Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Idiopathic Pulmonary Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 52
Healthy volunteers: no

Brief summary:
This trial is a multi-centre, open-label, single-arm phase 2 trial investigating the safety, efficacy and pharmacokinetics of C21 in subjects with idiopathic pulmonary fibrosis.

Detailed description:

Arms:
arm 1: C21 100 mg BID (twice daily)

Interventions: intervention 1: C21
Intervention descriptions: intervention 1: C21 100 mg BID (twice daily)

Protocol document:
Prot_SAP_000.pdf: 
 
Clinical Trial Protocol and Statistical Analysis Plan 
 
Title: 
A Phase 2, Multi-Centre, Open-Label, Single-Arm Trial Investigating 
the Safety, Efficacy and Pharmacokinetics of C21 in Subjects with 
Idiopathic Pulmonary Fibrosis 
 
Trial ID: 
 
VP-C21-005 
 
NCT No.: 
 
NCT04533022 
 
Version: 
 
7.0 
 
Date: 
 
15-Sep-2021 
 
 
 
 
 
 
 
 
 
 


 
Clinical Trial Protocol 
 
Vicore Pharma AB 
Version: 7.0 
Trial ID: VP-C21-005 
Date: 15-Sep-2021 
 
 
Confidential 
Page 1 of 59 
 
 
 
 
 
 
 
 
 
Clinical Trial Protocol 
 
Title: 
A Phase 2, Multi-Centre, Open-Label, Single-Arm Trial Investigating 
the Safety, Efficacy and Pharmacokinetics of C21 in Subjects with 
Idiopathic Pulmonary Fibrosis 
Short Title: 
C21 in IPF 
Sponsor: 
Vicore Pharma AB 
Kronhusgatan 11 
SE-411 05 Göteborg 
Sweden 
Trial ID: 
VP-C21-005 
EudraCT No.: 
2020-000822-24  
Investigational 
Medicinal Product: 
 
C21 
Indication: 
Idiopathic Pulmonary Fibrosis (IPF) 
Phase: 
2 
Version: 
7.0  
Date: 
15-Sep-2021 
 
 
 
 
 
 
 
 
 
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. 


 
Clinical Trial Protocol 
 
Vicore Pharma AB 
Version: 7.0 
Trial ID: VP-C21-005 
Date: 15-Sep-2021 
 
 
Confidential 
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Sponsor’s Approval of Clinical Trial Protocol 
 
This trial protocol was subject to critical review by the Sponsor. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational product, as well 
as with the ethical and scientific principles governing clinical research as set out in the latest 
version of the Declaration of Helsinki and the guidelines on Good Clinical Practice (GCP). 
This trial will be conducted in compliance with the protocol, GCP, and applicable regulatory 
requirements. 
 
 
 
 
Sponsor’s Medical Responsible: 
___________________ 
______________ 
   
 
 
 
 
 
 
 
 
Sponsor’s Statistical Expert: 
___________________ 
______________ 
    
 
 
 
 
 
 
 
 
VP Clinical Development: 
___________________ 
______________ 
   
 
 
 
 
 
 
 




 
Clinical Trial Protocol 
 
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Trial ID: VP-C21-005 
Date: 15-Sep-2021 
 
 
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TABLE OF CONTENTS 
SPONSOR’S APPROVAL OF CLINICAL TRIAL PROTOCOL ........................................ 2 
SIGNATORY INVESTIGATOR’S APPROVAL OF CLINICAL TRIAL PROTOCOL ... 3 
1 
PROTOCOL SUMMARY ......................................................................................... 7 
2 
SCHEDULE OF PROCEDURES ........................................................................... 11 
3 
BACKGROUND AND RATIONALE .................................................................... 14 
3.1 
Indication Idiopathic Pulmonary Fibrosis ........................................................ 14 
3.2 
Current Treatment for Idiopathic Pulmonary Fibrosis .................................. 14 
3.3 
Investigational Medicinal Product ..................................................................... 15 
3.4 
Preclinical Safety ................................................................................................. 16 
3.5 
Clinical Safety ...................................................................................................... 17 
3.6 
Rationale for Trial ............................................................................................... 18 
3.7 
Rationale for Trial Design .................................................................................. 18 
3.8 
Rationale for Dose and Dosing Regimen ........................................................... 19 
3.9 
Risk-Benefit Assessment ..................................................................................... 20 
4 
OBJECTIVES AND ENDPOINTS ......................................................................... 21 
4.1 
Primary Objective ............................................................................................... 21 
4.2 
Secondary Objectives .......................................................................................... 21 
4.3 
Exploratory Objectives ....................................................................................... 21 
4.4 
Primary Endpoint ................................................................................................ 21 
4.5 
Secondary Endpoints........................................................................................... 21 
4.6 
Exploratory Endpoints ........................................................................................ 21 
5 
TRIAL POPULATION ............................................................................................ 22 
5.1 
Inclusion Criteria................................................................................................. 22 
5.2 
Exclusion Criteria ................................................................................................ 23 
5.3 
Restrictions During the Trial ............................................................................. 25 
5.4 
Screening failure .................................................................................................. 25 
5.5 
Withdrawal Criteria ............................................................................................ 25 
6 
TRIAL DESIGN ....................................................................................................... 26 
6.1 
Overall Trial Design ............................................................................................ 26 
6.2 
Number of Subjects ............................................................................................. 27 
6.3 
Trial Diagram ...................................................................................................... 28 
6.4 
Trial Duration and Participating Centers ......................................................... 28 
6.5 
Schedule of Events ............................................................................................... 28 
7 
TRIAL TREATMENT ............................................................................................. 32 
7.1 
Investigational Medicinal Product ..................................................................... 32 
7.2 
Packaging, Labelling and Storage...................................................................... 32 
7.3 
IMP Administration ............................................................................................ 32 
7.4 
Compliance Check and Drug Accountability ................................................... 33 
7.5 
Blinding of the Trial ............................................................................................ 33 
7.6 
Procedures for Unblinding ................................................................................. 33 


 
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7.7 
Prior and Concomitant Medications ................................................................. 33 
8 
ASSESSMENTS ....................................................................................................... 34 
8.1 
Efficacy Assessments ........................................................................................... 34 
8.2 
Safety Assessments .............................................................................................. 35 
8.3 
Other Assessments ............................................................................................... 37 
9 
ADVERSE EVENTS ................................................................................................ 38 
9.1 
Adverse Event Definitions .................................................................................. 38 
9.2 
Adverse Event Assessment Definitions .............................................................. 38 
9.3 
Reporting of Adverse Events .............................................................................. 39 
9.4 
Follow-up on Adverse Events ............................................................................. 40 
9.5 
Pregnancies .......................................................................................................... 40 
10 
CHANGES TO TRIAL CONDUCT ....................................................................... 41 
10.1 
Protocol Amendments ......................................................................................... 41 
10.2 
Premature Termination of the Trial .................................................................. 41 
10.3 
Premature Termination of a Trial Site .............................................................. 41 
11 
DATA HANDLING AND RECORD KEEPING .................................................. 42 
11.1 
Data from Clinical Trial Sites ............................................................................ 42 
11.2 
Source Data .......................................................................................................... 42 
11.3 
Coding of Data ..................................................................................................... 43 
11.4 
Subject Confidentiality ....................................................................................... 43 
12 
RETENTION OF DOCUMENTS........................................................................... 43 
13 
STATISTICAL METHODS .................................................................................... 44 
13.1 
Sample Size and Power Considerations ............................................................ 44 
13.2 
Subject Disposition .............................................................................................. 44 
13.3 
Efficacy Analysis .................................................................................................. 44 
13.4 
Safety Analysis ..................................................................................................... 45 
14 
INDEPENDENT DATA MONITORING COMMITTEE ................................... 46 
15 
GOOD CLINICAL PRACTICE ............................................................................. 46 
16 
ETHICS ..................................................................................................................... 47 
16.1 
Independent Ethics Committees / Health Authorities ..................................... 47 
16.2 
Informed Consent ................................................................................................ 47 
17 
AUDITS AND INSPECTIONS ............................................................................... 47 
18 
MONITORING......................................................................................................... 48 
19 
REPORTING OF RESULTS .................................................................................. 48 
19.1 
Integrated Clinical Trial Report ........................................................................ 48 
19.2 
Use of Information ............................................................................................... 48 
19.3 
Publication of Results .......................................................................................... 48 
20 
INSURANCE AND LIABILITY............................................................................. 49 


 
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Date: 15-Sep-2021 
 
 
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21 
REFERENCES ......................................................................................................... 50 
22 
ABBREVIATIONS................................................................................................... 53 
23 
PROTOCOL AMENDMENT HISTORY .............................................................. 55 
 
 
 


 
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Date: 15-Sep-2021 
 
 
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1 
PROTOCOL SUMMARY   
Trial Title 
 
A Phase 2, Multi-Centre, Open-Label, Single-Arm Trial Investigating the Safety, Efficacy 
and Pharmacokinetics of C21 in Subjects with Idiopathic Pulmonary Fibrosis 
Trial ID 
VP-C21-005 
Trial Phase 
Phase 2 
Objectives 
 
Primary Objective 
To investigate the safety of C21 200 mg daily dose (100 mg b.i.d.) administered orally to 
subjects with IPF.   
Secondary Objectives 
To evaluate: 
x 
The efficacy of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects 
with IPF for 12 weeks 
x 
The efficacy of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects 
with IPF for 24 weeks 
x 
The efficacy of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects 
with IPF for 36 weeks 
x 
The pharmacokinetic (PK) profile of C21 200 mg daily dose (100 mg b.i.d.) after 
multiple dosing 
 
Exploratory Objectives 
To investigate a range of laboratory parameters as potential biomarkers of inflammation, 
proliferation and fibrosis following oral administration of C21 200 mg daily dose (100 mg 
b.i.d.).  
Endpoints 
 
Primary Endpoints 
Nature and frequency of adverse events occurring over the trial period. 
Secondary Endpoints 
x 
Change from baseline in forced vital capacity (FVC) value over 12, 24, and 36 weeks 
x 
Plasma concentration of C21 and derived PK parameters evaluated in a sub-set of 
subjects 
Exploratory Endpoints 
Blood samples will be saved for potential future analyses of biomarkers reflecting fibrosis and 
inflammation.  
Trial Design 
 
This is an multi-centre, open-label, single-arm trial investigating the safety and efficacy of 
C21 in which subjects with IPF will be treated for a maximum of 36 weeks. The aim is to 
enroll a total of 60 subjects with a completed 12-week visit.. 
To ensure careful and ongoing evaluation of the individual risk/benefit profiles, each subject 
will undergo a medical evaluation by the investigator at the end of every 12-week treatment 
period, where the investigator will evaluate if continuation into the next 12-week treatment 
period is considered safe for the individual subject. 


 
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Inclusion Criteria 
 
1)  Written informed consent, consistent with ICH-GCP R2 and local laws, obtained before 
the initiation of any trial related procedure 
2)  A diagnosis of IPF within 5 years prior to Visit 1, as per either 
ATS/ERS/JRS/ALAT/Fleischner guidelines (Raghu et al., 2018; Lynch et al., 2018)  
3)  Age ≥40 years 
4)  FVC ≥60% predicted at Visit 1 and 2 (Specific for UK: FVC ≥80% predicted at Visit 1 
and 2 or FVC ≥60% predicted at Visit 1 and 2 for subjects previously treated with 
antifibrotic treatment e.g., nintedanib and/or pirfenidone, or refused such treatments) 
5)  FEV1/FVC ratio >0.7 prebronchodilator at Visit 1 and 2 
6)  Oxygen saturation (SpO2) >85% by pulse oximetry while breathing ambient air at rest at 
Visit 1 
7)  High-resolution computed tomography (HRCT) within 36 months prior to Visit 1 with 
central reading demonstrating either a or b, and c: 
a. A pattern consistent with usual interstitial pneumonitis (UIP) according to either 
    ATS/ERS/JRS/ALAT or Fleischner guidelines (Raghu et al., 2018; Lynch et al., 2018): 
i.UIP 
ii.Probable UIP 
b. A pattern indeterminate for UIP according to either ATS/ERS/JRS/ALAT or Fleischner 
guidelines (Raghu et al., 2018; Lynch et al., 2018) and a historical biopsy consistent 
with IPF 
c. Extent of fibrosis > extent of emphysema 
8)  Fully vaccinated against COVID-19 prior to screening (Visit 1). Subjects are considered 
fully vaccinated for COVID-19 ≥14 days after they have received vaccination dose(s) 
according to local label 
Exclusion Criteria 
 
рҘ Previous use of antifibrotic treatment for an interstitial lung disease (e.g. nintedanib or 
pirfenidone) for > 6 months
2) Smoking (including e-cigarettes) within 6 months prior to Visit 1 
3) Body mass index (BMI) >35 or <18 
4) IPF exacerbation within 3 months prior to Visit 1, as defined by Collard et al. (2016): 
x 
Acute worsening or development of dyspnoea typically <1 month duration 
x 
Computed tomography with new bilateral ground-glass opacity and/or consolidation 
superimposed on a background pattern consistent with usual interstitial pneumonia 


 
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pattern (if no previous computed tomography is available, the qualifier “new” can be 
dropped) 
x 
Deterioration not fully explained by cardiac failure or fluid overload 
5) Concurrent serious medical condition with special attention to cardiac or ophthalmic 
conditions (e.g. contraindications to cataract surgery), or moderate to severe hepatic 
impairment, which in the opinion of the investigator makes the subject inappropriate for 
this trial 
6) Malignancy within the past 5 years with the exception of in situ removal of basal cell 
carcinoma and cervical intraepithelial neoplasia grade I  
7) Treatment with any of the medications listed below within 4 weeks prior to Visit 1: 
x 
Strong Cytochrome p450 (CYP) 3A4 inducers (e.g. rifampicin, phenytoin, St. John’s 
Wort) 
x 
Strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, nefazodone, 
itraconazole, ritonavir) 
x 
Medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 with a narrow 
therapeutic range 
x 
Experimental drugs 
x 
Antifibrotic treatment 
x 
Any systemic immunosuppressive therapies other than: 
o 
Inhaled corticosteroids which can be used throughout the trial period 
provided the dose is kept stable  
o 
Corticosteroids for the treatment of acute exacerbations 
o 
The continuation of stable doses of <15 mg daily doses of prednisolone or 
equivalent 
8) Treatment with any of the medications listed below within 2 weeks prior to Visit 1: 
o 
Proton pump inhibitors (PPIs) more than once daily  
o 
Histamine H2 receptor antagonists (H2RAs) 
o 
Sulphasalazine and rosuvastatin 
o 
High dose breast cancer resistance protein sensitive substrates (other than 
sulphasalazine or rosuvastatin)  
9) Any of the following  findings at Visit 1: 
o 
Prolonged QTcF (QT interval with Fridericia’s correction) (>450 ms), 
clinically significant cardiac arrhythmias or any other clinically significant 
abnormalities in the resting ECG, as judged by the investigator 
o 
Increased AST or ALT >3 times upper limit of normal (ULN), or bilirubin 
>1.5 times ULN 
o 
Positive results for hepatitis B surface antigen (HBsAg), hepatitis C virus 
antibody 
(HCVAb) 
or 
human 
immunodeficiency 
virus 
1+2 
antigen/antibody (HIV 1+2 Ag/Ab) 
o 
Positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of human chorionic gonadotropin [HCG])  
10) Inability to generate lung function data at Visit 1 meeting the minimum standards of the 
ATS/ERS 2005 guideline (Miller et al. 2005), as determined by central review 
11) Clinically significant abnormal laboratory value at Visit 1 indicating a potential risk for 
the subject if enrolled in the trial as evaluated by the investigator 
12) Pregnant or breast-feeding female subjects 
13) Female subjects of childbearing potential not willing to use contraceptive methods 
asdescribed in Section 5.3.1  
14) Male subjects not willing to use contraceptive methods as described in Section 5.3.1 
15) Subjects not willing to adhere to dietary restrictions during the trial period as described 
in Section 5.4 
16) Participation in any other interventional trial during the trial period 


 
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17) Subjects known or suspected of not being able to comply with this trial protocol (e.g. due 
to alcoholism, drug dependency or psychological disorder) 
18) Discontinuation or change of previous antifibrotic treatment (e.g. nintedanib or 
pirfenidone) due to disease progression 
  
IMP and dietary 
restrictions 
IMP will be administered twice daily by the subject at home as follows: 
x 
Morning dose: Two 50 mg capsules (100 mg C21) to be taken after minimum 2 
hours fasting with a glass of water 
x 
Afternoon/evening dose: Two 50 mg capsules (100 mg C21) to be taken after 
minimum 2 hours fasting with a glass of water 
In relation to IMP administrations, subjects should adhere to restrictions regarding food intake: 
x 
No food intake for 2 hours prior to taking the C21 capsules 
x 
No food intake for 1 hour after taking the C21 capsules 
Once daily PPIs must be taken 1 hour after the morning dose of C21 
Allowed 
medication 
If considered unlikely to interfere with IMP or the outcome of the trial results, concomitant 
medication may be given according to local standard of care.  
In addition, the following medications are allowed: 
o 
Inhaled corticosteroids provided the dose is kept stable throughout the trial 
period 
o 
Stable daily dose of <15 mg prednisolone, or equivalent 
o 
Corticosteroids for the treatment of acute exacerbations 
o 
PPIs if once daily and taken 1 hour after the morning dose of C21 
Disallowed 
medication 
4 weeks before Visit 1 and during the trial period: 
x Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, St John’s Wort) 
x Strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, nefazodone, itraconazole, 
ritonavir) 
x Medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 with a narrow therapeutic 
range 
x Experimental drugs 
x Any systemic immunosuppressive therapy other than: 
o 
Inhaled corticosteroids which can be used throughout the trial period 
o 
The continuation of a stable daily dose of <15 mg prednisolone, or equivalent 
x Antifibrotic treatment (e.g. nintedanib, pirfenidone) 
 
2 weeks before Visit 1 and during the trial period: 
x PPIs more than once daily 
x H2RAs  
x Sulphasalazine, rosuvastatin 
x High dose breast cancer resistance protein sensitive substrates (other than sulphasalazine or 
rosuvastatin)  
 
12 hours before spirometry/FVC assessments: 
x Long acting bronchodilators 
 
4 hours before spirometry/FVC assessments 
x Short acting bronchodilators 
 
Throughout the duration of the trial: 
x Antifibrotics 
x Systematic and continuous use of PPIs more than once daily and H2RA medications 








 
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3 
BACKGROUND AND RATIONALE 
3.1 
Indication Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible and devastating 
interstitial lung disease with no existing cure (King et al., 2011). IPF is characterised by a 
progressive deposition of extracellular matrix (ECM) proteins and fibrous tissue in the lungs, 
resulting in destruction of lung architecture and reduced lung capacity (Sakai and Tager, 2013). 
The aetiology of IPF is unknown. However, several risk factors are reported to be associated with 
development of IPF including cigarette smoking, environmental exposures, microbial pathogens, 
and genetic factors (Raghu et al., 2011). Symptoms of IPF include shortness of breath, fatigue, and 
a dry intractable cough. IPF is usually lethal and death is most commonly caused by acute or 
subacute respiratory failure due to progression of lung fibrosis (Ley et al., 2011). Increasing 
pulmonary vascular pressure often leads to pulmonary hypertension (PH) and subsequently to 
heart failure. The prevalence of PH in patients with IPF is between 32 and 85% (Farkas et al., 
2011). The prognosis of IPF is poor, with an estimated life expectancy of 3-5 years after diagnosis 
which is shorter than many malignancies (Vanchari et al., 2010). The mortality is also on the rise 
in the UK and globally (Navaratnam et al., 2019). 
Worldwide, approximately 3 million people are living with IPF and it is classified as an orphan 
disease in the EU and the USA. The incidence of IPF is estimated to be 2.8 to 19 per 100,000 
people per year and increases with age. Debilitating symptoms typically appear between the ages 
of 50 and 70 years and, while the disease is most common in men, the number of cases in women 
is increasing (Olson et al., 2018). Lung transplantation is rare; just 214 lung transplants were 
carried out for pulmonary fibrosis in England in 2017-18 (British Lung Foundation), although it 
is recommended in a small group of patients with moderate to severe IPF and improves survival 
rates. Median post-transplantation survival in IPF is estimated to 4.5 years (Kistler et al., 2014). 
However, patients are often referred late in the course of the disease and may die while waiting 
for a transplant (King et al., 2011). 
IPF is often associated with comorbidities including lung cancer, pulmonary hypertension, chronic 
obstructive pulmonary disease, and ischaemic heart disease (Raghu et al., 2015). The impact of 
comorbidities on the prognosis of IPF is not well established; however, mortality has been reported 
to be higher in patients with the comorbidities mentioned above, and treatment of comorbidities 
may therefore contribute to improved survival and quality of life (Raghu et al., 2015).  
3.2 
Current Treatment for Idiopathic Pulmonary Fibrosis  
Currently, there is no cure for IPF and treatment options are limited. Two antifibrotic drugs, 
nintedanib and pirfenidone, are approved and conditionally recommended for the treatment of 
patients with mild to moderate IPF (Raghu et al., 2015). Both nintedanib and pirfenidone slow 
disease progression without causing a long-term cure, while having significant, primarily 
gastrointestinal, side effects (Raghu et al., 2015).  
Two drugs (pirfenidone and nintedanib) have shown to slow down the decline of forced vital 
capacity (FVC) in IPF patients by up to 50%, and have been approved in multiple countries. 
However, these medicines are not curative and there is a lack of consensus on the effectiveness of 


 
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them in different disease stages such as “preserved lung capacity”. Not all patients can gain access, 
and the ones that do, can suffer quite profound gastrointestinal side effects.  
Thus, a major medical unmet need still exists for finding more efficacious treatment for IPF, 
targeting not only disease progression of IPF but also comorbidities including pulmonary 
hypertension and with acceptable safety and tolerability profiles.  
3.3 
Investigational Medicinal Product 
The investigational medicinal product (IMP) C21, is a selective angiotensin II (AngII) type 2 
receptor (AT2R) agonist presented as capsules for oral administration. 
Several studies demonstrate that AngII and angiotensin type 1 receptors (AT1R ) are involved in 
the pathogenesis of lung fibrosis, including IPF (Uhal et al., 2011; Marshall et al., 2004; Schüttert 
et al., 2003). The role of the AT2R in IPF is not fully established, but it is suggested that the AT2R 
mediates counteractive effects to the AT1R by mediating antifibrotic effects such as reducing 
fibroblast proliferation, cell growth, and ECM synthesis in addition to antiapoptotic and 
vasodilatory effects (Königshoff et al., 2007; Uhal et al., 2011).  
An upregulation of AT2Rs was demonstrated in septal and vascular areas (Parra et al., 2014) and 
in fibrotic fibroblasts from human IPF lungs (Königshoff et al., 2007) as well as in animal models 
of lung fibrosis and hyperoxia-induced lung injury (Königshoff et al., 2007; Wagenaar et al., 2013; 
Rey-Parra et al., 2012). Königshoff et al. (2007) demonstrated a differential expression of AT1Rs 
and AT2Rs in primary mouse fibrotic fibroblasts after bleomycin-induced lung injury when 
compared to healthy mice. In these experiments, the surface expression of AT2Rs on interstitial 
fibroblasts was increased after lung injury when compared to healthy animals whereas the surface 
expression of AT1Rs was similar in fibrotic and normal fibroblasts. Interestingly, AngII-induced 
proliferation of fibroblasts was mediated primarily via the AT1R in healthy fibroblasts whereas 
AngII induced antiproliferation via an AT2R-dependent mechanism in fibrotic fibroblasts, 
demonstrating a shift in the response to AngII in fibrotic lungs, probably due to an upregulation 
of AT2Rs (Königshoff et al., 2007).  
It has been demonstrated in 2 different animal models that C21 reduces pulmonary fibrosis. In the 
first study, pulmonary hypertension and fibrosis were induced in rats by a monocrotaline injection, 
and treatment with C21 for 2 weeks not only prevented, but also reversed pulmonary interstitial 
and perivascular fibrosis (Bruce et al., 2015). This effect was associated with significant 
improvements in right heart function and decreased pulmonary vessel wall thickness.  
In a second study, pulmonary fibrosis and associated pulmonary hypertension were induced in rats 
by bleomycin treatment (Rathinasabapathy et al., 2018). Treatment with C21 for 2 weeks almost 
completely prevented the progression of lung fibrosis and in addition, reduced pulmonary 
hypertension and muscularisation of the pulmonary vessels, and normalised cardiac function. In 
both models, C21 treatment also decreased gene expression of markers of fibrosis and 
inflammation (including transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, 
interleukin (IL)-1β, collagen I and III, and tissue inhibitor of metalloproteinases [TIMP]).    
Thus, C21 represents a potential novel treatment of fibrotic lung diseases such as IPF capable of 
reducing inflammation, proliferation, fibrosis, and vasculopathy. 












 
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4 
OBJECTIVES AND ENDPOINTS  
4.1 
Primary Objective 
To investigate the safety of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects 
with IPF.   
4.2 
Secondary Objectives 
To evaluate: 
x The efficacy of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects with 
IPF for 12 weeks 
x The efficacy of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects with 
IPF for 24 weeks 
x The efficacy of C21 200 mg daily dose (100 mg b.i.d.) administered orally to subjects with 
IPF for 36 weeks 
x The pharmacokinetic (PK) profile of C21 200 mg daily dose (100 mg b.i.d.) after multiple 
dosing 
4.3 
Exploratory Objectives 
To investigate a range of laboratory parameters as potential biomarkers of inflammation, 
proliferation and fibrosis following oral administration of C21 200 mg daily dose (100 mg b.i.d.).  
4.4 
Primary Endpoint 
Nature and frequency of adverse events occurring over the trial period. 
4.5 
Secondary Endpoints 
x Change from baseline in forced vital capacity (FVC) value over 12, 24, and 36 weeks 
x Plasma concentration of C21 and derived PK parameters evaluated in a sub-set of subjects 
4.6 
Exploratory Endpoints 
Blood samples will be saved for potential future analyses of biomarkers reflecting fibrosis and 
inflammation. 
 


 
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5 
TRIAL POPULATION 
5.1 
Inclusion Criteria 
1) Written informed consent, consistent with ICH-GCP R2 and local laws, obtained before the 
initiation of any trial related procedure 
2) A 
diagnosis 
of 
IPF 
within 
5 
years 
prior 
to 
Visit 
1, 
as 
per 
either 
ATS/ERS/JRS/ATLAT/Fleischner guidelines (Raghu et al., 2018; Lynch et al., 2018)  
3) Age ≥40 years 
4) FVC ≥60% predicted at Visit 1 and 2 (Specific for UK: FVC ≥80% predicted at Visit 1 and 2 
or FVC >60 % predicted at Visit 1 and 2 for subjects previously treated with antifibrotic 
treatment e.g., nintedanib and/or pirfenidone, or refused such treatments) 
5) FEV1/FVC ratio >0.7 prebronchodilator at Visit 1 and 2 
6) Oxygen saturation (SpO2) >85% by pulse oximetry while breathing ambient air at rest at 
Visit 1 
7) High-resolution computed tomography (HRCT) within 36 months prior to Visit 1 with central 
reading demonstrating either a or b, and c: 
a. A pattern consistent with usual interstitial pneumonitis (UIP) according to 
ATS/ERS/JRS/ALAT or Fleischner guidelines (Raghu et al., 2018; Lynch et al., 
2018) 
i. UIP 
ii. Probable UIP or 
b. A pattern indeterminate for UIP according to either ATS/ERS/JRS/ALAT or 
Fleischner guidelines (Raghu et al., 2018; Lynch et al., 2018) and a historical 
biopsy consistent with IPF 
c. Extent of fibrosis > extent of emphysema 
8) Fully vaccinated against COVID-19 prior to screening (Visit 1). Subjects are considered fully 
vaccinated for COVID-19 ≥14 days after they have received vaccination dose(s) according to 
local label 
 
 


 
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5.2 
Exclusion Criteria 
1) Previous use of antifibrotic treatment for an interstitial lung disease (e.g. nintedanib or 
pirfenidone) for >6 months 
2) Smoking (including e-cigarettes) within 6 months prior to Visit 1 
3) Body mass index (BMI) >35 or <18 
4) IPF exacerbation within 3 months prior to Visit 1, as defined by Collard et al. (2016): 
x Acute worsening or development of dyspnoea typically <1 month duration 
x Computed tomography with new bilateral ground-glass opacity and/or consolidation 
superimposed on a background pattern consistent with usual interstitial pneumonia pattern 
(if no previous computed tomography is available, the qualifier “new” can be dropped) 
x Deterioration not fully explained by cardiac failure or fluid overload 
5) Concurrent serious medical condition with special attention to cardiac or ophthalmic 
conditions (e.g. contraindications to cataract surgery), or moderate to severe hepatic 
impairment, which in the opinion of the investigator makes the subject inappropriate for this 
trial 
6) Malignancy within the past 5 years with the exception of in situ removal of basal cell 
carcinoma and cervical intraepithelial neoplasia grade I  
7) Treatment with any of the medications listed below within 4 weeks prior to Visit 1: 
x Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, St. John’s Wort) 
x Strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, nefazodone, itraconazole, 
ritonavir) 
x Medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 with a narrow therapeutic 
range 
x Experimental drugs 
x Antifibrotic treatment 
x Any systemic immunosuppressive therapies other than: 
o Inhaled corticosteroids which can be used throughout the trial period provided the 
dose is kept stable  
o Corticosteroids for the treatment of acute exacerbations 
o The continuation of a stable daily dose of <15 mg prednisolone, or equivalent  
8) Treatment with any of the medications listed below within 2 weeks prior to Visit 1: 
o Proton pump inhibitors (PPIs) more than once daily  
o Histamine H2 receptor antagonists (H2RAs) 
o Sulphasalazine and rosuvastatin 


 
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o High dose breast cancer resistance protein sensitive substrates (other than 
sulphasalazine or rosuvastatin)  
9) Any of the following  findings at Visit 1: 
o Prolonged QTcF (QT interval with Fridericia’s correction) (>450 ms), clinically 
significant cardiac arrhythmias or any other clinically significant abnormalities in 
the resting ECG, as judged by the investigator 
o Increased AST or ALT >3 times Upper Limit of Normal (ULN), or bilirubin >1.5 
times ULN 
 
o Positive results for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody 
(HCVAb) or human immunodeficiency virus 1+2 antigen/antibody (HIV 1+2 
Ag/Ab) 
o Positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
human chorionic gonadotropin [HCG])  
10) Inability to generate lung function data at Visit 1 meeting the minimum standards of the 
ATS/ERS 2005 guideline (Miller et al. 2005), as determined by central review 
 
11) Clinically significant abnormal laboratory value at Visit 1 indicating a potential risk for the 
subject if enrolled in the trial as evaluated by the investigator 
12) Pregnant or breast-feeding female subjects 
13) Female subjects of childbearing potential not willing to use contraceptive methods as described 
in Section 5.3.1 
14) Male subjects not willing to use contraceptive methods as described in Section 5.3.1 
15) Subjects not willing to adhere to dietary restrictions during the trial period as described in 
Section 5.4 
16) Participation in any other interventional trial during the trial period 
17) Subjects known or suspected of not being able to comply with this trial protocol (e.g. due to 
alcoholism, drug dependency or psychological disorder) 
18) Discontinuation or change of previous antifibrotic treatment (e.g. nintedanib or pirfenidone) 
due to disease progression 
 


 
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5.3 
Restrictions During the Trial 
5.3.1 
Contraception Requirements 
Women of child bearing potential must practice abstinence (if that is their preferred lifestyle) from 
Visit 1 to Visit 15, or must agree to use a highly effective method of contraception with a failure 
rate of <1% to prevent pregnancy (combined [oestrogen and progestogen containing] hormonal 
contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], 
progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, 
implantable], intrauterine device or intrauterine hormone-releasing system) from at least 4 weeks 
prior to first IMP administration to 4 weeks after last IMP administration. Their male partner must 
agree to use a condom during the same time frame, unless he has had a demonstrated successful 
vasectomy more than 6 months prior to first IMP administration. 
Males should use condom and their female partner of child-bearing potential must use a 
contraceptive method with a failure rate of <1% to prevent pregnancy (see above) and drug 
exposure of a partner and refrain from donating sperm from the date of dosing until 3 months after 
the last IMP administration. 
5.4 
Dietary Restrictions  
In relation to IMP administrations, subjects should adhere to restrictions regarding food intake: 
x No food intake for 2 hours prior to taking the C21 capsules 
x No food intake for 1 hour after taking the C21 capsules 
Once daily PPIs must be taken 1 hour after the morning dose of C21 
5.5 
Screening failure  
A screen failure occurs when a subject who consents to participate in the clinical trial is not 
subsequently assigned to IMP. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.  
Individuals who do not meet the criteria for participation in this trial (screen failure) can only be 
rescreened after discussion with the Medical Monitor. 
5.6 
Withdrawal Criteria 
5.6.1 
Evaluation for Withdrawal after each 12 Week Treatment Period 
After completion of each 12-week treatment period, the investigator will make a medical 
evaluation and decide if the subject may continue into the next 12-week treatment period. The 
decision will be based on: 
x No immediate need for other antifibrotics 
x A positive risk/benefit balance 


 
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Failure to pass the medical evaluation will result in the subject being withdrawn from the trial 
(see Section 5.4.2). 
5.7 
Withdrawal from Trial  
A subject will be withdrawn from trial if any of the following occurs: 
x A decline from baseline in FVC value of > 10% predicted on 2 consecutive occasions and 
an FVC <60% predicted (Specific for UK: FVC <80 % predicted ; or FVC <60%  
predicted  for subjects previously treated with nintedanib and/or pirfenidone, or refused 
such treatments) 
x A decline from baseline in FVC value of 5-10% predicted on 2 consecutive occasions 
and worsening of respiratory symptoms and FVC <60% predicted (Specific for UK: FVC 
<80 % predicted; or FVC <60% predicted for subjects previously treated with nintedanib 
and/or pirfenidone, or refused such treatments) 
x Consistent failure to comply with dietary requirements in Section 5.4, according to the 
investigators 
x The investigator judges it necessary due to medical reasons  
x Failure to pass the medical evaluation after each 12-week treatment period (see 
Section 5.6.1) 
x It is the wish of the subject to withdraw for any reason 
x Pregnancy 
 
An end-of-trial visit (Visit 15) must be completed for all subjects withdrawn from the trial.  
Subjects withdrawn due to pregnancy will be followed – as consented to – until termination or 
delivery and the infant must be followed at least until the age of one month. 
Subject who withdraws prior to week 12 will be replaced until 60 subjects have completed the 12-
week visit.  
6 
TRIAL DESIGN  
6.1 
Overall Trial Design 
This is a multi-centre, open-label, single-arm trial investigating the safety and efficacy of C21 in 
which subjects with IPF will be treated for a maximum of 36 weeks. In total, approximately 60 
subjects will be recruited.  
To ensure careful and ongoing evaluation of the individual risk/benefit profiles, each subject will 
undergo a medical evaluation by the investigator at the end of every 12-week treatment period, 
where the investigator will evaluate if continuation into the next 12-week treatment period is 
considered safe for the individual subject. 
In addition, throughout the duration of the trial, an independent data monitoring committee 
(IDMC) will evaluate all serious adverse events (SAEs) on an ongoing basis in accordance with 
the IDMC charter. The IDMC will monitor all available safety data during regular meetings as 


 
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defined in the IDMC charter and provide appropriate recommendations to the Sponsor on the 
overall safety of trial participants (see Section 14). 
The subjects will attend up to 15 visits to the clinic: 
x Visit 1: 
Screening 
x Visits 2 – 7: 
Treatment period 1 
 
x Visits 8 – 11: 
Treatment period 2 
x Visits 12 – 14: 
Treatment period 3 
x Visit 15: 
End-of-trial 
IMP will be administered as home treatment twice daily (b.i.d.) during all treatment periods 1-3. 
Final safety follow-up assessments at Visit 15 (end of trial visit), must be performed for all subjects 
who have received trial treatment. Visit 15 must be scheduled 2-4 weeks after the last IMP 
administration (see Section 7.3). 
The maximum duration of the trial for any subject will be approximately 44 weeks, including a 
screening period of up 4 weeks, a treatment period up to 36 weeks and a visit for safety follow up 
to be conducted maximum 4 weeks after the last dose of IMP (please see clinical trial design in        
Figure 1). 
6.2 
Number of Subjects 
The trial will enroll a sufficient number of subjects to ensure at least 60 subjects with a completed 
12-week visit. 


 
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6.3 
Trial Diagram 
 
Figure 1. VP-C21-005 Clinical Trial Design 
6.4 
Trial Duration and Participating Centers 
Planned first subject screened: 
Q3 2020 
Planned last subject enrolled: 
Q1 2022 
Planned last subject last visit: 
Q1 2023 
The end of trial date is defined as the date the last subject attends the last visit. 
The trial will be conducted at trial sites globally. 
6.5 
Schedule of Events 
6.5.1 
Screening (Visit 1) 
Prior to and no later than at start of screening (Visit 1) i.e. before any trial related activity takes 
place, the investigator or a qualified designee will explain the nature of the trial, it’s purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, and any 
discomfort it may entail. All explanations shall be in layman’s language. The subject will be 
provided with a copy of the information sheet. The subject must be given sufficient time to 
consider the trial before deciding whether to participate. 
After signed informed consent is obtained from the subject, the screening procedures can be 
initiated. 


 
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All subjects giving informed consent to participate in the trial will receive a screening number. 
During the screening visit, the subject is evaluated for eligibility (please refer to Section 5.1 and 
5.2). 
The following procedures are performed: 
x Written Informed Consent to be obtained 
x Assignment of screening number 
x Pregnancy testing (beta-HCG) 
x Check of in- & exclusion criteria  
x Assessment of eligibility which includes review of demographics, medical history, 
concomitant illnesses and medication, COVID-19 vaccination status, physical 
examination, height, weight, BMI and measurement of blood pressure, pulse and body 
temperature 
x Medical history and concomitant medication 
x 12-lead ECG 
x Spirometry 
x SpO2 
x HRCT to be collected and sent for central review 
x Slit lamp examination to be performed prior to Visit 2 
x Blood sampling for HBsAG, HCVab, HIV 1+2 Ag/Ab and safety (See Table 1 and 
Section 8) 
x Urinanalyses (dipstick) for bilirubin, glucose, ketones, protein, specific gravity, 
urobilinogen, pH 
x Information on restrictions prior to IMP administration (see Section 5.3) 
x Reporting of adverse events (AEs) 
6.5.2 
Treatment Periods (Visits 2-14) 
The total treatment period may last for maximum 36 weeks, comprising three 12 week treatment 
periods. At the end of treatment period 1 (Visit 7) and treatment period 2 (Visit 11), a medical 
evaluation is performed by the investigator to assess if treatment can be continued for an additional 
12 weeks  (see Section 5.4.1) 
x Treatment period 1 (Visit 2-7) 
o Subjects will  attend the clinic every 2 weeks for the first 6 weeks (Visit 2-5) and 
subsequently every 3 weeks for the last 6 weeks (Visit 6-7) 
x Treatment period 2 (Visit 8-11) 
o Subjects will attend the clinic every 3 weeks for 12 weeks (visit 8-11) 
x Treatment period 3 (Visit 12-14) 
o Subjects will attend the clinic every 4 weeks for 12 weeks (Visit 12-14) 
 
The procedures to be performed at each visit are specified below. 
Visit 2 
 


 
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Visit 2 can be scheduled as soon as the relevant screening assessments are available. Visit 2 must 
occur 3-30 days from Visit 1 (screening) to ensure that no eligibility assessments are older than 30 
days when treatment is initiated. 
 
The following procedures are performed: 
x Re-evaluation of in- & exclusion criteria (including physical examination, assessment of 
vital signs, ECG, spirometry, slit lamp and laboratory results from Visit 1) 
x Concomitant medication 
x Pregnancy testing (beta-HCG) 
x Assignment of enrollment number 
x 12-lead ECG 
x Holter ECG 
x Blood sampling for safety and biomarker assessments (See Table 1 and Section 8) 
x Urinanalysis (dipstick for bilirubin, glucose, ketones, protein, specific gravity, 
urobilinogen and pH) 
x Spirometry 
x IMP administration 
x PK sampling 
x Hand-out of medication 
x Re-instructions regarding dietary restrictions prior to IMP administration (see Section 5.4) 
x Reporting of AEs 
Visits 3-14 
x Concomitant medication 
x Pregnancy testing  (urine dipstick) 
x Physical examination, (including body weight and vital signs) 
x Blood sampling for safety 
x 12-lead ECG 
x Urinanalysis (dipstick for bilirubin, glucose, ketones, protein, specific gravity, 
urobilinogen and pH) 
x Spirometry 
x Return of medication  
x IMP compliance check  
x Drug accountability  
x Hand-out of medication (not applicable for visit 14) 
x Re-instructions regarding dietary restrictions prior to IMP administration (see Section 5.4. 
Not applicable for visit 14)  
x Reporting of AEs 
Additionally for Visit 7, 11 and 14 (end of each 12 week treatment period) 
x Medical evaluation by investigator for continued treatment with C21 for an additional 12 
weeks (Visits 7 and 11 only) 


 
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x Blood sampling for PK analyses prior to the morning dose and at 30 min, 1 hour, 2 hours, 
3 hours and 4 hours post-dose in a selected group of 20 subjects 
x Blood sampling for exploratory biomarker analyses 
 
6.5.3 
End-of-Trial (Visit 15) 
Visit 15 is performed minimum 2 weeks and maximum 4 weeks after the last IMP administration. 
The following procedures are performed: 
x Recording of concomitant medication 
x 12-lead ECG 
x Blood sampling for safety and biomarker assessments (See Table 1 and Section 8) 
x Urinanalysis 
x Pregnancy test (beta-HCG ) 
x Physical examination including body weight (See Table 1 and Section 8.2.4) 
x Vital signs 
x Spirometry 
x Slit lamp examination 
x Concomitant medication 
x Reporting of AEs 
If a subject is withdrawn from treatment (see Section 5.7), a Visit 15 (end-of-trial visit) must be 
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7.4 
Compliance Check and Drug Accountability 
Compliance with C21 administration will be assessed by capsule count performed by the trial 
staff at visits 3-14. Details of the capsule count and compliance check will be recorded in the 
patient medical record. 
After IMP accountability has been completed, all unused and partly used IMP will be returned to 
the Sponsor or Sponsor’s designee for destruction. All returned IMP will be reconciled.  
7.5 
Blinding of the Trial 
Not applicable. 
7.6 
Procedures for Unblinding 
Not applicable. 
7.7 
Prior and Concomitant Medications 
Concomitant medications are all medications being continued by the subject at trial entry, and all 
medications 4 weeks prior to screening and received in addition to IMP during the trial period. 
At each visit, the investigator or qualified designee will ask the subject about concomitant 
medication. All concomitant medications will be documented in the subject’s medical records and 
in the electronic case report form (eCRF). Any changes in concomitant medications (e.g. new 
treatment, discontinuation of treatment or change in dosage) during the trial period must be 
documented in the subject’s medical records and in the eCRF. 
The following information will be recorded in the eCRF: 
x Generic name (preferred) or trade name 
x Reason for prescription 
x Dose unit and frequency 
x Route of administration 
x Start date (if started > 3 months prior to Visit 1, then this can be stated instead of recording 
a date) 
x Stop date (unless ongoing at trial termination) 
7.7.1 
Allowed Concomitant Medication 
If considered unlikely to interfere with IMP or the outcome of the trial results, concomitant 
medication may be given according to local standard of care.  
In addition, the following medications are allowed: 
o Inhaled corticosteroids provided the dose is kept stable throughout the trial period 
o Stable daily dose of <15 mg prednisolone, or equivalent. 
o Corticosteroids for the treatment of acute exacerbations 
o PPIs if once daily and taken 1 hour after the morning dose of C21 
7.7.2 
Disallowed Concomitant Medication 
The following treatments are not allowed: 


 
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4 weeks before Visit 1 and during the 
trial period 
x Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, St John’s Wort) 
x Strong CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, 
nefazodone, itraconazole, ritonavir) 
x Medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 with 
a narrow therapeutic range1) 
x Experimental drugs 
x Any systemic immunosuppressive therapy other than: 
o 
Inhaled corticosteroids which can be used throughout the 
trial period 
o 
The continuation of a stable daily dose of <15 mg 
prednisolone, or equivalent 
x Antifibrotics (e.g. nintedanib, pirfenidone) 
2 weeks before Visit 1 and during the 
trial period 
x PPIs more than once daily 
x H2RAs  
x Sulphasalazine, rosuvastatin 
x High dose breast cancer resistance protein sensitive substrates (other 
than sulphasalazine or rosuvastatin)  
12 hours before spirometry/FVC 
assessments 
Long acting bronchodilators 
4 hours before spirometry/FVC 
assessments 
Short acting bronchodilators 
Throughout the duration of the trial 
x Systematic and continuous use of PPIs more than once daily and 
H2RA medications  
 
1) e.g. alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, phenytoin, pimozide, 
quinidine, sirolimus, tacrolimus, theophylline, pirfenidone, celecoxib and warfarin. Investigators will need to consult 
the product information of a concomitant drug as these lists may not be exhaustive. 
8 
ASSESSMENTS 
8.1 
Efficacy Assessments 
8.1.1 
Spirometry 
Throughout the trial, spirometry will be performed using equipment provided to all sites by the 
Sponsor, who will ensure that the equipment meets the minimal ATS/ERS recommendations for 
diagnostic spirometry equipment as defined in the guideline (Miller et al. 2005).  
 
All spirometry reports will be stored as source data (see Section 11.2).  
 
Spirometry procedures will be performed according to a manual. To reduce variability every effort 
should be made to assure consistent testing conditions throughout the trial: 
 
x The same spirometry equipment should be used for all assessments performed by a subject 
within the trial  
x All staff conducting the spirometry tests must have received appropriate training which 
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x Whenever possible the same technician should perform all manoeuvres for an individual 
subject. 
x Whenever possible, spirometry should be conducted at the same time of day (+/-1 hour) as 
the baseline measurement 
The subject’s gender, age and height as reported at Visit 1 are entered into the spirometer and will 
be used throughout the trial.  
Spirometry is an effort-dependent test which requires careful instruction and cooperation of the 
subject. The subject is recommended to be positioned in a seated position with nose clip to reduce 
risks related to dizziness or syncope. The technician should ensure that the subject maintains a 
good seal around the mouthpiece and confirm that the subject’s posture is correct. The subject 
should be instructed to perform tidal breathing followed by a maximal inspiration until no further 
air can be inhaled, followed rapidly by maximum forced expiration until no more air can be 
exhaled or the volume time cure displays a plateau marked by flow rates of <25ml/sec for at least 
one second.  This should be followed by a maximal inspiration.  Expiration must be rapid with 
exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 2005 
(Miller et al. 2005) for acceptability and repeatability.  
The highest FVC and FEV1 from any of the acceptable curves are recorded. The highest FVC and 
FEV1 may not necessarily result from the same acceptable curve. 
Spirometry data will be assessed by a central reader for quality control and be classified for 
acceptability. In addition an assessment for plausibility will be performed.   
8.1.2 
Biomarkers  
Blood samples for potential analysis of biomarkers related to inflammation and fibrosis will be 
obtained at Visit 2 and the end of each treatment period (Visits 7, 11, 14 and 15). 
Details of sampling and storage will be specified in the laboratory manual. 
8.1.3 
Pharmacokinetics 
Blood samples for pharmacokinetic will be analysed in a subset (20) of subjects. The samples 
will be collected at Visit 2, and at the end of each treatment period at Visit 7, Visit 11 and Visit 
14 prior to the morning dose and at 30 min, 1 hour, 2 hours, 3 hours, and 4 hours post-dose.  
8.2 
Safety Assessments 
8.2.1 
Adverse Events 
Adverse events (AEs) will be reported from signing of informed consent until end-of-trial 
participation (Visit 15). 
8.2.2 
Medical History and Concomitant Illnesses 
The medical history including date of first diagnosis of disease under study and concomitant 
illnesses will be obtained by interviewing the subject or by checking his/her medical records. 
 


 
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8.2.3 
Pregnancy Test 
Women of childbearing potential will undergo pregnancy tests at all visits 1).  
x Visit 1, 2 and Visit 15: Blood sample  
x Visit 3 -Visit 14: Urine dip-stick 
1) Women of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal 
ligation or permanent bilateral occlusion of fallopian tubes); or post-menopausal defined as 12 months of 
amenorrhea (in questionable cases a blood sample with simultaneous detection of Follicle-stimulating 
Hormone 25-140 IE/L and oestradiol <183 pmol/l is confirmatory). 
8.2.4 
Physical Examination 
A complete physical examination including assessments of the head, eyes, ears, nose, throat, skin, 
thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and 
extremities will be performed at Visit 1, 2, and Visit 15. 
A short version of the physical examination including assessments of selected body systems at the 
judgement of the investigator will be performed at all other visits (3-14) and must include a 
cardiovascular examination. 
Each body system will be reported as “normal”, “abnormal – non clinically significant” or 
“abnormal –clinically significant”. Any clinically significant abnormalities prior to initiation of 
IMP should be specified and recorded as medical history. New clinically significant 
abnormalities occurring after initiation of IMP should be reported as AEs. 
8.2.5 
Vital Signs  
Systolic and diastolic blood pressure, pulse, and body temperature will be measured in supine 
position after 10 minutes of rest.  
8.2.6 
Electrocardiogram 
12-lead electrocardiography (ECG) will be recorded at all visits to the clinic (Visit 1-15). 
Holter ECG will be recorded at Visit 2 from at least 30 mins prior to IMP administration until at 
least 180 mins after. 
ECG evaluations will be performed by a central reader. 
Any clinically significant ECG abnormalities prior to initiation of IMP should be specified and 
recorded as medical history. New clinically significant abnormalities occurring after initiation of 
IMP should be reported as AEs. 
8.2.7 
Safety Laboratory Parameters 
Safety laboratory parameters which are to be taken at every visit to the clinic: 
 
x Haematology: Haemoglobin (Hb), haematocrit (erythrocyte volume fraction), platelet 
count (thrombocyte particle concentration [TPC]), leucocyte count, mean corpuscular 
volume (MCV) 
x Biochemistry: Albumin, alanine transferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), bilirubin, blood urea nitrogen (BUN), calcium, creatinine, c-


 
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reactive protein (CRP), gamma glutamyl transferase (GGT), glucose, lactate 
dehydrogenase (LD), potassium, sodium 
x Urinanalysis: Dipstick for bilirubin, glucose, ketones, protein, specific gravity, 
urobilinogen, and pH 
 
Any laboratory abnormality, judged by the investigator to be a clinically relevant worsening since 
Visit 1, should be reported as an AE if the laboratory abnormality requires clinical intervention or 
further investigation, unless the laboratory abnormality is associated with an already reported 
event. 
8.3 
Other Assessments 
8.3.1 
Demographics and other Baseline Characteristics 
Demographic and baseline characteristics include but are not limited to age at screening, sex, 
height, and weight. 
8.3.2 
Slit Lamp Examination  
A slit lamp examination will be performed by an ophthalmologist prior to Visit 2 and at Visit 15, 
where the results in the form of a written report including acuity, lens state, and any 
contraindications to cataract surgery will be reviewed by the investigator. The conduct of the slit 
lamp examination could be delegated to a registered optometrist, provided that the report is 
reviewed and approved by an ophthalmologist. 
Each slit lamp examination will be reported as “normal”, “abnormal – non clinically significant” 
or “abnormal –clinically significant”. Any clinically significant abnormalities prior to initiation 
of IMP should be specified and recorded as medical history. New clinically significant 
abnormalities occurring after initiation of IMP should be reported as AEs. 
 
 


 
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9 
ADVERSE EVENTS 
9.1 
Adverse Event Definitions 
An adverse event (AE), an adverse drug reaction (ADR) and a serious adverse event (SAE) are 
defined according to ICH Guideline E2A (ICH 1994). 
An AE is any untoward medical occurrence in a subject administered the IMP and which may or 
may not have a causal relationship with this IMP. An AE can therefore be any unfavorable and 
unintended sign (e.g. a significant abnormal laboratory finding, symptom, or disease temporally 
associated with the use of the IMP, whether or not considered related to the IMP. 
An ADR is any noxious and unintended response to an IMP related to any dose of the IMP.  
An SAE is any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threatening (this refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it was more severe) 
x Requires in-patient hospitalisation or prolongation of existing hospitalisation 
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly or birth defect 
x Is judged medically important (this refers to an event that may not be immediately life-
threatening or result in death or hospitalisation, but may jeopardise the subject or may 
require intervention to prevent one of the other outcomes listed) 
A non-SAE is any AE that does not meet the definition of an SAE. 
The following will not be considered an AE: 
x Pre-planned procedure (documented at Visit 1) unless the condition for which the 
procedure was planned has worsened from the first trial related activity after the subject 
has signed the informed consent form 
x Concomitant illness identified as a result of screening procedures. However, if symptoms 
are worsened and/or become serious as defined in Section 9.1, this must be reported as a 
SAE. 
9.2 
Adverse Event Assessment Definitions 
9.2.1 
Severity 
The investigator should assess the severity of all AEs according to the following definitions: 
x Mild: awareness of sign or symptom, but easily tolerated (acceptable). 
x Moderate: discomfort to interfere with usual activities (disturbing). 
x Severe: incapacity to work or to perform usual activities (unacceptable).  


 
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Note the distinction between seriousness and severity: The term severe is used to describe the 
intensity of the event and a severe event is not necessarily serious. The seriousness criteria serve 
as a guide for defining regulatory reporting obligations. 
9.2.2 
Relationship to IMP 
Assessment of causality is based on the following considerations: associative connections (time 
and/or place), pharmacological explanations, previous knowledge of the drug, presence of 
characteristic clinical or pathological phenomena, exclusion of other causes, and/or absence of 
alternative explanations. 
The investigator will be asked to assess causal relationship to the trial treatment according to the 
following classifications: 
Related:  
x Time relationship exists; and previous knowledge of the trial product supports a causal 
relationship although another cause cannot be ruled out; and/or improvement on dechallenge 
or dose reduction has occurred (if performed); and/or recurrence of symptoms on rechallenge 
has occurred (if performed); and/or a specific laboratory test supports a causal relationship 
 
Not related:  
x No time relationship between administration of the trial product and occurrence or worsening 
of the AE exists; and/or another cause is confirmed and no indication for involvement of the 
trial product in the occurrence/worsening of the AE exists. The alternative, most likely other 
cause(s) should be indicated 
 
9.2.3 
Outcome 
The investigator will be asked to record the most appropriate outcome of the following: 
x Recovered 
x Ongoing  
x Not recovered 
x Recovered with sequelae 
x 
Death 
x 
Unknown 
9.3 
Reporting of Adverse Events 
All events meeting the definition of an AE must be reported in the period from the subject has 
signed the informed consent form until the end of trial participation (Visit 15). 
At each visit the subject will be asked about AEs in an objective manner, e.g.: “Have you 
experienced any problems since the last visit?” 
Only medically qualified personnel (investigators) must assess AEs. 


 
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AEs must be reported on the AE form. In the eCRF the diagnosis should be recorded, if available. 
If no diagnosis is available each sign and symptom should be recorded as individual AEs. 
AEs concerning cardiac or ophthalmic conditions are of special interest and must be reported to 
the Sponsor within 24 hours of obtaining knowledge of the event.  
SAEs, in addition, must be reported within 24 hours of obtaining knowledge of the event. The 
information to be reported will include assessment of severity, causal relationship to IMP or trial 
procedures, action taken, outcome, and a narrative description of the course of the event. 
Additional information may be subsequently provided. 
The SAE form and all other relevant documents supporting the reported SAE (e.g. diagnostic 
procedures, hospital records, autopsy reports) must be faxed or scanned/emailed to the Sponsor or 
Sponsor’s designee.  
The independent ethics committees (IEC) and regulatory authorities will be notified of SAEs 
according to current regulation and local requirements. 
All suspected unexpected serious adverse reactions (SUSARs) are subject to expedited reporting 
to regulatory authorities.  
The expectedness of a SUSAR will be assessed against the reference safety information. Any 
SUSARs will be reported by the clinical research organisation (CRO) to the relevant competent 
authority. SUSARS will also be reported to the IEC by the site/CRO. Fatal and life threatening 
SUSARs will be reported as soon as possible and no later than seven calendar days from the date 
of first knowledge of the event. Relevant follow-up information will subsequently be expedited 
within an additional eight days. All other SUSARs will be expedited no later than 15 calendar days 
of first knowledge of the event. 
For AEs concerning hair symptoms, additional information may be collected, such as location and 
extent of hair loss, outcomes of dermatologist consultations, results from special investigations, 
and any photographs taken. 
9.4 
Follow-up on Adverse Events 
All AEs should be followed until they are resolved or the subject’s participation in the trial ends, 
whichever comes first. 
SAEs and non-serious AEs considered related to trial drug should be followed on a regular basis 
according to the investigator’s clinical judgment until a final outcome has been established. 
9.5 
Pregnancies 
Any pregnancy that occurs during trial participation must be reported and administration of trial 
drug must be terminated immediately. A pregnancy must be reported to Sponsor or designee within 
2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and infant. Pregnancy complications and 
elective terminations for medical reasons must be reported as AEs or SAEs, as applicable. 
Spontaneous abortion must be reported as an SAE. 


 
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In addition, the investigator must attempt to collect pregnancy information on any female partners 
of male trial participants who become pregnant while the participant is enrolled in the trial. 
Pregnancy information must be reported to Sponsor as described above. 
 
10 
CHANGES TO TRIAL CONDUCT 
10.1 
Protocol Amendments 
Before implementation of substantial changes (as defined in EU guidance documents [European 
Commission 2006, 2010]) unless considered an Urgent Safety Measure, approval/favourable 
opinion must be obtained from the appropriate regulatory authority(ies) and IEC(s). 
10.2 
Premature Termination of the Trial 
In case of premature termination of the trial, health authorities, and IECs will be notified in writing, 
including the reason for premature termination. 
Conditions that may warrant premature termination of the trial include, but are not limited to the 
following: 
x The discovery of an unexpected and significant or unacceptable risk to the subjects enrolled in 
the trial 
x A decision of the Sponsor to discontinue development of the drug 
10.3 
Premature Termination of a Trial Site 
The Sponsor can decide to prematurely terminate a site. Conditions that may warrant termination 
include, but are not limited to: 
x Insufficient adherence to protocol requirements 
x Failure to enrol subjects at an acceptable rate 
 
 


 
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11 
DATA HANDLING AND RECORD KEEPING  
11.1 
Data from Clinical Trial Sites 
Data from clinical trial sites will be entered in an eCRF. 
The investigator will sign relevant eCRF sections by use of an electronic signature. Only the 
investigator (i.e. medically qualified personnel) can sign data on medical assessments. Any 
corrections made by the investigator or authorised staff to the eCRF after original entry will be 
documented in an audit trail. The person making the change and the date, time and reason for the 
change will be identified in the audit trail. Changes to the data already approved/signed by an 
investigator will require re-signature by the investigator. The investigator (principal investigator 
or sub-investigator) will sign all patient data in the eCRF by an electronic signature. 
Subject data will be recorded anonymously and the subjects will be identified only by a screening 
number. 
The monitor will check the eCRF for accuracy and completion and perform source data 
verification. Data entered in the eCRF will be verified against source data. The level of source data 
verification is described in Section 11.2. 
11.2 
Source Data 
All data entered in the eCRF should be verifiable by source data in the subject’s medical record 
or other records at the trial site, as applicable: 
x Details of the trial (trial ID and subject screening and enrollment number) 
x Date(s) of informed consent of the subject 
x Data of each trial visit including signature and /or initials of person(s) conducting the visit 
x Data and information of any relevant telephone contact with the subject and signature and/or 
initials of person(s) conducting or receiving the call 
x Subject’s date of birth 
x Diagnosis of IPF including start date, HRCT date and report/image 
x Medical history and concomitant illness including start and stop dates 
x Concomitant medication including start and stop dates 
x Overall conclusion of the subject’s eligibility  
x Conclusion and results for each in-/exclusion criterion with respect to fulfillment of trial 
eligibility or not 
x Physical examination  
x Slit lamp data 
x Height and body weight  
x Blood pressure, pulse, body temperature and ECG 


 
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x All laboratory samplings and data, including date and time of blood sampling (including 
subjects in PK subset) 
x Investigator’s evaluation of haematology and biochemistry results being out of range 
x Date and times of blood sampling 
x Spirometry data 
x All AEs, SAEs and pregnancies described in details 
x IMP dispensed and date of dispensing, IMP retrieval and date of retrieval 
x Premature withdrawal of subject from the trial including reason and withdrawal criteria 
fullfilled 
x Investigator treatment evaluations 
11.3 
Coding of Data 
Medical history and AEs will be coded using the lastest version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
Concomitant medication will be coded using the latest version of World Health Organisation 
(WHO) Drug Reference List. 
11.4 
Subject Confidentiality 
The confidentiality of the subject data and subject records shall be protected, respecting the 
privacy and confidentiality rules in accordance with applicable regulatory requirements. 
12 
RETENTION OF DOCUMENTS 
The monitor will instruct the investigator to maintain source documents and the signed informed 
consent form for each subject. 
Furthermore, the monitor will instruct the investigator to archive essential documents for the 
duration defined in the ICH Guideline E6 (Note for Guidance on Good Clinical Practice 
[ICH 1997]) or for 15 years, whichever comes first. 
The duration of archiving defined in the ICH Guideline E6 is as follows: 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer 
period however if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. 
The Sponsor will notify the investigator when retention of the trial-related records is no longer 
required. 
 


 
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13 
STATISTICAL METHODS  
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, which will be signed and approved prior to the database lock. 
13.1 
Sample Size and Power Considerations 
Sample size is based on assumptions of a 40 mL decline in FVC/24 weeks and a standard 
deviation of 200 mL With 55 evaluable subjects there is a 90% power that the 90% confidence 
interval for the decline in FVC at 24 weeks exclude the value 120 mL, a value considered to 
represent the natural course decline in 24 weeks for an untreated subject. The total of 60 subjects 
will be included to compensate non-evaluable subjects for reasons such as early drop out.  
Analysis Data Sets 
The full analysis set (FAS) will consist of all subjects who have received at least one dose of IMP 
and who has at least one post-baseline assessment of efficacy.  
The per protocol analysis set (PPAS) will be a subset of FAS and consist of all subjects without 
any major protocol deviations that are judged to compromise the analysis of the data and with data 
collection up to at least week 24. All protocol deviations will be judged as major or minor prior to 
database lock. 
The safety analysis set (SAS) will consist of all subjects who have received at least one dose of 
IMP. 
The pharmacokinetic (PK) dataset will consist of all subjects selected for PK assessments and with 
at least one post-dose plasma sample analysed. 
13.2 
Subject Disposition 
13.2.1 
Baseline Characteristics 
Demographics, medical history, baseline characteristics, and prior medications will be listed and 
summarised in terms of descriptive statistics: mean, standard deviation, median, and range for 
continuous outcomes and frequencies and percentages for categorical outcomes. 
13.3 
Efficacy Analysis 
13.3.1 
Efficacy Endpoint Analysis 
The change in FVC from baseline to week 12, 24, and 36 will be calculated for each subject and 
summarised using the population mean and corresponding 90% two-sided confidence intervals. 
For early withdrawn subjects, the value representing week 24 will be calculated assuming a decline 
rate of 60 mL/12 weeks for the period between last visit and week 24.  
As a secondary approach, a mixed model will be fitted to the FVC data collected from each time 
point within a subject up to week 36 or last visit if withdrawn earlier. A linear or piece-wise linear 
relation for the FVC decline using one or several slopes will be used to model the data depending 
on the actual curve shape. Model parameters will be summarised. Model will be used to assess the 


 
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average decline in FVC after 12, 24, and 36 weeks of treatment together with 90% two-sided 
confidence intervals.  
The number of rapid decliners in FVC, fulfilling the withdrawal criteria during the trial, will be 
summarised. 
FVC and FEV1 will further be summarised by visit using descriptive statistics and visualised using 
mean value plots (with imputation). For FVC, further a plot of the model fit, that is observed means 
verssus the model predicted curve, will be constructed.  
13.3.2 
Pharmacokinetic Data 
Plasma concentrations of C21 and derived pharmacokinetic parameters will be summarised by 
time point using descriptive statistics.  
13.3.3 
Biomarker Data 
Biomarker data will be exploratory and the analyses data-driven. Collected data will be 
visualised graphically and summarised descriptively. 
13.3.4 
Statistical/Analytical Issues 
13.3.4.1 Missing Data 
To summarise the change in FVC from baseline to week 24, missing data at week 24 will be 
imputed assuming a decline rate of 60 mL/12 weeks for the period between last visit and week 24. 
No imputation will be done for the mixed model or for the safety summaries. 
13.3.4.2 Examination of Subgroups 
Important demographic and baseline value-defined subgroups may be investigated. 
Subgroups or alternate imputations to investigate the  impact of the COVID-19 pandemic on the 
analyses due to an expected increased number of subjects with missing data will also be 
investigated. 
A detailed description will be provided in the Statistical Analysis Plan. 
13.4 
Safety Analysis 
13.4.1 
Adverse Events 
An overview of all treatment-emerging AEs including severity, relationship to IMP, serious AEs 
(SAEs) and AEs leading to withdrawals of treatment and withdrawal from trial or death will be 
presented by treatment group. 
AEs will be summarised by treatment group, system organ class (according to MedDRA), and 
preferred term (according to MedDRA) displaying number of subjects in treatment group, number 
and percentage of subjects having the AE as well as number of AEs. Furthermore, AEs will be 
summarised according to severity, relationship, outcome, and seriousness. 
SAEs and AEs leading to withdrawal from treatment will be listed and tabulated, if appropriate. 


 
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13.4.2 
Electrocardiogram 
12-lead ECG data  will be summarised by visit including the change from baseline. The number 
of abnormal assessments will be summarised by visit and for changes from baseline to end-of-
trial.  
13.4.3 
Vital Signs 
Vital signs data (blood pressure and pulse)  will be summarised by visit including the change from 
baseline.  
13.4.4 
Laboratory Safety Assessments 
Continuous laboratory data  will be summarised by visit including the change from baseline. 
Categorical data will be summarised by visit using frequency and percentages. Laboratory 
parameters will be categorised as ‘low’, ‘normal’ or ‘high’ (i.e. below, within, or above the 
reference ranges, respectively) and summarised by visit and for changes from baseline to end-of-
trial in a shift table.  
13.4.5 
Physical examination 
Abnormal findings on the physical examination will be summarised by visit. 
 
14 
INDEPENDENT DATA MONITORING COMMITTEE 
An independent data monitoring committee (IDMC) has been established and will have their first 
meeting before the trial starts. 
The functions and responsibilities of the IDMC is described in an IDMC charter. 
Throughout the duration of the trial, the IDMC will evaluate all SAEs on an ongoing basis. 
Further, the IDMC will monitor the overall safety of the trial during regular meetings and provide 
appropriate written recommendations to the Sponsor regarding trial continuation, protocol 
modifications or trial suspension. 
Any safety related IDMC recommendations that may result in protocol changes or to the 
management of subjects in the trial will be reported to the Competent Authorities (CAs) and IECs. 
A letter of trial continuation after each IDMC meeting will be supplied to the CAs and IECs if 
required. 
15 
GOOD CLINICAL PRACTICE 
This trial will be carried out in compliance with the protocol, ICH-GCP R2, Standard Operating 
Procedures of the CROs and applicable regulatory requirements. 
The investigator agrees, when signing this protocol, to adhere to the instructions and procedures 
described in it, to the principles of the Declaration of Helsinki, ICH-GCP R2 and applicable 
regulatory requirements.  


 
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16 
ETHICS 
16.1 
Independent Ethics Committees / Health Authorities 
Before implementing this trial, the protocol, the proposed subject information and subject consent 
form, and other documents as required, will be reviewed by properly constituted independent 
ethics committees (IECs) and by the national regulatory authorities. 
A signed and dated statement that the protocol and subject information and subject consent form 
have been approved by the IECs and regulatory authorities will be obtained before trial initiation. 
For each individual IEC, the name and occupation of the chairman and the members of the IEC 
will be collected as well as a statement that the IEC works in accordance with ICH GCP. 
IECs will receive updates on trial progress according to local regulations. 
16.2 
Informed Consent 
The subject’s signed and dated informed consent to participate in the trial will be obtained prior to 
any trial related procedure being carried out. 
Before any trial related procedure the investigator will explain to the potential subject the aims, 
methods, reasonably expected benefits. and potential hazards of the trial and any discomfort 
participation in the trial may entail. Subjects will be informed that participation in the trial is 
voluntary and that the subject may withdraw from the trial at any time and for any reason. Subjects 
will be informed that if they choose not to participate, this will not affect the care the subject will 
receive for the treatment of his or her disease. Finally, subjects will be informed that their records 
may be accessed by health authorities and authorised Sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws or regulations. 
All subjects will be given opportunity to ask questions and will be given sufficient time to consider 
before consenting. The subjects may choose to be accompanied, e.g. by a family member, during 
the information process. After having consented, a copy of the informed consent form will be 
given to the subject. 
17 
AUDITS AND INSPECTIONS 
A representative of the Sponsor may visit the trial site(s) at any time during the trial or after 
completion of the trial to conduct an audit of the trial. These audits will require access to all trial 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy will, however, be respected. The investigator and other trial personnel will be responsible 
for being present and available for consultation during routinely scheduled site audit visits 
conducted by the Sponsor’s representative. 
Similar auditing procedures (inspections) may also be conducted by agents of regulatory health 
authorities, either as part of a national GCP compliance program or to review the results of this 
trial in support of a regulatory submission. The investigator should notify the Sponsor’s 
representative or Sponsor immediately, if he/she has been contacted by a regulatory agency 
concerning an upcoming inspection. 
 


 
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18 
MONITORING 
Before trial initiation a monitor from the Sponsor’s representative will review the protocol and the 
CRF with the investigators and their trial personnel. During the trial the monitor will visit the trial 
site regularly to check the completeness of subject records, the accuracy of entries in CRFs, the 
adherence to the protocol and to GCP, the progress of enrolment and the handling and accounting 
of IMP. Key trial personnel must be available to assist the monitor during these visits. 
The investigator must give the monitor direct access to source data/documents (e.g. relevant 
hospital or medical records) to confirm their consistency with the entries in CRFs. No information 
in these records about the identity of the subjects must leave the trial site. 
19 
REPORTING OF RESULTS 
19.1 
Integrated Clinical Trial Report 
Data will be reported in an integrated clinical trial report in compliance with the requirements of 
the current version of ICH E3: Structure and Content of Clinical Study Report (ICH 1995). The 
signatory investigator will review and sign the integrated clinical trial report. 
The results and interpretation of the exploratory biomarker analyses may not be included in the 
clinical trial report but may be reported and/or published separately at a later stage. 
19.2 
Use of Information 
All unpublished information relating to this trial and/or to the trial drug is considered confidential 
by the Sponsor and shall remain the sole property of the Sponsor. 
The investigator must accept that the Sponsor may use the information from this clinical trial in 
connection with the development of the IMP, and therefore, may disclose it as required to other 
investigators, to government licensing authorities, to regulatory agencies of other governments, 
stock exchange market, and commercial partners. 
19.3 
Publication of Results 
Basic information of this trial will be posted by the Sponsor on the website: www.clinicaltrials.gov 
before the first subject enters the trial. 
The Sponsor is committed to publishing the trial results, whether positive or negative, in a peer-
reviewed journal (Wager, 2003; Graf 2009). 
The criteria for authorship as set out by the Committee of Medical Journal Editors 
(www.icmje.org) will be applied. 
The contributorship model will be applied and contributors who do not meet the criteria for 
authorship will be listed in an acknowledgments section with descriptions of the role of each 
contributor in order to ensure indexation in the National Library of Medicine. 
Publications are subject to the following conditions: 


 
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x Data are the property of the Sponsor and cannot be published without prior authorisation from 
the Sponsor 
x Publications should be drafted with protection of individual privacy, intellectual property, and 
contract rights in mind, and also conform to legislation and current national practices in patent 
and other laws 
x The primary publication (i.e. the results from all centers) should be published before, or in 
parallel with, any secondary publications 
x Publications shall not disclose any Sponsor confidential information or property 
 
20 
INSURANCE AND LIABILITY 
The Sponsor has subscribed to an insurance policy covering, in its terms and provision, its legal 
liability for injuries caused to participating subjects and arising out of trial procedures performed 
in accordance this protocol, in accordance with applicable law and with the ICH Guideline E6 
(Note for Guidance on Good Clinical Practice) (ICH 1997). 
 


 
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21 
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22 
ABBREVIATIONS 
Ab 
Antibody 
ADR 
Adverse drug reaction 
AE 
Adverse event 
Ag 
Antigen 
ALP 
Alkaline phosphatase 
ALT 
AngII 
Alanine aminotransferase 
Angiotensin II 
AST 
AT1R 
AT2R 
Aspartate aminotransferase 
Angiotension type 1 receptor 
Angiotension type 2 receptor 
AUC 
Area under the curve 
b.i.d. 
bis in die (i.e. twice a day) 
BMI 
Body mass index 
BUN 
CA 
Blood urea nitrogen 
Competent authorities 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CRO 
Contract research organisation 
CRP 
C-reactive protein 
CYP 
Cytochrome p450 
eCRF 
Electronic case report form 
ECG 
ECM 
Electrocardiography 
Extracellular matrix 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in the first second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HCVAb 
Hepatitis C virus antibody 
HIV 
Human immunodeficiency virus  
HRCT 
High-resolution computed tomography 
H2RA 
Histamine H2 receptor antagonist 
ICH 
International Conference on Harmonisation 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IPF 
Idiopathic pulmonary fibrosis 
LD 
Lactate dehydrogenase 
MAD 
Multiple ascending dose 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
PH 
No observed adverse effect level 
Pulmonary hypertension 
PK 
Pharmacokinetic 
PPAS 
Per protocol analysis set 
PPI 
Proton pump inhibitor 
RP 
Raynaud’s phenomenon 
SAD 
Single ascending dose 


 
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SAE 
Serious adverse event 
SAS 
Safety analysis set 
SpO2 
Oxygen saturation 
SSc 
Systemic sclerosis 
SSc-RP 
Raynaud’s phenomenon secondary to SSc 
SUSAR 
TEAE 
tmax 
Suspected unexpected serious adverse reaction 
Treatment-emergent adverse event 
Maximal plasma concentration 
TPC 
UIP 
Thrombocyte particle concentration 
Usual interstitial pneumonitis 
WHO 
World Health Organisation