 
At home: C21 will be self-administered by the subject at home BID (morning and 
evening) from the evening of Day 6 until the morning of Day 16. The subjects will be 
instructed to avoid food/drinks from 2 hours prior to IMP intake until 1 hour after C21 
intake. 
4. Alcohol: The consumption of alcohol is not allowed from 48 hours prior to admission to 
the trial site for Visit 2 and until end-of-trial at Visit 4. 
5. Drugs of abuse: The use of drugs of abuse is not allowed from the screening visit to the 
end-of-trial visit. In addition to the urine drug screens described in the schedule of events, 
additional random testing can be performed at the site visits. 
6. Coffee, tea and other caffeine-containing beverages: No coffee, tea or other caffeine-
containing beverages are allowed from 48 hours prior to admission to the trial site for 
Visits 2 and 3 or during these visits. Subjects may be served caffeine-free coffee or tea 
during Visit 2 and Visit 3. 
7. Taurine-containing beverages: Beverages containing taurine, e.g., energy drinks such as 
Red Bull and Monster Energy, are not allowed from the screening visit until the 
end-of-trial visit. 
8. Nicotine: Smoking or the use of nicotine-containing products, including non-tobacco oral 
nicotine products, is not allowed from the screening visit until the end-of-trial visit. 
9. Grapefruit and grapefruit-containing products: The consumption of grapefruit and/or 
grapefruit-containing products such as jams, jellies, preserves and fruit juices will not be 
allowed from the screening visit until the end-of-trial visit. This also includes Seville 
oranges, pomelo, exotic citrus fruits, and other grapefruit hybrids. 
10. Exercise: The subjects must refrain from strenuous exercise, defined as greater than 70% 
of the maximal pulse rate for one hour or more, from screening visit to end-of-trial visit.  
11. Blood donation: The subjects must not donate blood or plasma from the screening visit 
until 3 months after the final medical examination at the end-of-trial visit.  
12. Participation in other clinical studies: The subjects are not allowed to participate in any 
other interventional clinical trial from the screening visit until the end-of-trial visit.  


 
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9.6.2 
Prior and concomitant therapy 
9.6.2.1 
Prohibited medications 
The regular use of any prescribed or non-prescribed medication within 2 weeks prior to the 
first administration of IMP until the end-of-trial visit is not allowed (except as detailed in 
Section 9.6.2.2), as judged by the Investigator. This includes, e.g., anticoagulants (including 
but not limited to warfarin, heparin and derivative substances), non-steroidal anti-
inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen, antacids, analgesics, 
herbal remedies, vitamins and minerals.  
9.6.2.2 
Allowed medications 
• Paracetamol in doses up to 2000 mg/day for a maximum of 3 consecutive days. If this 
amount of paracetamol is insufficient for the treatment of the subject, withdrawal should 
be considered. 
• Nasal decongestants without cortisone, antihistamine or anticholinergics for a maximum 
of 10 days. 
Other medications considered necessary for the subject’s safety and wellbeing may be given 
at the discretion of the Investigator. 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 included 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 ICF and reason(s) 
for screening failure. 
Subjects who do not meet the criteria for participation in this trial may be rescreened. 
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). 
• Replacement subjects not used in a previous group of subjects. 
For subjects who are re-screened, a new screening number will be assigned and new, signed 
ICF must be collected. 
9.8 
Subject withdrawal 
9.8.1 
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 discontinued from the trial at any time at the discretion of the Investigator. 
Reasons for discontinuation can include: 
• Withdrawal of consent (subject decision). 


 
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• 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 as detailed in 
Section 12.5. 
9.8.2 
Electrocardiogram withdrawal criteria 
IMP administration will be stopped for any subject meeting any of the ECG withdrawal 
criteria below, and the subject 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 QTc > 60 ms. 
Withdrawal decisions will be based on an average QTc value of triplicate ECGs. If an ECG 
demonstrates a prolonged QT interval, two more ECGs will be obtained over a brief period 
and the averaged QTc values of the three ECGs will be used to determine whether the subject 
must be discontinued from the trial. 
9.8.3 
Liver chemistry withdrawal criteria 
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event aetiology. IMP administration will be stopped for any subject meeting 
any of the following liver chemistry stopping criteria, defined in the US Food and Drug 
Administration (FDA) guidance on drug-induced liver injury [15], and the subject will be 
withdrawn from the trial. 
• Alanine aminotransferase (ALT) 3x upper limit of normal (ULN) and total bilirubin 
≥ 2x ULN (> 35% direct bilirubin); or ALT 3x ULN and international normalised ratio 
(INR) > 1.5. Plasma bilirubin fractionation will be performed. 
• ALT ≥ 5x ULN. 
• ALT ≥ 3x ULN if associated with symptoms (new or worsening) believed to be related 
to hepatitis (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice), or believed to be related to hypersensitivity (e.g., fever, rash or 
eosinophilia). 
9.8.4 
Renal function withdrawal criterion 
IMP administration will be stopped for any subject meeting the renal function criterion below, 
and the subject will be withdrawn from the trial. 
• Estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 (determined by the 
revised Lund-Malmö GFR estimating equation). 


 
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9.8.5 
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. Any ongoing AEs will be 
followed-up as described in Section 11.5.1.16. 
The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final drug accountability must be performed. If the reason for discontinuation was an AE, the 
AE must be specified in the eCRF. 
9.8.6 
Subject replacement 
Subjects who are prematurely withdrawn from the trial for any reason except the occurrence 
of AEs assessed as related to the IMP administration, may be replaced. 
9.9 
Randomisation 
Not applicable. 
9.10 
Blinding 
Not applicable. 
9.11 
Emergency unblinding during the trial 
Not applicable. 


 
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10 
TRIAL TREATMENTS 
10.1 
Identity of investigational medicinal products 
The IMPs used in the trial are listed in Table 10. 
10.2 
Identity of auxiliary medicinal products 
Not applicable. 
10.3 
Manufacturing, packaging, labelling and release 
All manufacturing, packaging, labelling and release of IMP will comply with applicable good 
manufacturing practice (GMP) requirements [16]. 
The C21 capsules will be manufactured, packed, labelled, and released to qualified person 
(QP) by Ardena Gent NV, Mariakerke, Belgium. The C21 capsules will be packed in high-
density polyethylene (HDPE) bottles with desiccant caps, containing 56 capsules per bottle. 
The C21 bottles will be packaged in outer cartons (secondary package). C21 will be shipped 
to the trial site by the trial pharmacy, Apoteket AB Clinical Trial Unit, Uppsala, Sweden. 
On Day 6 of the trial, each subject will receive 1 tamper proof bottle of 56 C21 capsules for 
at-home administration from the evening of Day 6 and until the morning of Day 16. IMP 
administration compliance will be checked as described in Section 10.8. 
The CYP and P-gp substrate drug products (caffeine, tolbutamide, midazolam, and 
nintedanib) are commercial drug product available within the EU (Table 10). The caffeine, 
midazolam and nintedanib drug products will be ordered from, labelled for the trial, and 
shipped to the trial site by the trial pharmacy, Apoteket AB Clinical Trial Unit, Uppsala, 
Sweden. The tolbutamide drug product will be imported from The Netherlands by 
ClinStorage AB, Solna, Sweden. It will be labelled for the trial and shipped to the trial site by 
the trial pharmacy. 
10.4 
Conditions for storage 
The IMP will be stored in an access-controlled storage area at the trial site. The IMP will be 
stored at controlled room temperature, 15-25°C. 
Temperature logs will be kept for the area where the IMP is stored. The temperature will be 
noted on a daily basis (working days only unless automatic temperature readings are 
available).  
10.5 
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 the trial site.  
The trial site and the Investigator will maintain a storage and accountability log as well as a 
drug dispensing log detailing the dates and quantities of trial medication received, prepared 
for and used by each subject, as well as trial medication 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 trial site or the subject 
must be accounted for. 
 


 
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Table 10 
Investigational medicinal products 
IMP 
Type 
Drug product and manufacturer 
Formulation and 
strength 
Dose and number of doses 
SmPC 
C21 
Test/perpetrator 
drug 
N/A 
Oral capsules 50 mg 
100 mg BID Day 4 to Day 18. 
N/A 
Caffeine 
CYP1A2 substrate 
Koffein Meda, 100 mg. Meda AB, Solna, Sweden. 
Oral tablets 100 mg 
Single dose 100 mg on Days 2, 5 and 
18. 
3 
Tolbutamide CYP2C9 substrate 
Tolbutamide CF, 500 mg. Centrafarm, Breda, Netherlands. 
Oral tablets 500 mg 
Single dose 500 mg on Days 2, 5 and 
18. 
4 
Midazolam 
CYP3A4 substrate 
Midazolam APL, 1 mg/mL. Apotek Produktion & 
Laboratorier AB, Stockholm, Sweden. 
Oral solution 1 mg/mL Single dose 2 mg on Days 2, 5 and 18. 
5 
Nintedanib 
P-gp substrate 
Ofev, 150 mg. Boehringer Ingelheim, Ingelheim am Rhein, 
Germany. 
Oral soft capsules 
150 mg 
Single dose 150 mg on Days 1, 4 and 
17. 
6 
 


 
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10.6 
Administration of investigational medicinal products 
The IMP will be administered according to Table 10. From the evening of Day 6 until the 
morning of Day 16, subjects will self-administer C21 at home BID (morning and evening, a 
total of 20 doses). All IMP will be administered under fasting conditions and swallowed 
within a time span of 5 minutes with approximately 240 mL of tap water. 
Subjects must fast overnight (at least 10 hours) prior to the anticipated morning IMP 
administrations on Day 1 (nintedanib), Day 2 (caffeine, tolbutamide, midazolam cocktail), 
Day 4 (C21 and nintedanib), Day 5 (C21 and caffeine, tolbutamide, midazolam cocktail), 
Day 17 (C21 and nintedanib), and Day 18 (C21 and caffeine, tolbutamide, midazolam 
cocktail), and until 4 hours post-dose. C21 should always be taken in a fasted state, i.e., no 
food intake for at least 2 hours before and 1 hour after C21 intake. The latter applies to 
evening administrations of C21 in-clinic and to all at-home administrations. Water will be 
allowed ad libitum at the trial site except from 1 hour pre-dose to 1 hour post-dose.  
10.7 
Continued administration of investigational medicinal product 
This is a phase 1 trial in healthy volunteers who will receive no medical benefit from the 
administration of IMP and thus there will be no continued administration of C21 or the 
substrates after the end of trial participation. 
10.8 
Administration compliance 
During treatment visits to the trial site, the IMPs will be administered at the trial site under 
medical supervision to ensure compliance.  
During at-home administration of C21, subjects will be contacted via telephone on Day 9 
(±1 day) and Day 13 (±1 day) for a verbal confirmation of C21 self-administration and 
reminder of the importance of compliance with the planned dosing schedule and fasting 
conditions. 
At Visit 3, the subjects will be asked to return any unused IMP and all empty IMP containers. 
A compliance count of the remaining C21 capsules will be performed by the trial site 
personnel. 
10.9 
Return and destruction of investigational medicinal product 
Any unused trial medication will be returned to the Sponsor or destroyed at the trial site after 
approval from the Sponsor. Empty containers will be destroyed at the trial site. 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 assessments are 
detailed in the schedule of events (Table 3 to Table 9). 
11.1 
Recording of data 
The PI will provide the Sponsor with all data produced during the trial from the scheduled 
assessments. They will ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to Sponsor in the eCRF and in all required reports. 
It is important that blood sampling for PK, biomarker analysis and MIST occurs as close as 
possible to scheduled time. To achieve this, the timing priority order at a particular timepoint 
is: 
• Blood sampling for PK, biomarker analysis and MIST 
• Safety ECG 
• Vital signs 
• Clinical laboratory blood sampling 
Timepoints for blood sampling, clinical laboratory sampling, safety ECG, and vital signs are 
outlined in in the schedule of events (Table 3 to Table 9). Time deviation allowances are 
detailed in Table 11. 
For further details regarding the timing of blood sampling for PK, biomarker analysis and 
MIST, including time allowances, refer to Section 11.3. 
11.2 
Demographics and other baseline characteristics 
11.2.1 
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. Consent for CYP2C9 
genotyping at the screening visit will be included in the main ICF. 
There will be an additional, optional ICF for the exploratory genetic sampling (refer to 
Section 11.6.2). 
11.2.2 
Eligibility criteria 
Eligibility criteria should be checked at the screening visit and verified before IMP 
administration on Day 1. The criteria are specified in Sections 9.4 and 9.5. 
11.2.3 
Demographic information 
The following demographic data will be recorded: gender, age, ethnicity and race. 
11.2.4 
Height, weight and body mass index 
Weight and height will be measured without shoes. Body mass index (BMI) will be 
calculated, with one decimal, from the recorded height and weight. 


 
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11.2.5 
Medical/surgical history 
Medical/surgical history will be obtained by subject interview to verify that the eligibility 
criteria are met. 
The medical/surgical history must include all relevant diseases and surgeries within 2 weeks 
prior to the screening visit, as judged by the Investigator. 
11.2.6 
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. 
11.2.7 
Urine drug screen and alcohol tests 
Urine will be screened for drugs of abuse at timepoints outlined in the schedule of events 
(Table 3 to Table 9) using the Drug-Screen Multi-15 Dip Test (nal von minden GmBH or 
equivalent). Additional random tests can be performed during the trial period.  
An alcohol test will be performed at timepoints outlined in the schedule of events (Table 3 to 
Table 9). Additional random tests can be performed during the trial period. 
11.2.8 
Physical examinations 
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph 
nodes and extremities. Complete physical examinations will be done at the screening visit 
(Visit 1) and at end-of-trial visit (Visit 4). 
Symptom-driven physical examinations will be done upon discharge from the trial site on 
Day 6 and Day 19. A symptom-driven physical examination is only warranted when the 
subject has previously indicated any symptoms, or when the Investigator or site nurse has 
reason to believe there may be a problem and will only include the affected organ system or 
systems. 
Any abnormalities will be specified and documented as clinically significant or not clinically 
significant in the eCRF. Abnormal post-IMP administration findings assessed by the 
Investigator as clinically significant will be reported as AEs. 
11.2.9 
Blood sampling for CYP2C9 genotyping 
A venous blood sample (approximately 5 mL) will be drawn at the screening visit for 
genotyping of CYP2C9. Subjects with CYP2C9 genotypes hetero- or homozygous for 
CYP2C9*2 (Arg144Cys) and/or CYP2C9*3 (Ile359Leu) variant alleles associated with 
altered CYP2C9 activity and tolbutamide metabolism will be excluded from trial participation 
[14] (see exclusion criterion no. 9). 
CYP2C9 genotyping will be done by Clinical Chemistry and Pharmacology, Uppsala 
University Hospital, Uppsala, Sweden, on samples collected at screening, and results will be 
reviewed prior to subject inclusion. 


 
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11.2.10 Prior and concomitant medication 
Prior medications taken within 2 weeks prior to first IMP administration will be obtained by 
subject interview to verify that the eligibility criteria are met (see also Section 11.2.10). 
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 (i.e., the 
first day of IMP administration), 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 prior/concomitant medication from the screening visit until the 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 must be noted in the eCRF. 
11.3 
Blood sampling for pharmacokinetics, biomarker analysis and metabolites in 
safety testing 
Venous blood samples (approximately 4 mL) will be collected through an indwelling venous 
catheter or by venepuncture at the pre-specified visits and time-points detailed in Table 4 to 
Table 9. Allowed deviations from planned sampling time points are detailed in Table 11 
below. Blood sampling outside these time allowances will be considered protocol deviations. 
The date and time of collection of each sample will be recorded in the eCRF. 
The blood samples will be collected in pre-labelled tubes. All the collected blood samples will 
be centrifuged to separate plasma. The separated plasma from each blood sample will be 
divided into 5 aliquots in pre-labelled cryotubes (approximately 300 µL in each tube) and 
frozen at <-20°C within 1 hour of centrifugation. Further details will be described in a 
separate laboratory manual. 
The aliquoted plasma samples will be used for the determination of plasma concentration and 
PK analysis (Section 11.4.1), biomarker analysis (Section 11.6.1), and MIST (Section 11.6.2). 
 
 


 
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Table 11 
Blood sampling schedule 
Sampling time points (hh:mm)1 
Allowed time deviations 
Pre-dose 
-60 minutes2 
00:15 
±2 minutes 
00:30 
±3 minutes 
00:45 
±5 minutes 
01:00 
±6 minutes 
01:30 
±9 minutes 
02:00 
±12 minutes 
03:00 
±18 minutes 
04:00 
±24 minutes 
06:00 
±36 minutes 
08:00 
±48 minutes 
10:00 
±1 hour 
12:00 
±1 hour and 12 minutes3 
16:00 
±1 hour and 36 minutes 
24:00 (Day 6 and Day 19) 
±2 hours 
1. 
Sampling time points as shown in Table 4 to Table 9. Time points at 24:00, 36:00, and 48:00 post-dose correspond to pre-dose, 12:00, 
and 24:00 (Day 6 and Day 19) post-dose time points, respectively, on the following days, and the corresponding time deviation 
allowances should be used. 
2. 
Relative to anticipated morning IMP administration (00:00). All other allowed time deviations are relative to each planned time point. 
3. 
On Day 4, Day 5, Day 17 and Day 18, the 12:00 samples must be collected prior to evening administration of C21 (second BID dose). 
11.4 
Assessments related to pharmacokinetic endpoints 
11.4.1 
Pharmacokinetic analysis 
Plasma samples for the determination of plasma concentrations and PK characterization of 
C21, caffeine, tolbutamide, midazolam, nintedanib, as well as their metabolites (M1, 
paraxanthine, 4-hydroxy-tolbutamide, carboxy-tolbutamide, 1-hydroxy-midazolam, and 
BIBF 1202) after the administration of IMP will be analysed by Lablytica Life Science AB, 
Uppsala, Sweden, by means of a validated liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) method. The details of the analytical method used will be described in a 
separate bioanalytical report. 
Other nintedanib metabolites may be analysed if considered appropriate. 
11.5 
Assessments related to safety endpoints 
11.5.1 
Adverse events 
The PI 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 phase 1 studies. 
AEs will be handled in accordance with applicable regulations and guidelines [17, 18]. For 
the purpose of this trial, AEs will be assessed in relation to each IMP used in the trial, i.e., 
C21, caffeine, tolbutamide, midazolam and nintedanib. 


 
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11.5.1.1 
Definition of adverse event 
An AE is defined as any untoward medical occurrence in a subject to whom a medicinal 
product is administered, and which does not necessarily have a causal relationship with this 
treatment.  
An AE can 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. 
11.5.1.2 
Definition of adverse reaction 
An AR is any noxious and unintended response to a medicinal product related to any dose of 
the product. 
The definition of an adverse reaction implies a reasonable possibility of a causal relationship 
between the AE and the IMP. 
11.5.1.3 
Definition of serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalisation or prolongation of existing hospitalisation, 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as "important medical events" that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsion that do not result in hospitalisation; or 
development of drug dependency or drug abuse. 
11.5.1.4 
Definition of serious adverse reaction 
The term serious adverse reaction (SAR) is used whenever either the Investigator or Sponsor 
or designee assesses that there is a reasonable possibility of a causal relationship between the 
SAE and the IMP. 


 
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11.5.1.5 
Definition of suspected unexpected serious adverse reaction 
A serious adverse reaction, the nature, severity or outcome of which is not consistent with the 
reference safety information (Investigator's Brochure for an unapproved investigational 
medicinal product, Summary of Product Characteristics for an approved medicinal product 
used in accordance with the terms of the marketing authorisation). 
11.5.1.6 
Time period and frequency for collecting adverse events 
All AEs (including SAEs) will be collected from the signing of the ICF until the end-of-trial 
visit.  
Any AE with start date on the day of the first 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 
during events must be recorded as applicable. 
Investigators will not be obliged 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 they consider the event to be 
reasonably related to the trial intervention or trial participation, the Investigator must 
promptly notify the Sponsor. 
11.5.1.7 
Collection of 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. 
11.5.1.8 
Recording of adverse events 
AEs must be recorded in the AE log of the eCRF. The Investigator must provide information 
on the AE, preferably as a diagnosis or at least as signs and symptoms; start and end dates, 
start and end time; intensity; causal relationship to IMPs, action taken, and outcome. Any AE 
with start date on the day of the first IMP administration must be recorded with start time. 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. 
11.5.1.9 
Assessment of seriousness 
The Investigator must assess and document the seriousness (serious or non-serious) of each 
AE using the definitions in Section 11.5.1.3. If the event is assessed as serious it must be 
reported as an SAE by the Investigator to the Sponsor according to Section 11.5.1.14. 


 
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For the seriousness criteria of inpatient hospitalisation or prolongation of existing 
hospitalisation to be fulfilled, the AE requires at least an overnight admission (24 hours) or 
prolongs a hospitalisation beyond the expected length of stay. Emergency room visits that do 
not result in admission to the hospital should be evaluated for one of the other serious 
outcomes. 
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 
approach will be taken, and the AE will be reported as an SAE. 
11.5.1.10 Assessment of intensity 
The grading of the intensity of AEs will follow the common terminology criteria for adverse 
events (CTCAE) v5.0 [19]. 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 in the AE Log of 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 refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
11.5.1.11 Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and the use of each IMP, 
i.e., C21, caffeine, tolbutamide, midazolam and nintedanib, using the definitions below. Each 
assessment should be recorded in the AE log of the eCRF. 
Related 
There is a reasonable possibility that the AE was caused by the IMP. There 
is a reasonable time relationship to IMP 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. 


 
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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 IMP.  
11.5.1.12 Outcome of adverse event 
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 (e.g., 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 (e.g., an atrial fibrillation has become chronic). 
Fatal 
Unknown 
11.5.1.13 Action taken with administration of investigational medicinal product 
The Investigator must document the action taken with IMP administration using the 
definitions below and record it on the AE Log of the eCRF. 
IMP not changed 
IMP withdrawn 
Not applicable 
If the withdrawal of any of the IMPs (C21, caffeine, tolbutamide, midazolam or nintedanib) 
due to an AE is required, subject withdrawal should be considered as described in Section 9.8 
following consultation with the Sponsor. 
11.5.1.14 Reporting of serious adverse events 
The Investigator must report SAEs within 24 hours of awareness to PrimeVigilance (refer to 
Section 5), this includes both initial information and any subsequent relevant/significant 
follow up information to a previously reported SAE. The primary mechanism for reporting an 
SAE will be via the paper SAE form provided in the investigator site file (ISF). The 
Investigator must fill in the SAE form, make a scanned copy, and send it by e-mail to 
PrimeVigilance. The trial site must notify the site Monitor via phone or e-mail about the 
submission of the SAE report. 
All available information regarding the SAE must be entered in the AE log for the specific 
subject, i.e., AE term, intensity, causality, outcome, seriousness criteria, action taken with trial 
drug, a narrative including the Investigators rationale for the causality assessment. 


 
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The SAE report will be reviewed by PrimeVigilance to ensure that the report is valid. 
PrimeVigilance will then acknowledge receipt of the SAE report to the reporting Investigator. 
For SAEs where important or relevant information is missing, follow-up queries to the site are 
raised promptly to keep the regulatory reporting timelines specified in Section 11.5.1.15.  
On behalf of the Sponsor, PrimeVigilance will perform an independent assessment of 
causality, including a rationale for the assessment, which will be reviewed and approved by 
the Sponsor. The causality assessment given by the Investigator should not be downgraded by 
the Sponsor. If the Sponsor disagrees with the Investigator’s causality assessment, the opinion 
of both the Investigator and the Sponsor should be provided with the report. 
If any additional information or documentation (e.g., autopsy report) on the SAE is required 
for PrimeVigilance’s assessment of the SAE, PrimeVigilance will request this information 
from the Investigator, and the Investigator is required to promptly respond to the request.  
Any subsequent relevant/significant follow up information to a previously reported SAE must 
be entered in the AE log for the specific subject. If the Investigator makes any changes to the 
assessment of the case e.g., changes in seriousness, causality, or intensity, a justification for 
the change should be provided in the case narrative. 
Detailed information on the SAE handling and SUSAR reporting will be described in a trial 
specific safety management plan (SMP). 
11.5.1.15 Reporting of suspected unexpected serious adverse reactions 
An SAE will be classified as a SUSAR when either the Investigator or the Sponsor assesses 
that there is a reasonable possibility of a causal relationship between the SAE and the IMP, 
and the Sponsor assesses the event as unexpected based on the applicable reference safety 
information (i.e., in the IB/SmPC). 
SAEs which are assessed by Sponsor to be a SUSAR will be reported by PrimeVigilance to 
the competent authority (CA) via EudraVigilance and to the IEC (if required) in accordance 
with local regulations and 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) starts as soon as the Sponsor or 
PrimeVigilance, has received the information containing the minimum reporting criteria. The 
date will be documented on the acknowledgement receipt to the reporting Investigator.  
The Sponsor’s trial physician 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 Sponsor or PrimeVigilance is responsible for informing the Investigators at the 
participating site of relevant information about potential SUSARs.  
The Sponsor or a designee is responsible for once a year throughout the clinical trial (or on 
request), submit a safety report to the CA and the IEC taking into account all new available 
safety information received during the reporting period. 
Detailed information on the SAE handling and SUSAR reporting are described in a trial 
specific SMP. 


 
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11.5.1.16 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 resolution or to the end-of-trial visit, 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 
recovered, stabilised, or recovered with sequelae, 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. 
11.5.1.17 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy of any female partners of male trial 
subjects, the outcome of the pregnancy (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 and must be handled and 
reported as such using the paper SAE form as described in Section 11.5.1.14. Spontaneous 
miscarriages should be reported and handled as AEs. All outcomes of pregnancy must be 
reported to the Sponsor and the PI on the pregnancy outcomes report form provided in the 
ISF. 
11.5.1.18 Treatment of overdose 
An overdose is a dose in excess of the dose specified in this clinical trial protocol (CTP). 
In cases of accidental overdose of C21, standard supportive measures will be adopted as 
required. No known antidotes are available in case of overdose with C21. There have been no 
reported cases of C21 overdose. 
In case of accidental caffeine overdose, standard supportive measures will be adopted as 
required, with special care to symptomatic treatment. The use of intravenous diazepam 
5-10 mg should be considered in case of central nervous system excitation and/or seizures. In 
case of tachycardia and/or increased blood pressure, the use of a beta blocker should be 
considered. Antacids should be used as needed, complemented with the use of intravenous 
omeprazole 40 mg in case of hematemesis.  
In case of accidental overdose with tolbutamide, standard supportive measures will be 
adopted as required, taking specific care to monitor the subject’s blood glucose and providing 
standard treatment in case of hypoglycaemia. No specific antidotes are available in case of 
tolbutamide overdose. 
In case of accidental overdose with midazolam, standard supportive measures will be adopted 
as required, with special care to symptomatic treatment of effects on the cardiovascular, 
pulmonary and central nervous systems. In case of a serious depression of the central nervous 
system, the use of the benzodiazepine antagonist flumazenil under careful observation of the 
subject should be considered. 


 
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In case of accidental overdose with nintedanib, standard supportive measures will be adopted 
as required. There are no known antidotes in case of nintedanib overdose. 
Overdoses must be documented in the eCRF. An overdose with associated AE will be 
recorded as the AE diagnosis/symptoms in the AE log of the eCRF. An overdose without 
associated symptoms will only be reported in the subject’s medical records and documented 
in the PD log. 
11.5.2 
Vital signs 
Systolic and diastolic blood pressure and pulse rate will be measured in supine position after 
10 minutes of rest.  
Any vital signs outside of normal ranges will be judged as clinically significant or not 
clinically significant. The assessment will be recorded in the eCRF. Abnormal post-IMP 
administration findings assessed by the Investigator as clinically significant will be reported 
as AEs. 
11.5.3 
Safety electrocardiogram 
Single 12-lead ECGs will be recorded in supine position after 10 minutes of rest using an 
ECG machine. The resting heart rate (HR) and PQ/PR, QRS, QT and QTcF intervals will be 
recorded.  
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-IMP administration findings assessed by the Investigator as 
clinically significant will be reported as AEs. 
11.5.4 
Clinical laboratory assessments 
Blood samples for the 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. 
The clinical laboratory parameters are defined in Table 12 and will be assessed at visits and 
timepoints specified in Table 3 to Table 9. 
Any laboratory values outside of normal ranges will be specified and documented as normal, 
abnormal not clinically significant, or abnormal clinically significant in the eCRF. Abnormal 
values assessed by the Investigator as clinically significant will be reported as AEs. If an 
abnormal value is associated with corresponding clinical signs or symptoms, the 
sign/symptom should be reported as the AE. 
 
 


 
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Table 12 
Laboratory parameters 
Category 
Parameter 
Clinical chemistry 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bilirubin (total and conjugated) 
Calcium 
Creatinine (eGFR included) 
Glucose 
Potassium 
Sodium 
Urea 
Haematology 
Erythrocyte count 
Leukocyte count with differential count 
Haematocrit (B-EVF) 
Haemoglobin (Hb) 
Mean corpuscular volume (MCV) 
Mean corpuscular haemoglobin (MCH) 
Platelet count 
Coagulation 
Activated Partial Thromboplastin Time (APTT) 
Prothrombin Complex International Normalised Ratio (PK[INR]) 
FSH-test (at the screening 
visit, postmenopausal females 
only) 
Follicle stimulating hormone (FSH) 
eGFR: Estimated glomerular filtration rate. 
11.6 
Assessments related to exploratory endpoints 
11.6.1 
Biomarker analysis 
Aliquots of plasma collected on Day 1 and Day 17 will be used for the analysis of the plasma 
concentration profiles of endogenous biomarkers of transporter inhibition and/or induction. 
The timepoints for biomarker sample analysis are specified Table 4 (Day 1) and Table 8 
(Day 17). Biomarker plasma concentrations will be analysed by Lablytica Life Science AB, 
Uppsala, Sweden. 
The primary exploratory biomarker will be coproporphyrin I, a biomarker of OATP1B 
activity, which will be assessed until 12 hours post-dose. Other exploratory biomarkers of 
transporter inhibition and/or induction may be analysed, including for longer than 12 hours, if 
considered appropriate. 
Exploratory endpoints related to coproporphyrin I biomarker analysis will be reported in the 
CTR. Exploratory endpoints related to other biomarkers will not be reported in the CTR but 
may be included in a separate report. 


 
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11.6.2 
Metabolites in safety testing 
Aliquots of plasma collected on Day 17 (as detailed in Table 8) will be used for MIST 
analysis of C21 in plasma at steady state. A pre-IMP administration reference aliquot of 
plasma will be collected at pre-dose on Day 1 (as detailed in Table 4). Additional MIST 
analysis may be done on samples from other days, not only from Day 17, if considered 
appropriate. 
MIST analyses will be done by MetaSafe Sweden AB, Södertälje, Sweden. Plasma samples 
for MIST analyses will be disposed of as detailed in Section 12.3 once analysed, and may be 
stored for a maximum of 10 years prior to analysis. 
Exploratory endpoints related to MIST will not be reported in the CTR but may be included in 
a separate report. 
11.6.3 
Exploratory genetic blood sampling 
Venous blood samples (approximately 5 mL) will be drawn for future genotyping of genes 
encoding enzymes and/or transporters of relevance for C21 and substrate metabolism and/or 
transport. This sampling is optional for the subjects and may be performed at any time during 
the trial.  
A separate ICF will be prepared for this assessment as it is optional. 
Exploratory endpoints related to genotyping will not be reported in the CTR but may be 
included in a separate report. 
11.7 
Appropriateness of measurements 
All methods used are commonly used in standard medical care and in phase 1 clinical studies. 
Non-compartmental analysis of PK parameters is standard for phase 1 clinical studies. 


 
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12 
PROCEDURES FOR BIOLOGICAL SAMPLES 
12.1 
Sample collection 
The sample collection procedure for PK analysis is described in Section 11.3.  
Blood sampling procedures for genotyping (CYP2C9), coproporphyrin I (exploratory 
biomarker for OATP1B1 inhibition) and exploratory genotyping are described in 
Sections 11.2.9, 11.6.1 and 11.6.2, respectively. 
Blood and urine samples for safety parameters 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 be 
approximately 428 mL (Table 13) over the full trial duration. For reference, a regular blood 
donation consists of between 350 mL to 450 mL (±10 %) for persons weighing at least 
45-50 kg [20]. 
Table 13 
Estimated blood volumes 
Assessment 
Estimated number of 
sampling occasions 
Estimated volume 
per occasion 
Total 
Blood sampling for PK, biomarker analysis, MIST 
81 
4 mL 
324 mL 
HIV, Hepatitis B/C 
1 
4 mL 
4 mL 
CYP2C9 genotyping 
1 
5 mL 
5 mL 
Clinical laboratory profile (clinical chemistry, 
haematology, coagulation) 
6 
15 mL 
90 mL 
Exploratory genotyping (optional) 
1 
5 mL 
5 mL 
 
 
Total: 
428 mL 
12.3 
Handling, storage and destruction of laboratory samples 
All biological samples will be registered in a biobank at CTC (Swedish Health and Social 
Care Inspectorate biobank registry number 893).  
The samples for analyses of PK, biomarkers, MIST, and exploratory genotyping will be 
stored at ≤ -70 °C until analysed.  
Any remains of the CYP2C9 genotyping, clinical laboratory profile, as well as HIV and 
hepatitis B/C screening samples will be disposed of after analyses. 
All plasma samples transferred to the Sponsor’s biobank or to third party laboratories 
(including exploratory analyses) will, if not used, be disposed of after 10 years. 
12.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
The trial site keeps full traceability of collected biological samples from the trial subjects 
while in storage at the trial site until shipment and keeps documentation of receipt of arrival. 
The sample receiver (the analytical laboratory) will keep full traceability of the samples while 
in their storage and during use until used or disposed of. 
The Sponsor will keep oversight of the entire lifecycle of the samples through internal 
procedures, monitoring of trial sites and auditing of external laboratory providers. 


 
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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 PI will ensure that: 
• Subject withdrawal of consent is notified immediately to the Sponsor. 
• Biological samples from the subject, if stored at the trial site, are immediately 
identified, disposed of/destroyed and the action is documented. 
The Sponsor has to ensure that the laboratories holding the samples are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed or returned to the 
trial site 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 the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6(R2) 
guideline [21]. 
Identified risks will be categorised separately from the CTP. 
13.2 
Quality assurance and quality control 
The Sponsor has delegated the responsibilities outlined below to CTC whilst maintaining 
overall trial oversight: 
• Implementing and maintaining quality assurance (QA) and quality control (QC) systems 
with written SOPs with regard to management of identified risks, CTP compliance, good 
clinical practice (GCP) compliance and applicable regulatory requirements.  
• Securing agreements with involved subcontractors and to perform regular subcontractor 
oversight to ensure CTP compliance, GCP compliance and compliance with applicable 
regulatory requirements.  
• Implementing a risk-based validated EDC system and maintain SOPs for the whole life- 
cycle of the system.  
• QC application to each stage of data handling to ensure that all data are reliable and have 
been processed correctly. 


 
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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 [22] and are consistent with the ICH E6 (R2) guideline for GCP [21], 
the EU Clinical Trials Directive 2001/20/EC [23], and applicable local regulatory 
requirements. 
14.2 
Ethics and regulatory review 
The PI 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 has delegated to CTC the responsibility to submit trial documents to the 
applicable CA according to local regulatory requirements. 
Approval must be obtained in writing from both the IEC and CA before the first subject can 
be recruited. 
The Sponsor will provide the CA, IEC and PI 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 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 emphasised 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 and 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 card 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. 
A separate ICF will be provided for the optional exploratory genotyping. Procedures for 
collection and documentation of this consent will follow the procedures described above for 
the consent for the main trial. 
14.4 
Subject information card 
The subject will be provided with a subject information card including the following 
information:  
• That they are participating in a clinical trial. 
• Subject trial ID. 


 
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• That they are treated with the IMP. 
• The name and phone number of the Investigator. 
• The name and address of the Sponsor. 
14.5 
Subject privacy and data protection 
The clinical personnel affirm and uphold the principle of the subject’s right to privacy during 
and after the trial. 
The ICF includes information that data will be recorded, collected and processed and 
information related to potential transfer to European Economic Area (EEA) or non-EEA 
countries. In accordance with the General Data Protection Regulation (GDPR [EU] 2016/679) 
[24], these pseudonymised data will not identify any persons taking part in the trial. If any 
part of the data is handled by any other organisation, inside or outside the European Union, 
appropriate agreements and/or other documentation will be established, to ensure that the data 
processing is performed in accordance with the provisions of the GDPR and other relevant 
legislation before any data transfer takes place. 
The potential subject should be informed that by signing the ICF they approve that authorised 
representatives from the Sponsor and CTC, as well as the concerned IEC and CA, have direct 
access to their 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 their personal data and the right to request 
rectification of any data that is not correct and/or complete in accordance with GDPR [24] and 
the request will be raised to the PI.  
The Investigator must file a subject identification list which includes sufficient information to 
link records, i.e., the eCRF and clinical records. This list must 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 pseudo anonymised, 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. After the trial end, only 
pseudo anonymised data can be used, i.e., aggregated data sets, can be used. 
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 trial site (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 the Sponsor, a CA, or an IEC may perform audits or inspections 
at the trial site, including source data verification (SDV). The purpose of an audit or 
inspection is to systematically and independently examine all investigation-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the CTP, 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 trial site. 
14.8 
Insurance 
Subjects will be covered under the Sponsor’s liability insurance policy through the Swedish 
Pharmaceutical Insurance (Läkemedelsförsäkringen) (via CTC’s share in the Swedish 
Pharmaceutical Insurance Service AB). 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. 


 
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15 
TRIAL MANAGEMENT 
15.1 
Training of trial site personnel 
Before inclusion of the first trial subject, a Sponsor representative or delegate will perform a 
trial initiation visit at the trial site. 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 
delegated trial-specific duties. 
15.2 
Clinical monitoring 
The Sponsor is responsible for securing agreement from all involved parties to ensure direct 
access to all participating sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities.  
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. At 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 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. 
• verify that the correct informed consent procedure has been adhered to for participating 
subjects. 
• 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. 
• 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 project team members at the 
trial site in accordance with the RBM plan. When the trial has been completed, all queries 
have been resolved and the database has been locked, the Monitor will perform a close-out 
visit. 


 
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15.3 
Source data documents 
A separate origin of source data list will be generated before the start of enrolment, specifying 
the location of the source of derived information appearing in the eCRF. This document must 
be signed by the PI 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, and that verify 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 must guarantee access to source documents to the Monitor, CAs and the 
IECs, if required. 
15.4 
Trial agreements 
This trial is fully financed by the Sponsor, Vicore Pharma AB. The management and conduct 
of the clinical trial have been outsourced to the contract research organisation (CRO), CTC. 
The PI is an employee of CTC AB.  
The agreements between Sponsor and CTC, and between Sponsor and the trial site, must be in 
place before any trial-related procedures can take place, or subjects be enrolled.  
The Sponsor and CRO responsibility and duty split is regulated in a separate clinical trial 
agreement.  
The PI must comply with all the terms, conditions, and obligations of the clinical trial 
agreement for this clinical trial.  
15.5 
Trial timetable and end of trial 
The trial is expected to start in Q1 2023 and to be completed by Q2 2023. 
A subject is considered to have completed the trial if they have 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 must be informed promptly. Conditions that may warrant trial termination 
include, but are not limited to the following: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects 
included in the trial or potential trial subjects. 
• A decision by the Sponsor to suspend or discontinue the development of the IMP. 
If the CA obtains information that raises doubts about the safety or scientific validity of the 
trial, the CA may also 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 Investigator for their 
opinion, to be delivered within one week (Directive 2001/20/EC, Article 12, Section 1) [23]. 
If the trial is prematurely terminated or suspended for any reason, the Investigator/institution 
must promptly inform the trial subjects and must assure appropriate follow-up for the 
subjects. 


 
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15.7 
Reporting and publication 
15.7.1 
Clinical trial report 
A summarising report will be submitted to a publicly available database (EudraCT) within 12 
months after completion of the trial, in accordance with applicable regulations.  
After completion of the trial, an ICH E3 [25] guideline-compliant CTR describing the conduct 
of the trial, any statistical analyses performed, and the results obtained will be prepared by the 
Sponsor or their designee. The CTR will be reviewed and approved by, as a minimum, the PI 
and the Sponsor.  
Results obtained from exploratory analyses may be reported separately. 
15.7.2 
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 must 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. 
15.7.3 
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. 
15.7.4 
Publication 
The results from this trial may be submitted for publication at the discretion of the Sponsor. 
15.8 
Archiving 
The PI is responsible for maintaining essential documents, (as defined in ICH E6(R2), 
Section 8 [21]) for 15 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 pseudonymous eCRF data), the original signed ICFs and 
detailed records of IMP disposition.  
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 the ICH E6(2) guideline, Section 8 
[21], and applicable regulatory requirements. 
The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the site and 
filed in the investigator trial file for archiving for 15 years after finalisation of the CTR. 
The completed original eCRFs are the sole property of the Sponsor and must 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 prior to 
being used on final 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 project 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 
during or after the subject’s visit. To avoid inter-observer variability, every effort should be 
made to ensure that preferably same individual who made the initial baseline determinations 
completes all corresponding follow-up evaluations. 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 will record such information in the eCRF. The Investigator will be required to 
electronically sign off on 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.  


 
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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 
answer the queries in the eCRF either by correcting the data or by entering a response to 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 may be received in 
electronic format or as a paper printout. Key variables are defined to uniquely identify each 
sample record. File and data formats are agreed with the external data provider. 
16.6 
Medical coding 
Medical coding will be performed by trained personnel at the trial site. AEs and 
medical/surgical history verbatim terms are coded using the medical dictionary of regulatory 
activities (MedDRA, latest version available at eCRF setup).  
Prior and concomitant medications will be coded according to the World Health Organisation 
(WHO) drug dictionary classification system WHODrug. 
All coding will be approved by the Sponsor prior to database lock.  
16.7 
Database lock 
When all data have been entered and discrepancies solved, clean file will be declared, the 
database will be locked, 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. 
The endpoint analyses will be performed by CTC, except future analyses of exploratory 
endpoints after completion of the CTR. 
17.1 
General 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic 
mean, standard deviation (SD), median, minimum and maximum value. For AUC and Cmax 
parameters, the geometric mean and geometric coefficient of variation (CV%) will be 
presented. 
Categorical data will be presented as counts and percentages. When applicable, summary data 
will be presented by treatment, and by assessment time. Individual subject data will be listed 
by subject number, treatment, 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 PK parameters will be calculated by non-
compartmental analysis (NCA) using the software Phoenix WinNonlin® version 8.3 or later 
(Certara, U.S.A.). 
Baseline will be defined as the last non-missing data collection point prior to the first 
administration of IMP. All hypothesis testing will use a significance level of 5 %. 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 to meet the trial objectives. 
17.3 
Analysis data sets 
Table 14 
Definitions of analysis sets 
Analysis set 
Definition 
Full analysis set 
(FAS) 
All included subjects who have received at least 1 dose of any IMP and provided at least 
1 post-baseline data point. This analysis set will be used for safety assessments. 
PK analysis set 
(PKAS) 
All included subjects who received at least 1 dose of IMP and provided an evaluable 
plasma concentration profile, and who have no AEs or protocol deviations judged to affect 
the PK analysis. Individual PK values may be excluded from the analysis as specified in 
the SAP. 
PK ratio analysis 
set (PKRAS) 
All subjects who completed the trial up until at least Day 19 and provided evaluable 
plasma concentration profiles, and who have no AEs or protocol deviations judged to 
affect the PK analysis. Individual PK values may be excluded from the analysis as 
specified in the SAP. 


 
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17.4 
Description of trial population 
17.4.1 
Demographics and baseline characteristics 
Descriptive statistics for demographics, weight, height and BMI will be presented for all 
subjects. All data will be listed by subject. 
17.4.2 
Medical/surgical history and prior/concomitant medication 
Medical/surgical history will be presented by system-organ-class (SOC) and preferred term 
(PT). Prior/concomitant medications will be presented by the WHO anatomical therapeutic 
chemical (ATC) classification level 4 and WHODrug preferred names. 
All data will be listed by subject. 
17.4.3 
Administration compliance 
All administered individual doses will be listed by subject. 
17.5 
Analysis of primary endpoints 
17.5.1 
Analysis of pharmacokinetics 
The PK analysis will be performed by CTC. PK parameters will be calculated based on the 
PKAS by standard non-compartmental analysis (NCA) using the software Phoenix 
WinNonlin® version 8.3 or later (Certara Inc, USA). 
The primary PK evaluation is to evaluate the impact of C21 on the PK of caffeine, 
tolbutamide, midazolam, nintedanib and their primary metabolites. PK parameters to be 
calculated for caffeine, tolbutamide, midazolam, nintedanib and their primary metabolites are 
Cmax, Tmax, AUC0-last and AUCinf. Additional parameters may be calculated if data permits and 
considered appropriate. The ratios of Cmax, AUC0-last and AUCinf with C21 and without C21 
will be calculated based on the PKRAS. 
The secondary PK evaluations are to evaluate the PK of C21 and its main metabolite M1. 
PK parameters to be calculated for C21 and M1 are Cmax, Tmax, AUC0-last and AUCtau. 
Additional parameters may be calculated if data permits and considered appropriate. 
For AUCinf, the area under the plasma concentration vs. time curve will be calculated to the 
timepoint of the last quantifiable plasma concentration of respective IMP and then 
extrapolated to infinity using the concentration in the last quantifiable sample and the 
estimated terminal elimination rate constant (Lambdaz).  
In general, PK data will be presented by substance (C21, caffeine, tolbutamide, midazolam, 
nintedanib and their main metabolites) using summary statistics with number of 
measurements, arithmetic mean, SD, as well as median, minimum and maximum values. For 
AUC and Cmax parameters, the geometric mean and geometric CV% will be presented. Cmax 
and AUC ratios will be analysed using a paired t-test and summarised by substance using 
geometric means and their 90% confidence intervals. 
All data will be listed by subject. 
17.6 
Analysis of secondary endpoints 
17.6.1 
Secondary pharmacokinetic endpoints 
Refer to Section 17.5.1. 


 
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17.6.2 
Adverse events 
An overview of all AEs, including SAEs, intensity, relationship to IMP and deaths will be 
presented. The incidence of AEs and SAEs will be summarised by SOC and PT by treatment 
and overall. All AE data will be listed by subject and include the verbatim term entered by the 
Investigator. 
17.6.3 
Vital signs 
Vital signs will be summarised by trial day. Data will be presented with absolute change from 
baseline. All data will be listed by subject. 
17.6.4 
Electrocardiogram 
All ECGs will be categorised as ”normal”, ”abnormal, not clinically significant”, or 
”abnormal, clinically significant” (as judged by the Investigator) and summarised by trial day 
using frequency tables. Changes over time will be presented using shift tables, if appropriate. 
All data will be listed by subject. 
17.6.5 
Clinical laboratory 
Clinical laboratory data will be summarised by trial day with absolute change from baseline. 
Abnormal, clinically significant values will be summarised separately, if considered 
appropriate. All data will be listed by subject. 
17.7 
Analysis of exploratory objectives 
Biomarker data related to coproporphyrin I will be summarised by trial day with absolute 
change from baseline. All data will be listed by subject. 
The analysis of other exploratory endpoints, including other biomarkers, MIST and 
exploratory genotyping, will not be reported in the CTR. The analyses related to these 
exploratory endpoints will be specified elsewhere and may not be included in the SAP. 


 
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19 
SIGNATURES 
19.1 
Principal Investigator statement 
I, the undersigned, 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 
Approval of the clinical trial protocol 
I, the undersigned, approve this CTP. 
 
Sponsor signatories