Relative Bioavailability of Two Different Formulations of Nerandomilast and Investigation of the Food Effect on New Formulation Following Oral Administration in Healthy Adult Male and Female Subjects (an Open-label, Randomised, Single-dose, Three-way Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0) 
Clinical Trial Protocol 
TITLE PAGE 
Document Number: 
Global ID: 
VV-TMF-986619
228892_986736_2.0
EUCT No. 
Universal Trial No. 
2024-511245-18-00 
U1111-1304-2287  
BI Trial No. 
1305-0029
BI Investigational 
Medicinal Product 
BI 1015550, nerandomilast 
Title 
Relative bioavailability of two different formulations of 
nerandomilast and investigation of the food effect on new 
formulation following oral administration in healthy adult male 
and female subjects (an open-label, randomised, single-dose, 
three-way crossover trial)
Lay Title 
A study in healthy people to compare 2 different formulations 
of nerandomilast tablets when taken with or without food 
Clinical Phase 
I 
Clinical Trial Leader 
Phone: 
 Fax: 
  
 Investigator 
Phone: 
 Fax: 
 
Current Version, Date 
Version 2.0, 11 April 2025
Original Protocol Date 
06 May 2024 
Page 1 of 66 
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 

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BI-VQD-11906_40-106_AD-13 (8.0) 
CLINICAL TRIAL PROTOCOL SYNOPSIS 
Company name 
Boehringer Ingelheim 
Original protocol date 
06 May 2024  
Revision date 
11 April 2025 
BI trial number 
1305-0029 
Title of trial 
Relative bioavailability of two different formulations of nerandomilast and 
investigation of the food effect on new formulation following oral administration in 
healthy adult male and female subjects (an open-label, randomised, single-dose, 
three-way crossover trial) 
 Investigator  
 
Trial site 
Clinical phase 
I 
Trial rationale 
BI plans to develop a paediatric formulation of nerandomilast for the treatment of 
fibrosing interstitial lung disease in paediatric patients. This trial is conducted to 
compare bioavailability between the paediatric and adult tablet formulations of 
nerandomilast, and to evaluate a potential food effect on the paediatric formulation 
(1 mg film-coated tablets).  
Trial objective 
 To investigate the  
i. 
relative bioavailability of paediatric and adult tablet formulation under 
fasted condition.  
ii. 
effect of food on the pharmacokinetics of paediatric formulation 
Trial endpoints 
Primary endpoints: AUC0-tz and Cmax of nerandomilast 
Secondary endpoint: AUC0- of nerandomilast 
Trial design 
Randomised, open-label, single dose, three-way crossover design  
Number of subjects  
 
 
total entered 
15 
 
on each treatment 
15 
Diagnosis 
Not applicable  
Main inclusion criteria 
Healthy male and female subjects, age of 18 to 55 years (inclusive), body mass 
index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) 
 
 

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BI-VQD-11906_40-106_AD-13 (8.0) 
Test product 
Nerandomilast film-coated tablets, 1 mg (paediatric formulation) 
 
dose 
18 mg (18 x 1 mg film-coated tablets) 
 
mode of 
 
administration 
Oral with 240 mL of water after an overnight fast of at least 10 h (T1)  
Oral with 240 mL of water after a high-calorie breakfast (T2) 
Reference product 
Nerandomilast film-coated tablet (Formulation C1), 18 mg (adult formulation)   
 
dose 
18 mg (1 film-coated tablet) 
 
mode of admin. 
Oral with 240 mL of water after an overnight fast of at least 10 h (R) 
Duration of treatment 
Single dose of each treatment (R = 1 x 18 mg film-coated tablet, fasted, T1= 18 x 1 
mg film-coated tablets, fasted, T2= 18 x 1 mg film-coated tablets, fed), separated by 
a washout phase of at least 7 days  
Statistical methods 
Relative bioavailability will be estimated by the ratios of the geometric means for 
the comparison of interest, i.e. T1/R or T2/T1, for the primary and secondary 
endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be 
provided. This method corresponds to the two one-sided t-test procedure, each at a 
5% significance level. Since the main focus is on estimation and not testing, a 
formal hypothesis test and associated acceptance range is not specified. The 
statistical model will be an analysis of variance (ANOVA) on the logarithmic scale 
including effects for sequence, subjects nested within sequences, period and 
treatment. CIs will be calculated based on the residual error from the ANOVA. The 
statistical model will be applied only to data that contribute to the particular 
comparison of interest. 
Descriptive statistics will be calculated for all endpoints. 
 

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BI-VQD-11906_40-106_AD-13 (8.0) 
FLOW CHART 
Period 
Visit 
Day 
Planned time (relative 
to drug 
administration)
Approximate clock 
time  of actual day 
Event and comment 
Safety laboratory 7 
PK nerandomilast 
12-lead ECG 
Vital signs (BP, PR) 
Questioning for AEs 
and concomitant 
therapy 6
SCR 
1 
-21 to -1 
 
 
Screening (SCR)1 
xA 
 
x 
x 
 
1/2/3 (three identical periods separated by a wash-out of at least 7 days 
2
/
3
/
4 
-1 
-12:00 
20:00 Admission to trial site8 
x5,8 
 
 
 
x8 
1 
-1:00 
07:00 Allocation to treatment2 (visit 2 only) 
 
x2 
 
x2 
x2 
- 0:30 
07:30 High fat, high calorie breakfast 
(treatment T2 only) 
 
 
 
 
 
0:00 
08:00 nerandomilast administration 
 
 
 
 
 
0:30 
08:30  
 
x 
 
 
 
0:45 
08:45  
 
x 
 
 
 
1:00 
09:00  
 
x 
 
 
 
1:15 
09:15  
 
x 
 
 
 
1:30 
09:30  
 
x 
 
 
 
1:45 
09:45  
 
x 
 
 
 
2:00 
10:00 240 mL fluid intake 
 
x 
 
 
 
2:30 
10:30  
 
x 
 
 
 
3:00 
11:00  
 
x 
 
 
 
4:00 
12:00 240 mL fluid intake, thereafter lunch3 
 
x 
 
 
x 
6:00 
14:00  
 
x 
 
 
 
8:00 
16:00 Snack (voluntary)3 
 
x 
 
 
 
10:00 
18:00  
 
x 
 
 
 
11:00 
19:00 Dinner3 
 
 
 
 
 
12:00 
20:00  
 
x 
 
 
x  
2 
24:00 
08:00 Breakfast (voluntary) 3, 
discharge from trial site 
 
x 
 
x 
x 
 
34:00 
18:00 Ambulatory visit 
 
x 
 
 
 x 
3 
48:00 
08:00 Ambulatory visit 
 
x 
 
 
x 
 
58:00 
18:00 Ambulatory visit 
 
x10 
 
 
 x10 
4 
72:00 
08:00 Ambulatory visit 
 
x10 
 
 
x10 
 
 
5 
96:00 
08:00 Ambulatory visit 
 
x10 
 
 
x10 
FU 
5 
6 to 209 
 
  End of study (EoS) examination4 
xB 
 
x 
x 
x 
 
1. 
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test in women), demographics (including determination of body height and weight, smoking status and 
alcohol history trial subject`s age on the day of informed consent, subject’s sex at birth, and ethnicity and race), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed. 
2. 
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration. 
3. 
If several actions are indicated at the same time, the intake of meals will be the last action. 
4. 
At the end of study (synonym for end of trial), the EoS examination includes physical examination, vital signs, ECG, 
safety laboratory, pregnancy test in women,  recording of AEs and concomitant therapies.  
5. 
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time 
6. 
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above. 
7. 
Letters A and B define different sets of safety laboratory examinations (see Section 5.2.3) 
8. 
The time is an approximate. The procedure is to be completed no later than 10 hours prior to drug administration. 
9. 
Referring to last study drug administration. 
10.  Starting from 58h after dosing a tolerance of +/- 120 minutes is given for all procedures 

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BI-VQD-11906_40-106_AD-13 (8.0) 
TABLE OF CONTENTS 
TITLE PAGE ......................................................................................................1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2 
FLOW CHART ...................................................................................................4 
TABLE OF CONTENTS ...................................................................................5 
ABBREVIATIONS AND DEFINITIONS ........................................................9 
1. 
INTRODUCTION .................................................................................... 12 
1.1 
MEDICAL BACKGROUND ............................................................................12 
1.2 
DRUG PROFILE ...............................................................................................12 
1.2.1 Residual Effect Period of Nerandomilast ...........................................12 
1.2.2 Clinical Pharmacology Profile of Nerandomilast ..............................12 
1.2.3 Overview of Safety of Nerandomilast .................................................13 
1.2.4 Clinical Experience with other PDE4 inhibitors ................................15 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ........................................17 
1.4 
BENEFIT - RISK ASSESSMENT ...................................................................17 
1.4.1 Benefits ...................................................................................................17 
1.4.2 Risks .......................................................................................................17 
1.4.3 Discussion...............................................................................................22 
2. 
TRIAL OBJECTIVES AND ENDPOINTS........................................... 23 
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......23 
2.1.1 Main objectives......................................................................................23 
2.1.2 Primary endpoints ................................................................................23 
2.1.3 Secondary endpoint ..............................................................................23 
2.2.2.2 Safety and tolerability .............................................................. 24 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION .............. 25 
3.1 
OVERALL TRIAL DESIGN ............................................................................25 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ..........................................................................................25 
3.3 
SELECTION OF TRIAL POPULATION ......................................................26 
3.3.1 Main diagnosis for trial entry ..............................................................26 
3.3.2 Inclusion criteria ...................................................................................26 
3.3.3 Exclusion criteria ..................................................................................27 
3.3.4 Withdrawal of subjects from treatment or assessments ...................28 
3.3.4.1 Withdrawal from trial treatment .............................................. 29 
3.3.4.2 Withdrawal of consent to trial participation ............................ 30 

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3.3.4.3 Discontinuation of the trial by the sponsor .............................. 30 
3.3.5 Replacement of subjects .......................................................................30 
4. 
TREATMENTS ........................................................................................ 31 
4.1 
INVESTIGATIONAL TREATMENTS ..........................................................31 
4.1.1 Identity of the Investigational Medicinal Products ...........................31 
4.1.2 Selection of doses in the trial ................................................................31 
4.1.3 Method of assigning subjects to treatment groups ............................31 
4.1.4 Drug assignment and administration of doses for each subject .......32 
4.1.5 Blinding and procedures for unblinding ............................................33 
4.1.6 Packaging, labelling, and re-supply ....................................................34 
4.1.7 Storage conditions .................................................................................34 
4.1.8 Drug accountability ..............................................................................34 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................35 
4.2.1 Other treatments and emergency procedures ....................................35 
4.2.2 Restrictions ............................................................................................35 
4.2.2.1 Restrictions regarding concomitant treatment ......................... 35 
4.2.2.2 Restrictions on diet and life style ............................................. 35 
4.2.2.3 Contraception requirements ..................................................... 36 
4.3 
TREATMENT COMPLIANCE .......................................................................36 
5. 
ASSESSMENTS ....................................................................................... 37 
5.1 
ASSESSMENT OF EFFICACY .......................................................................37 
5.2 
ASSESSMENT OF SAFETY ............................................................................37 
5.2.1 Physical examination ............................................................................37 
5.2.2 Vital signs ...............................................................................................37 
5.2.3 Safety laboratory parameters ..............................................................37 
5.2.4 Electrocardiogram ................................................................................39 
5.2.5 Other safety parameters .......................................................................40 
5.2.6 Assessment of adverse events ...............................................................40 
5.2.6.1 Definitions of adverse events ................................................... 40 
5.2.6.1.1 Adverse event ............................................................ 40 
5.2.6.1.2 Serious adverse event ................................................ 41 
5.2.6.1.3 AEs considered ‘Always Serious’ ............................. 41 
5.2.6.1.4 Adverse events of special interest ............................. 42 
5.2.6.1.5 Intensity (severity) of AEs ......................................... 42 
5.2.6.1.6 Causal relationship of AEs ........................................ 42 
5.2.6.2 Adverse event collection and reporting ................................... 43 
5.2.6.2.1 AE collection ............................................................. 43 
5.2.6.2.2 AE reporting to the sponsor and timelines ................ 44 
5.2.6.2.3 Pregnancy .................................................................. 45 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ..................................................................................45 
5.3.1 Assessment of pharmacokinetics .........................................................45 

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5.3.2 Methods of sample collection ...............................................................45 
5.3.2.1 Blood sampling for pharmacokinetic analysis ......................... 45 
5.4 
ASSESSMENT OF BIOMARKERS ................................................................46 
5.5 
BIOBANKING ...................................................................................................46 
5.6 
OTHER ASSESSMENTS .................................................................................46 
5.6.1 Pharmacogenomic evaluation ..............................................................46 
5.7 
APPROPRIATENESS OF MEASUREMENTS .............................................47 
6. 
INVESTIGATIONAL PLAN .................................................................. 48 
6.1 
VISIT SCHEDULE ............................................................................................48 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................48 
6.2.1 Screening ................................................................................................48 
6.2.2 Treatment periods .................................................................................48 
6.2.3 Follow-up period and trial completion ...............................................49 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ......................................................................................... 50 
7.1 
NULL AND ALTERNATIVE HYPOTHESES ..............................................50 
7.2 
PLANNED ANALYSES ....................................................................................50 
7.2.1 General considerations .........................................................................50 
7.2.1.1 Analysis sets............................................................................. 50 
7.2.1.2 Pharmacokinetics ..................................................................... 50 
7.2.2 Primary endpoint analyses ...................................................................51 
7.2.3 Secondary endpoint analyses ...............................................................52 
7.2.5 Safety analyses .......................................................................................53 
7.2.6 Interim analyses ....................................................................................54 
7.3 
HANDLING OF MISSING DATA ..................................................................54 
7.3.1 Safety ......................................................................................................54 
7.3.2 Pharmacokinetics ..................................................................................54 
7.4 
RANDOMISATION ..........................................................................................54 
7.5 
DETERMINATION OF SAMPLE SIZE ........................................................54 
8. 
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE ...................................................... 56 
8.1 
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................56 
8.2 
DATA QUALITY ASSURANCE .....................................................................57 
8.3 
RECORDS ..........................................................................................................57 

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8.3.1 Source documents .................................................................................57 
8.3.2 Direct access to source data and documents.......................................58 
8.3.3 Storage period of records .....................................................................59 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS .................................59 
8.5 
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY .......59 
8.5.1 Collection, storage and future use of biological samples and 
corresponding data ...............................................................................59 
8.6 
TRIAL MILESTONES .....................................................................................60 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................60 
9. 
REFERENCES ......................................................................................... 62 
9.1 
PUBLISHED REFERENCES ...........................................................................62 
9.2 
UNPUBLISHED REFERENCES .....................................................................64 
10. APPENDICES .......................................................................................... 65 
11. DESCRIPTION OF GLOBAL AMENDMENTS ................................. 66 
11.1 GLOBAL AMENDMENT 1 .............................................................................66 

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ABBREVIATIONS AND DEFINITIONS 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALAT 
Alanin-Aminotransferase 
ANOVA 
Analysis of variance 
ATS 
American Thoracic Society 
AUC0-∞ 
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity 
%AUCtz-∞ 
Percentage of AUC0-∞ obtained by extrapolation 
AUC0-tz 
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point 
BA 
Bioavailability 
BI 
Boehringer Ingelheim 
BMI 
Body mass index (weight divided by height squared) 
BP 
Blood pressure 
CA 
Competent authority 
cAMP 
Cyclic adenosine monophosphate 
CI 
Confidence interval 
CL 
Total clearance of the analyte in plasma after intravascular administration 
Cmax 
Maximum measured concentration of the analyte in plasma 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’) 
CT Leader 
Clinical Trial Leader 
CT Manager 
Clinical Trial Manager 
CTP 
Clinical trial protocol 
CTR 
Clinical trial report 
CV 
Arithmetic coefficient of variation 
DILI 
Drug induced liver injury 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDC 
Electronic data capture  
EDTA 
Ethylenediaminetetraacetic acid 
EoS 
End of Study (synonym for End of Trial) 
ERS 
European Respiratory Society 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in one second  

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FU 
Follow-up 
GCP 
Good Clinical Practice 
gCV 
Geometric coefficient of variation 
GI 
Gastro-intestinal 
gMean 
Geometric mean 
HR 
Heart rate 
IB 
Investigator’s brochure 
iCF 
Intended Commercial Formulation 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IPD 
Important protocol deviation 
IPF 
Idiopathic Pulmonary Fibrosis 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
JRS 
Japanese Respiratory Society 
z 
Terminal rate constant of the analyte in plasma 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
MDA 
Methylenedioxyamphetamine 
MDMA 
Methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Multiple Rising Dose 
PCR 
Polymerase chain reaction 
PDE4B 
Preferential inhibitor of the phosphodiesterase 
PE 
Polyethylene 
PF-ILDs 
Progressive fibrosing interstitital lung diseases 
PKS 
Pharmacokinetic set 
PP 
PPF 
Polypropylene 
Pulmonary Progressive Fibrosis 
PR 
Pulse rate 
QT interval 
ECG interval from the start of the QRS complex to the end of the T wave 
QTc interval 
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB) 
R 
Reference treatment 
REP 
Residual effect period 
SAE 
Serious adverse event 
SCR 
Screening 
SOP 
Standard operating procedure 

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SRD 
Single rising dose 
SUSAR 
Suspected unexpected serious adverse reaction 
T 
Test product or treatment 
TEAE 
Treatment-Emergent Adverse Event 
TF2 
Trial Formulation 2 
TMF 
Trial master file 
TNF-α 
Tumornekrosefaktor-α 
t1/2 
Terminal half-life of the analyte in plasma 
tmax 
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma 
TS 
Treated set 
tz 
Time of last measurable concentration of the analyte in plasma 
TSAP 
Trial statistical analysis plan 
ULN 
Upper limit of normal 

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BI-VQD-11906_40-106_AD-13 (8.0) 
1. 
INTRODUCTION 
Nerandomilast (BI 1015550), a preferential inhibitor of the phosphodiesterase 4B (PDE4B) 
isoenzyme which hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), is 
being developed by Boehringer Ingelheim (BI) for the treatment of Idiopathic Pulmonary 
Fibrosis (IPF) and Progressive Pulmonary Fibrosis (PPF). 
1.1 
MEDICAL BACKGROUND 
IPF and other PF-ILDs share common pathophysiologic characteristics; alveolar epithelial 
cell injury and subsequent dysregulated repair, characterized by excessive deposition of 
extracellular matrix and loss of normal parenchymal architecture and lung function (P11-
07084). In IPF, fibroblasts exhibit unregulated proliferation and differentiate into 
myofibroblasts. The latter is considered the hallmark cell in the development and 
establishment of lung fibrosis (P12-03241). Several growth factors are implicated in the 
proliferation, migration and transdifferentiation of the fibroblast and myofibroblast pool in 
pulmonary fibrosis. 
 
Nerandomilast is an oral preferential inhibitor of the PDE4B with broad anti-inflammatory 
and antifibrotic activities. Based on its mode of action, as well as available pre-clinical and 
clinical data, nerandomilast is hypothesised to have complementary activity to current 
therapies in IPF and other forms of progressive pulmonary fibrosis. 
1.2 
DRUG PROFILE 
1.2.1 
Residual Effect Period of Nerandomilast 
The Residual Effect Period (REP) of nerandomilast is 7 days. This is the period after the last 
dose with measurable drug levels and / or pharmacodynamic effects still likely to be present. 
 
For a more detailed description of the nerandomilast profile, please refer to the current 
Investigator’s Brochure (IB) [c02094779] nerandomilast. 
1.2.2 
Clinical Pharmacology Profile of Nerandomilast 
The PK of nerandomilast was linear over all dose groups tested in SRD and MRD studies. 
After oral administration, nerandomilast is rapidly absorbed with peak plasma concentrations 
occurring at a median tmax around 1.25 h (range between 0.5-4 h) post-dose. The gMean t1/2 
was approximately 10-17 h. After single and multiple oral doses, nerandomilast exposure 
(Cmax and AUC0-∞) appeared to increase dose proportionally. Steady state of nerandomilast 
was achieved by Day 4 of bid administration. Accumulation ratio based on Cmax and AUC 
were 1.30 and 1.38, respectively. Administration of nerandomilast together with food did not 
change the exposure to a clinically relevant extent. 
In the human ADME (mass balance) study (1305-0016) following a single oral dose 
administration of [14C]nerandomilast, the total recovery of [14C]drug-related material was 
on average 95.0% of the administered dose with 58.0% excreted in faeces and 36.4% 
excreted in urine where 11.9% was excreted unchanged as parent compound [c36151567]. 

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Exposures are slightly higher in Asian healthy subjects (around 1.5-fold) compared to 
Caucasian healthy subjects, likely due to lower body weight rather than a race effect. The 
impact of renal or hepatic impairment on nerandomilast exposure was not substantial. 
Compared with healthy subjects with normal renal and hepatic function, AUC was increased 
by 29-37% in subjects with moderate and severe renal impairment and increased by 31% in 
subjects with moderate hepatic impairment Child-Pugh B (no relevant change in subjects 
with Child-Pugh A). 
Nerandomilast is mainly metabolized by CYP3A with contributions from UGTs. Chiral 
inversion from administered pharmacologically active R-enantiomer to inactive S-enantiomer 
occurs to a small extent (11%) in human also via metabolism. Administration of 
nerandomilast together with a strong CYP3A4 inhibitor itraconazole increased nerandomilast 
AUC by 2.2-fold and Cmax by 1.3-fold. Furthermore, nerandomilast did not induce CYP3A 
enzyme based on the clinical DDI study with midazolam [c40607236]. 
Results from the Phase II trial 1305-0013 in patients with IPF showed that pre- and post-dose 
concentration levels of nerandomilast (measured via non-chiral bioanalytical method) were 
similar between patients treated with nintedanib and those not treated with any antifibrotic, 
suggesting nintedanib did not impact the exposure of nerandomilast. However, a 35-50% 
lower exposure was observed in IPF patients on background treatment with pirfenidone 
[c37065416]. 
1.2.3 
Overview of Safety of Nerandomilast 
Data from non-clinical studies 
The toxicity profile for nerandomilast has been assessed in safety pharmacology studies, 
genetic toxicology studies, and repeat dose studies in the rat, minipig, and monkeys of up to 
13, 26,  and 39 weeks, respectively.  
Vasculopathy and mortality secondary to vasculopathy are the primary findings defining the 
no adverse effect level (NOAEL) and lowest observed adverse effect Level (LOAEL) in the 
rat and minipig, respectively.  
In contrast, vascular changes were not observed in a 39-week monkey study at 30 mg/kg/day, 
supporting the decreased sensitivity of primates to PDE4i-induced vascular changes. 
Vasculopathy is a well characterized class-effect pathology associated with PDE4 inhibitors 
[R10-1559] and has not been demonstrated in humans administered marketed PDE4i 
apremilast and roflumilast 
 
In addition, a fertility and early embryonic development (rat) and embryo-fetal development 
toxicity studies (rat and rabbit) were conducted. Decreased mating, fertility, and pregnancy 
indices were observed in male and female rats at a dose level that also level caused evidence 
of severe toxicity in both sexes. In rats but not in rabbits foetal loss was increased. 
Teratogenicity and fetotoxicity was not observed. In long-term toxicity studies in rats (26-
weeks), minipig and monkeys (13-weeks) there was no microscopic evidence of changes in 
female reproductive organs or on male spermatogenesis. Sporadic menstrual cycle 
prolongation was observed in the 39-week NHP toxicology study in females at exposures 
corresponding to approximately ≥4- fold human exposure at 18 mg bid. Menstrual cycles 
were not affected in monkeys at exposures equivalent to humans.    
 

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toxicity similar to the observations made for nerandomilast with respective labellingFor more 
details, please refer to the current Investigator’s Brochure (IB) (c02094779). 
 
Data from clinical studies 
A total of 13 clinical studies in healthy volunteers have been completed with nerandomilast. 
Overall, 271 healthy volunteers have been exposed to nerandomilast: 222 subjects to single-
dose administration with up to 48 mg and 49 subjects to multiple administrations for up to 14 
days with up to 18 mg bid.  
 
Clinical safety in healthy subjects 
 
Overall, nerandomilast, up to a 48 mg single-dose and 18 mg bid multiple-dose appeared to 
show acceptable safety and tolerability. The most common AEs were nervous system events, 
particularly headache, and GI events, particularly diarrhoea and abdominal pain. Overall, no 
clear dose-dependency in the frequency and intensity of these AEs was observed. 
(c02094779) No severe, serious, fatal events or suspected unexpected serious adverse 
reactions (SUSARs) have been reported in healthy volunteers.  
 
In the SRD trial single doses up to 24 mg nerandomilast have been tested (54 subjects on 
active treatment + 16 subjects on placebo in total). AEs were reported by 27 of 70 subjects. 
The most frequent AE to be reported was headache in 9  subjects, followed by diarrhea in 3 
subjects. A total of 9 subjects were reported with drug related AEs. [U13-1792-01] 
 
In another trial (1305-0011) single doses of 36 mg and 48 mg nerandormilast (6 subjects on  
active treatment + 3 subjects on placebo in each DG) and multiple doses of 6 mg bid and 12 
mg bid, administered for 11 days followed by a morning dose on the next day (8 subjects on 
active treatment + 4 subjects on placebo in each DG) have been tested in healthy subjects. In 
the SRD part AEs related to the intake of nerandomilast were reported by 3 of 12 subjects (48 
mg DG only). The most frequent drug related AE was headache reported by 3 subjects. 
Further drug related AEs comprise diarrhoea, abdominal distension, upper abdominal pain, 
constipation, and nausea. [c22991937]. 
 
The trial 1305-0033 (DDI with midazolam) investigated the CYP3A induction potential of BI 
1015550, which required the administration of the expected therapeutic dose (18 mg bid) 
over 14 days to healthy subjects. Drug related AEs were reported by 9 of 15 subjects and 
comprise myalgia (3 subjects), diarrhoea (2x), headache (2x), flatulence (2x) and 
hyperaesthesia (1x). All these AEs were of mild intensity. No relevant changes of lab values, 
vital signs and ECG parameters have been reported [c40607236, draft report].  
Clinical safety in patients 
 
Two clinical trials have been completed in patients with IPF:  
A Phase 1c study of nerandomilast at 18 mg twice daily in patients with IPF not on 
background antifibrotic therapy showed similar PK to healthy volunteers along with an 
acceptable safety and tolerability profile. A total of 10 patients were treated with 
nerandomilast 18 mg bid and 5 patients were treated with placebo. 

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The most frequently reported AEs by system organ class were gastrointestinal disorders. 
Gastrointestinal disorders were more frequent in the nerandomilast group (8 patients, 80%) 
than in the placebo group (2 patients, 40%). On preferred term level, diarrhoea and flatulence 
were the most frequently reported gastrointestinal disorders; they occurred with similar 
incidences in both treatment groups (diarrhoea: 40% each in nerandomilast and Placebo 
group, flatulence: 30% in nerandomilast, 20% in placebo group). SAEs were reported for 1 
patient (anal fistula and anal incontinence) that were related to a long-lasting pre-existing 
condition and subsequent elective surgery. No fatal events were reported (c25085412). 
 
Treatment with nerandomilast at 18 mg twice daily in a Phase II proof-of-concept trial 
preserved lung function in patients with IPF over a period of 12 weeks, either as a 
monotherapy or on top of approved antifibrotic standard of care (nintedanib or pirfenidone). 
nerandomilast showed acceptable safety and tolerability in the overall study population and in 
the subgroups of patients without or with background antifibrotic treatment. 
 
In this trial 97 patients were exposed to nerandomilast and 50 patients to placebo. The most 
frequently reported AEs were gastrointestinal disorders (32.0% in the nerandomilast group, 
24.0% in the placebo group). Diarrhea was the most common AE, with a higher frequency in 
the nerandomilast group (23.7%) than in the placebo group (12.0%) and diarrhea was also the 
most common event leading to treatment discontinuation (3 patients, all in the nerandomilast 
group and all on background treatment with nintedanib). However, the majority of diarrhea 
events were mild in intensity. 
AEs leading to discontinuation of trial treatment were only observed in the nerandomilast 
treatment group. Apart from the mentioned 3 patients with diarrhoea and 2 patients with 
Covid-19, all events occurred in single patients without any pattern or cluster. 
 
Serious adverse events were reported in 10.0% of patients in the placebo group and 6.2% of 
patients in the nerandomilast treatment group. There were two events with fatal outcome in 
the nerandomilast treatment group, one patient with Covid-19 pneumonia and one patient 
with suspected IPF exacerbation and suspected vasculitis (the diagnosis of vasculitis could 
not be confirmed by the sponsor nor the independent external data monitoring committee). 
Risk factors were present in both fatal events. 
There were no clinically relevant changes in vital signs (including body weight) and/or ECG 
parameters (including QTc) observed. No changes in the Columbia Suicidal Severity Rating 
Scale (C-SSRS) and no AEs of suicidal ideation or behaviour were reported during trial 
treatment (c37065416). 
For a more detailed description of the nerandomilast profile, please refer to the current 
Investigator’s Brochure (IB) (c02094779). 
1.2.4 
Clinical Experience with other PDE4 inhibitors 
Selective PDE4 inhibitors have been approved for chronic obstructive pulmonary disease 
(COPD) with chronic bronchitis and a history of exacerbations (roflumilast), and for 
moderate to severe plaque psoriasis and active psoriatic arthritis (apremilast).  

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Roflumilast has been tested in Phase III studies for asthma and apremilast in Phase III studies 
for active Behcet’s disease. No PDE4 inhibitor has been tested in IPF, yet. 
 
Roflumilast 
Only one PDE4 inhibitor, roflumilast (Daxas® in EU, Daliresp® in US), has received 
marketing authorization by regulatory agencies for a respiratory indication, COPD. 
More than 5,000 patients with COPD were included in the “COPD Safety Pool” of the large 
roflumilast clinical development program. The most frequently reported AEs associated with 
the treatment with roflumilast were diarrhoea, weight loss, nausea, abdominal pain and 
headache followed by insomnia, dizziness and decreased appetite. 
The most common AEs leading to withdrawal in approximately 14% of the patients treated 
with roflumilast were nausea, diarrhoea and headache. The rate of withdrawal due to AEs 
among patients receiving placebo was 9%.  
The mechanism of weight loss, which was observed in approximately 7% of the patients 
receiving roflumilast, is not fully understood (R10-1555).  
The SPCs of Daxas®/Daliresp®, recommend the close monitoring of patient’s body weight 
and its cautious use in patients with previous or existing psychiatric symptoms or if 
concomitant treatment with other medicinal products, which are likely to cause psychiatric 
events, is intended.  
 
Apremilast 
One PDE4 inhibitor for treatment of active psoriatic arthritis (Otezla®) has been approved by 
the FDA on March 2014, in September 2014 for moderate to severe plaque psoriasis and in 
July 2019 for the treatment of oral ulcers associated with Behçet’s disease. 
Otezla® has been evaluated in 1493 patients with active psoriatic arthritis in three 
randomised placebo-controlled studies (R17-1427).  
The most common adverse reactions were diarrhoea, headache and nausea, followed by 
vomiting, upper respiratory tract infection, nasopharyngitis and abdominal pain.  
The most common adverse reactions leading to discontinuation were diarrhoea (1.8%), 
nausea (1.8%) and headache (1.2%). 
 
 

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The proportion of patients with psoriatic arthritis who discontinued treatment due to any 
adverse reaction was 4.6% for patients taking Otezla® 30 mg twice daily and 1.2% for 
placebo-treated patients. 
The product information of Otezla® recommends the close monitoring of patient’s body 
weight and its cautious use in patients with history of depression and/or suicidal thoughts or 
behaviour (R14-1795). 
1.3 
RATIONALE FOR PERFORMING THE TRIAL 
Nerandomilast 18 mg film-coated tablet (Formulation C1) is currently used in two Phase 3 
safety and efficacy trials in adult patients. A new formulation, 1 mg film-coated tablet, has 
been developed and is planned to be used in paediatric trial evaluating nerandomilast in 
paediatric fibrosing ILD patients. This trial is conducted to show the relative bioavailability 
of the 18 mg film-coated tablet of nerandomilast and 18 tablets of a new formulation of 1 mg 
film-coated tablets of nerandomilast. In addition, the food effect of the new formulation will 
be evaluated. 
1.4 
BENEFIT - RISK ASSESSMENT 
1.4.1 
Benefits 
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of paediatric 
formulation.  
1.4.2 
Risks 
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. An overview of trial-related risks is given in Table 1.4.2: 1. 
There are no identified risks for nerandomilast, based on the toxicology program or any 
clinical trials conducted for this product to date. Vasculitis and foetal loss are considered as 
important potential risk based only on nonclinical findings (see Section 1.2.1). 
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs and from preclinical and clinical data of  
compounds with a comparable mode of action (see Section 1.2.3). For adverse events 
reported during clinical trials with nerandomilast please refer to Section 1.2.1. 
 
 

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Table 1.4.2: 1 
Overview of trial-related risks for this trial 
Possible or known risks 
of clinical relevance  
Summary of data, rationale for 
the risk 
Mitigation strategy 
Investigational Medicinal Product: nerandomilast 
Vasculitis 
• 
Vasculopathy is an 
established preclinical 
toxicity of PDE 4 
inhibitors 
• 
Vasculitis has been 
shown in rats and 
minipigs following oral 
administration of 
nerandomilast but not in 
monkeys 
• 
Vasculitis is listed as an 
important potential risk 
for the marketed PDE4 
inhibitor apremilast 
• 
In marketed PDE4 
inhibitors, vasculitis has 
not been identified as an 
adverse drug reaction in 
humans. 
• 
The risk in a single 
dosing trial is considered 
to be very low. 
• 
Active vasculitis 
(unstable or uncontrolled) 
is an exclusion criterion 
for participants. 
• 
Close monitoring for AEs 
of vasculitis. 
• 
Treatment discontinuation 
in case of suspected 
vasculitis. 

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Table 1.4.2: 1  
Overview of trial-related risks for this trial (cont.) 
Reproductive toxicity: 
foetal loss, decreased 
fertility 
• 
No teratogenicity was 
seen in 2 species in 
preclinical studies and 
exposure with 
nerandomilast via the 
semen is expected to be 
very low. 
• 
In rats, male and female 
fertility was potentially 
reduced. Long term 
toxicity studies with 
nerandomilast in rat and 
monkey showed no 
microscopic evidence of 
changes in female 
reproductive organs or 
male spermatogenesis. 
For another PDE4 
inhibitor with comparable 
nonclinical findings, 
clinical data showed no 
effect on male fertility 
and sperm in humans. 
• 
In monkeys, a sporadic 
prolongation in menstrua 
cycles was observed at 
approximately ≥ 4-fold 
human exposure at 18 mg 
nerandomilast bid. 
• 
Fetal loss was increased 
in female rats treated with 
nerandomilast. 
• 
Women of childbearing 
potential (WOCBP) need 
to use a highly effective 
method of contraception. 
• 
WOCBP taking oral 
contraceptives (OCs) also 
have to ensure the use of 
one barrier method during 
sexual intercourse with 
their partner, e.g., 
condom to account for the 
risk of potentially reduced 
efficacy of the OCs in the 
event of severe vomiting 
and diarrhoea 
• 
Pregnancy testing for 
WOCBP 
• 
Treatment discontinuation 
in case of pregnancy 
Weight decrease in 
underweight patients 
(BMI < 18.5 kg/m2) 
• 
For the marketed PDE4i 
apremilast and 
roflumilast weight loss in 
underweight participants 
is an identified important 
risk  
• 
Presumably caused by 
increased energy 
expenditure and causing 
predominately loss of 
body fat. 
• 
With single dosing, the 
risk is considered to be 
negligible. 
• 
Only participants with 
BMI > 18.5 kg/m2 will be 
included. 
 
 

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Table 1.4.2: 1  
Overview of trial-related risks for this trial (cont.) 
Psychiatric disorders: 
• 
Depression and 
anxiety 
• 
Suicidality  
For the marketed PDE4i 
depression is listed as side effect 
and they are associated with 
increased risk of depression with 
some patients reporting suicidal 
ideation and attempts and also 
with some reported cases of 
completed suicide. 
• 
The risk after a single 
administration 
nerandomilast is 
considered very low and 
will be addressed by 
careful close clinical 
monitoring for AEs and 
increased awareness by 
the investigator for signs 
and symptoms of 
depression and anxiety as 
well as for signs and 
symptoms of suicidal 
ideation and behavior 
• 
Only participants with no 
relevant medical history 
including psychiatric 
disorders will be enrolled 
• 
Treatment discontinuation 
in case of signs for 
suicidality 
Severe infections 
including, serious, 
opportunistic and 
mycobacterium 
tuberculosis infections 
• 
Inhibition of the immune 
response due to the anti-
inflammatory mode of 
action of nerandomilast 
potentially increases the 
risk of severe and serious 
infections. 
• 
Serious infections were 
balanced between 
placebo and 
nerandomilast in Phase II 
trial 
• 
Nasopharyngitis was 
more frequently reported 
under treatment with 
nerandomilast in Phase 
Ic/II but not in Phase I 
trials and the numbers 
were very small. 
• 
This risk is considered to 
be low in a single dosing 
trial 
• 
Participants with any 
relevant chronic or acute 
infections are excluded 
from the trial 
• 
Treatment of infections 
should be initiated 
promptly according to 
standards of care 
 
 

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Table 1.4.2: 1  
Overview of trial-related risks for this trial (cont.) 
Major Adverse 
Cardiovascular Events 
(MACE) and 
tachyarrhythmia 
• 
Important potential risk 
for marketed PDE4 
inhibitor apremilast. 
• 
In preclinical studies with 
nerandomilast no adverse 
cardiovascular findings 
detected. 
• 
In clinical trials with 
nerandomilast no relevant 
findings were observed. 
• 
The risk in a single 
dosing trial is considered 
to be very low. 
• 
Only healthy subjects 
without relevant 
cardiovascular risk factors 
will be included 
Malignancies 
• 
Inhibition of the immune 
response with an 
immunomodulatory drug 
may potentially impair 
immune defences and 
thus, theoretically 
decrease immune defence 
against malignancies. 
• 
The risk in a single 
dosing trial is considered 
to be very low. 
• 
Participants with a recent 
history of malignancy 
within 5 years will be 
excluded from 
participation in this trial. 
Gastrointestinal 
disorders (e.g., 
diarrhoea, nausea, 
vomiting, abdominal 
pain) 
• 
Vomiting and diarrhoea 
are important dose-
limiting side effects of 
marketed oral PDE-4 
inhibitors.  
• 
In Phase II study 
nerandomilast, diarrhoea 
was the most frequently 
reported AE. 
• 
The risk in a single 
dosing trial is considered 
to be low. 
• 
Careful monitoring and 
symptomatic treatment if 
required 
Drug-induced liver 
injury (DILI) 
Rare but severe event, thus under 
constant surveillance by sponsors 
and regulators. 
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure subjects´ 
safety. 
Trial procedures 
Inflammation of the wall 
of the vein. Injuring of a 
nerve while inserting the 
venous catheter, 
potentially resulting in 
paraesthesia, reduced 
sensibility, and/or pain 
for an indefinite period. 
General risk by venipuncture for 
blood sampling, acceptable in the 
framework of trial participation. 
Evaluation of the medical 
expertise of the trial sites is part 
of site feasibility assessment. 
Trial treatment discontinuation 
criteria as well as criteria for trial 
treatment restart are implemented 
for relevant cases. 

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Table 1.4.2: 1  
Overview of trial-related risks for this trial (cont.) 
Skin irritation, redness, 
itching 
General risk by ECG electrodes, 
acceptable in the framework of 
trial participation. 
Exclusion of subjects from trial 
participation with known 
clinically relevant hypersensitivity 
reactions to adhesive tapes 
 
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood. 
1.4.3 
Discussion 
The nature of the target and the mechanism of action of nerandomilast is well understood.  
Based on its mode of action, nerandomilast is hypothesized to have complementary activity 
to current therapies in IPF. 
In the context of the unmet medical need and anticipated benefit of nerandomilast, the benefit 
risk evaluation of the compound, based upon the available preclinical and clinical 
information, is favourable. 

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2. 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS 
2.1.1 
Main objectives 
The main objective of this trial is to investigate the relative bioavailability of 1 x 18 mg of 
nerandomilast film-coated tablet (Formulation C1, adult formulation) compared with 18 x 
1 mg of nerandomilast film-coated tablets (paediatric formulation) and the effect of food on 
the PK of paediatric formulation following oral administration. 
2.1.2 
Primary endpoints 
The following pharmacokinetic parameters will be determined for nerandomilast: 
• AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point) 
• Cmax (maximum measured concentration of the analyte in plasma) 
2.1.3 
Secondary endpoint 
The following pharmacokinetic parameter will be determined for nerandomilast: 
• AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity) 

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2.2.2.2 
Safety and tolerability 
Safety and tolerability of nerandomilast will be assessed based on:   
• Adverse events (including clinically relevant findings from the physical examination) 
• Safety laboratory tests 
• Vital signs (blood pressure, pulse rate) 
• ECG 

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a randomised, open-label, three-way crossover trial in healthy 
male and female subjects in order to compare the test treatment 1 (T1) to the reference 
treatment (R) and to compare test treatment 2 (T2) to test treatment 1 (T1) . 
The treatments will be 
•
one 18 mg nerandomilast film-coated tablet, adult formulation, administered to 
subjects in the fasting state (R) 
•
eighteen 1 mg nerandomilast film-coated tablets, pediatric formulation, administered 
to subjects in the fasting state (T1)
•
eighteen 1 mg nerandomilast film-coated tablets, pediatric formulation, administered 
to subjects in the fed state (T2)
The subjects will be randomly allocated to one of the 3 treatment sequences: R-T1-T2, T1-
T2-R, or T2-R-T1. There will be a washout period of at least 7 days between the treatments 
(referring to day 1). In each treatment period (1, 2, 3), the subject is planned to receive 1 
single dose of medication (R, T1, or T2). See Figure 3.1.: 1
Figure 3.1: 1
Trial design
For details on the treatments, refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his/her own control, the comparison between treatments is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
At least 7 days
R
T1
T1
R
R
T2
T1
T2
T2
Treatment period
1
2
3
Treatment
sequence
1
2
3
At least 7 days

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The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation. 
3.3 
SELECTION OF TRIAL POPULATION 
It is planned that 15 healthy male and female subjects will enter the trial. They will be 
recruited from the volunteers' pool of the trial site.  
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not. 
3.3.1 
Main diagnosis for trial entry 
The trial will be performed in healthy subjects. 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria. 
3.3.2 
Inclusion criteria 
Subjects will only be included in the trial if they meet the following criteria: 
1. Healthy male or female subjects according to the assessment of the investigator, as 
based on a complete medical history including a physical examination, vital signs 
(BP, PR), 12-lead ECG, and clinical laboratory tests  
2. Age of 18 to 55 years (inclusive)  
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)  
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial 
5. Either male subject, or female subject who meet any of the following criteria for a 
highly effective contraception from at least 30 days before the first administration of 
trial medication until 30 days after trial completion: 
- 
Use of combined (estrogen and progestogen containing) hormonal 
contraception that prevents ovulation (oral, intravaginal or transdermal), plus 
condom 
- 
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom 
- 
Use of intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS) 

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- 
Sexually abstinent 
- 
A vasectomised sexual partner who received medical assessment of the 
surgical success (documented absence of sperm) and provided that partner is 
the sole sexual partner of the trial participant 
- 
Surgically sterilised (including hysterectomy) 
- 
Postmenopausal, defined as no menses for 1 year without an alternative 
medical cause (in questionable cases a blood sample with levels of FSH above 
40 U/L and estradiol below 30 ng/L is confirmatory) 
3.3.3 
Exclusion criteria 
Subjects will not be allowed to participate, if any of the following general criteria apply: 
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator 
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 
mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate 
outside the range of 45 to 90 bpm 
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance 
4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator 
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders 
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair) 
7. Diseases of the central nervous system (including but not limited to any kind of 
seizures or stroke), and other relevant neurological or psychiatric disorders  
8. History of relevant orthostatic hypotension, fainting spells, or blackouts 
9. Relevant chronic or acute infections 
10. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin 
11. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients)  
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation) 

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13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered  
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) 
15. Inability to refrain from smoking on specified trial days 
16. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day 
for males) 
17. Drug abuse or positive drug screening 
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial 
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial 
20. Inability to comply with the dietary regimen of the trial site 
21. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) or any 
other relevant ECG finding at screening  
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)  
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, 
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study  
24. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of first administration of trial 
medication until 7 days after the last administration of nerandomilast 
25. For female subjects: Lactation, pregnancy, or plans to become pregnant during the 
trial or within 30 days after trial completion 
26. For female subjects: Positive pregnancy test 
27. Active vasculitis, unstable or uncontrolled within 8 weeks prior to enrolment 
For restrictions of the trial, refer to Section 4.2.2. 
3.3.4 
Withdrawal of subjects from treatment or assessments 
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below. 
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). 

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If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR.  
Following removal or withdrawal, a complete end-of-trial examination should be performed. 
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.1), the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject. 
3.3.4.1 
Withdrawal from trial treatment 
An individual subject will be withdrawn from trial treatment if: 
1. The subject wants to withdraw from trial treatment. The subject will be asked to 
explain the reasons but has the right to refuse to answer  
2. The subject has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor representative, 
the safety of the subject cannot be guaranteed as he / she is not willing or able to 
adhere to the trial requirements in the future 
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment 
4. The subject can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, adverse events (AEs), or diseases) 
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of 
total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be 
followed up according to the DILI checklist provided in the ISF 
If any of the following adverse events is reported, the treatment has to be discontinued: 
- 
Severe or serious infections, opportunistic or mycobacterium tuberculosis infection 
- 
Vasculitis 
- 
Occurrence of malignancies other than appropriately treated basal cell carcinoma or 
squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix 
- 
Suicidal ideation or behaviour 
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment. 
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy.  

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The subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.3.  
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects. 
3.3.4.2 
Withdrawal of consent to trial participation 
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above. 
3.3.4.3 
Discontinuation of the trial by the sponsor 
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately): 
- 
Failure to meet expected enrolment goals overall or at a particular trial site 
- 
The sponsor decides to discontinue the further development of the investigational 
products 
- 
Deviation from GCP, or the CTP impairing the appropriate conduct of the trial 
- 
New toxicological findings, serious adverse events, or any safety information 
invalidating the earlier positive benefit-risk-assessment (see Section 3.3.4.1)  
- 
More than 50% of the subjects show drug-related and clinically relevant adverse 
events of moderate or severe intensity in one treatment periods or if at least one drug-
related serious adverse event is reported in the trial 
3.3.5 
Replacement of subjects 
In case more than 3 subjects do not complete the trial (including subjects non- evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial. 
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 5 subjects. A replacement subject 
will be assigned a unique trial subject number, and will be assigned to the same treatment 
sequence as the subject he or she replaces. 

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4. 
TREATMENTS 
4.1 
INVESTIGATIONAL TREATMENTS 
4.1.1 
Identity of the Investigational Medicinal Products 
The characteristics of the test product (T) are given below: 
Substance: 
 
 
nerandomilast 
Pharmaceutical formulation: film-coated tablets 
Source: 
 
 
BI Pharma GmbH & Co. KG, Germany 
Unit strength:  
 
1 mg 
Posology: 
 
 
18-0-0 
Mode of administration: 
Oral 
Duration of use: 
 
single dose  
The characteristics of the reference product (R) are given below: 
Substance: 
 
 
nerandomilast 
Pharmaceutical formulation: film-coated tablet, formulation C1 
Source: 
 
 
BI Pharma GmbH & Co. KG, Germany 
Unit strength:  
 
18 mg 
Posology: 
 
 
1-0-0 
Mode of administration: 
Oral 
Duration of use: 
 
single dose 
4.1.2 
Selection of doses in the trial 
18 mg bid of nerandomilast is one of the doses that is currently used in Phase 3 clinical trials. 
For the investigation of relative bioavailability and food effect using single dose is sufficient.  
4.1.3 
Method of assigning subjects to treatment groups 
The randomisation scheme will be provided to the trial site in advance.  
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 of Visit 2. For this purpose, numbers of the 
randomisation scheme will be allocated to the subjects by drawing lots. Subjects are then 
assigned to a treatment sequence according to the randomisation scheme. 
Once a subject number has been assigned, it cannot be reassigned to any other subject. 
 
 

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All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. Treatment of all subjects on the same 
calendar day is acceptable  
For discussion of trial-associated risks and safety measurements, see Section 1.4. 
The randomisation procedure is described in Section 7.4. 
4.1.4 
Drug assignment and administration of doses for each subject 
This is a 3-way crossover trial. All subjects will receive the 3 treatments in randomised order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below.  
Table 4.1.4: 1 
Dosage and treatment schedule 
Treatment 
Substance 
Formulation 
Unit 
strength 
Dosage for a 
single application 
Metabolic 
state 
Total 
dose 
T1 (Test 1) 
nerandomilast 
film-coated tablet 
(paediatric) 
1 mg 
18 tablets  
Fasted 
18 mg 
T2 (Test 2) 
nerandomilast 
film-coated tablet 
(paediatric) 
1 mg 
18 tablets  
Fed 
18 mg 
R (Reference) nerandomilast 
film-coated tablet 
formulation C1 (adult) 
18 mg 
1 tablet  
Fasted 
18 mg 
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise. 
Administration of trial medication in two treatment periods (T1 and R) will be performed 
after subjects have fasted overnight; fasting is to start no later than 10 h before the scheduled 
dosing. Furthermore, subjects in these periods will continue to fast 4 additional hours after 
the dose administration.  
In treatment period receiving T2, the subjects will consume a high-fat, high-calorie meal 
within 30 min before drug administration. The subjects must completely consume the meal 
prior to drug intake. The composition of the standard high-fat, high-calorie meal is detailed in 
Table 4.1.4: 2; this meal is in compliance with the FDA guidance ‘Food-Effect 
Bioavailability and Fed Bioequivalence Studies’ [R03-2269]. For restrictions with regard to 
diet, see Section 4.2.2.2. 
 
 

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Table 4.1.4: 2 
Composition of the high-fat, high-calorie meal 
Ingredients 
kcal 
2 chicken eggs (whole content) for scrambled eggs 
192 
10 g butter for frying scrambled eggs 
75 
35 g fried bacon 
186 
2 toasted slices of wheat bread 
130 
15 g butter for buttering toast slices 
113 
115 g hash brown potatoes 
132 
240 mL whole milk (3.5% fat) 
156 
Sum1 
984 
1 
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat.  
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture). 
The treatments will be separated by a wash-out phase of at least 6 days. 
4.1.5 
Blinding and procedures for unblinding 
The table below summarizes the masking/blinding level of individual functions, roles and 
responsibilities involved in the trial. 
Table 4.1.5: 1  
Blinding level of individual functions 
Role/function 
Timing of receiving access to the treatment information  
Subject/Participant 
As soon as treatment sequence has been assigned. 
Investigator/Site Staff 
The randomization scheme will be provided to the trial site prior 
to setup. 
Sponsor trial team and data 
Unblinded as requested. 
Bioanalytical Staff 
Persons directly involved in bioanalyses of PK samples will be 
blinded to trial treatments. 
Pharmacokineticist/ 
Pharmacometrician 
Unblinded as requested for analysis. 
 
During the time a role/function is blinded according to the table above, the randomisation 
schemes (i.e., the treatment information) are kept restricted by the global Randomization 
Team per Sponsor SOP. 
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site. 
 

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4.1.6 
Packaging, labelling, and re-supply 
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP).  
For details of packing and the description of the label, refer to the ISF. 
The labels will be prepared according to Regulation (EU) No 536/2014, Annex 6 omitting 
certain particulars with the following justifications:  
- 
The visit number is not relevant for the label because the product will remain at the 
clinical site. 
- 
The investigator name was omitted from the label because it is included on the Trial 
Identification Card, which will be issued to each trial participant. 
- 
The "keep out of reach of children" statement was omitted from the label because the 
product will remain at the clinical site 
 
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.  
No re-supply is planned. 
4.1.7 
Storage conditions 
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted 
immediately. 
4.1.8 
Drug accountability 
The investigator or designee will receive the investigational drugs delivered from the sponsor 
when the following requirements are fulfilled: 
• Approval of the clinical trial protocol by the IRB / ethics committee 
• Approval/notification of the regulatory authority, e.g. competent authority 
• Availability of the curriculum vitae of the Principal Investigator 
• Availability of a signed and dated clinical trial protocol   
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.  

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These records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, 
and the unique code numbers assigned to the investigational medicinal product and trial 
subjects. The investigator or designee will maintain records that document adequately that the 
subjects were provided the doses specified by the CTP and reconcile all investigational 
medicinal products received from the sponsor. At the time of disposal of remaining trial 
medication, the investigator or designee must verify that no remaining supplies are in the 
investigator’s possession.  
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies. 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS 
4.2.1 
Other treatments and emergency procedures 
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable. 
4.2.2 
Restrictions 
4.2.2.1 
Restrictions regarding concomitant treatment 
In principle, no concomitant therapy is allowed. In particular strong CYP3A inhibitors are 
restricted medication due to potential drug-drug interactions. All concomitant or rescue 
therapies will be recorded (including time of intake on trial days) on the appropriate pages of 
the CRF. 
4.2.2.2 
Restrictions on diet and life style 
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times 
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake. 
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), to the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). From lunch until 24 h 
post-dose, total fluid intake is restricted to 3000 mL.  
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each trial period is collected.  

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Alcoholic beverages are not permitted starting 48 h before first trial drug administration until 
last PK sampling of each trial period. 
Poppy seeds containing products should not be consumed starting 3 days before first trial 
drug administration until last PK-sampling of the trial.  
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during in-house confinement at the trial site. 
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination. 
Smoking is not allowed during in-house confinement. 
4.2.2.3 
Contraception requirements 
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures). 
4.3 
TREATMENT COMPLIANCE 
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance. 
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 

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5. 
ASSESSMENTS 
5.1 
ASSESSMENT OF EFFICACY 
Not applicable.  
5.2 
ASSESSMENT OF SAFETY 
5.2.1 
Physical examination 
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history, relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory 
tests, and a physical examination.  
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, a physical examination and an AE/CT questioning. 
5.2.2 
Vital signs 
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100,
 at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible. 
5.2.3 
Safety laboratory parameters 
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.  
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF.  
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.  
 
 
 

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Table 5.2.3: 1 
Routine laboratory tests 
Functional lab group 
BI test name [comment/abbreviation] 
A 
B 
Haematology 
Haematocrit 
Haemoglobin 
Red Blood Cell Count/Erythrocytes  
White Blood Cells/Leucocytes  
Platelet Count/Thrombocytes (quant) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Automatic WBC 
differential, relative  
 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes  
X 
 
X 
Automatic WBC 
differential, absolute  
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol. 
X 
X 
Manual differential 
WBC (if automatic 
differential WBC is 
abnormal) 
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.;  
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol. 
 
 
Coagulation 
Activated Partial Thromboplastin Time  
Prothrombin time (Quick) 
Prothrombin time – INR (International Normalization Ratio) 
X 
X 
X  
X 
X 
X  
Enzymes 
AST [Aspartate aminotransferase] /GOT, SGOT  
ALT [Alanine aminotransferase] /GPT, SGPT 
Alkaline Phosphatase 
Gamma-Glutamyl Transferase  
X 
X 
X 
X 
X 
X 
X 
X 
Hormones 
Thyroid Stimulating Hormone  
X 
-- 
Substrates 
Glucose (Plasma) 
Creatinine  
Bilirubin, Total  
Bilirubin, Direct 
C-Reactive Protein (Quant)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrolytes 
Sodium 
Potassium 
X 
X 
X 
X 
Urinalysis (Stix) 
Urine Nitrite (qual) 
Urine Protein (qual) 
Urine Glucose (qual) 
Urine Ketone (qual) 
Urobilinogen (qual) 
Urine Bilirubin (qual) 
Urine HGB (qual) 
Urine Leucocyte esterase (qual) 
Urine pH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sediment 
(microscopic) 
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes) 
 
 
 
A: parameters to be determined at Visit 1 (screening examination)  
B: parameters to be determined at Visit 5(end of trial examination) 
 
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening prior to each treatment period, it is 

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planned to perform these tests. Pregnancy testing in women will be performed at screening, 
prior to each treatment period, and as part of the end of trial examination. Drug screening will 
be performed at screening and prior to each treatment period. 
Table 5.2.3: 2 
Exclusionary laboratory tests 
Functional lab group 
Test name  
Drug screening (urine) 
Amphetamine/MDA 
Barbiturates 
Benzodiazepine 
Cannabis 
Cocaine  
Methadone 
Methamphetamines/MDMA/Ecstasy 
Opiates  
Phencyclidine 
Tricyclic antidepressants 
Infectious serology (blood) 
Hepatitis B surface antigen (qualitative) 
Hepatitis B core antibody (qualitative) 
Hepatitis C antibodies (qualitative) 
HIV-1 and HIV-2 antibody (qualitative) 
Pregnancy test (urine) 
Beta human chorionic gonadotropin (beta-HCG) 
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® M, 
) will be performed prior to each treatment period, and 
may be repeated at any time during the trial at the discretion of an investigator or designee. 
The results will not be included in the CTR. 
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at
 with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT Surestep Multiline test and Cleartest® Diagnostik HCG test, respectively, or 
comparable test systems. If a quantitive confirmation of the drug screening is needed this also 
may be performed by
Laboratory data will be transmitted electronically from the laboratory to the trial site. 
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6).  
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).  
5.2.4 
Electrocardiogram 
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System,
 at the times provided in the Flow Chart.  

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To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest. 
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality.  
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment.  
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons.  
5.2.5 
Other safety parameters 
Not applicable. 
5.2.6 
Assessment of adverse events 
5.2.6.1 
Definitions of adverse events 
5.2.6.1.1 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not. 
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable): 
• Worsening of the underlying disease or of other pre-existing conditions  
• Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator 
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only. 

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5.2.6.1.2 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria: 
• Results in death  
• Is life-threatening, which 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 that hypothetically might have 
caused death if more severe  
• Requires inpatient hospitalisation, or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity  
• Is a congenital anomaly/birth defect  
• Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse  
SUSAR 
A suspected unexpected serious adverse reaction (SUSAR) is an untoward and unintended 
response to a study drug. A SUSAR should be considered as unexpected if the nature, 
seriousness, severity, or outcome of the reaction is not consistent with the reference safety 
information of the investigational drug (e.g. the investigator's brochure, or the corresponding 
defined local label such as the summary of product characteristics). 
 
5.2.6.1.3 
AEs considered ‘Always Serious’ 
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above. 
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2. 
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in Section 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’. 

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5.2.6.1.4 
Adverse events of special interest 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2. 
The following are considered as AESIs: 
• Potential severe DILI 
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
1. 
AST (aspartate aminotransferase) and/ or ALT (alanine aminotransferase) 
elevation ≥3x ULN and TB (total bilirubin) ≥2x ULN measured at the same visit, or in 
samples drawn within 30 days of each other, OR 
2. 
AST and/ or ALT elevation ≥3x ULN and INR ≥1.5x ULN measured at the 
same visit, or in samples drawn within 30 days of each other, OR 
3. 
AST and/ or ALT elevation ≥3x ULN with new onset, or worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/ or 
eosinophilia (>5%), OR 
4. 
AST and/ or ALT elevation ≥5x ULN 
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eDC. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed. 
5.2.6.1.5 
Intensity (severity) of AEs 
The intensity (severity) of the AE should be judged based on the following: 
Mild:  
Awareness of sign(s) or symptom(s) that is/are easily tolerated 
Moderate: 
Sufficient discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
5.2.6.1.6 
Causal relationship of AEs 
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 

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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be: 
• The event is consistent with the known pharmacology of the drug  
• The event is known to be caused by or attributed to the drug class 
• A plausible time to onset of the event relative to the time of drug exposure 
• Evidence that the event is reproducible when the drug is re-introduced 
• No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications) 
• The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome) 
• An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced) 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
• Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger 
• There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned 
• Disappearance of the event even though the trial drug treatment continues or remains 
unchanged  
5.2.6.2 
Adverse event collection and reporting 
5.2.6.2.1 
AE collection 
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently.  
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE. 

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A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome. 
The following must be collected and documented on the appropriate CRF(s) by the 
investigator: 
• From signing the informed consent onwards until an individual subject’s end of trial 
(the End of Study (EoS) visit):  
o All AEs (serious and non-serious) and all AESIs  
o The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR. 
• After the individual subject’s end of trial:  
o The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs 
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF. 
5.2.6.2.2 
AE reporting to the sponsor and timelines 
The Investigator must report SAEs, SUSAR, AESIs, and non-serious AEs which are relevant 
for the reported SAE, SUSAR or AESI, on the BI SAE form to the sponsor’s unique entry 
point within 24 hours of becoming aware of the event, the country specific reporting process 
will be provided in the ISF. The same timeline applies if follow-up information becomes 
available. On specific occasions, the Investigator could inform the sponsor upfront via 
telephone. This does not replace the requirement to complete and send the BI SAE form.  
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained. 

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5.2.6.2.3 
Pregnancy 
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point. 
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition. 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS 
5.3.1 
Assessment of pharmacokinetics 
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters.  
5.3.2 
Methods of sample collection 
5.3.2.1 
Blood sampling for pharmacokinetic analysis 
For quantification of nerandomilast concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle. 
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 minutes with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented.  
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 

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analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.  
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, and planned sampling time.  
After analysis, the plasma samples may be used for further methodological investigations 
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived. 
5.4 
ASSESSMENT OF BIOMARKERS  
 Not applicable. 
5.5 
BIOBANKING 
Not applicable. 
5.6 
OTHER ASSESSMENTS 
5.6.1 
Pharmacogenomic evaluation  
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling. 
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 

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ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary. 
5.7 
APPROPRIATENESS OF MEASUREMENTS 
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine parameters in an appropriate 
way. The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG parameters that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an orally administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure.  
 

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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart. 
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration. 
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, AE questioning and laboratory tests will be ± 60 min. 
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters. In all periods subjects may have their dinner together. 
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters. Starting from 58h after dosing a tolerance 
of ± 120 minutes is given for all procedures. 
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting. 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 
6.2.1 
Screening  
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial. 
For information regarding laboratory tests (including drug and virus screening, pregnancy), 
ECG, vital signs, and physical examination, refer to Sections 5.2.1 to 5.2.5. 
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.6). 
6.2.2 
Treatment periods 
Each subject is expected to participate in 3 treatment periods (Days -1, 1, 2, 3, 4 and 5 in each 
period). At least 7 days will separate drug administrations in the first, second and third 
treatment period. 
On the evening of Day -1 of each treatment period, trial participants will be admitted to the 
trial site and kept under close medical surveillance for at least 24 h following drug 
administration.  
 

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The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. On all other trial days, subjects will be treated in an ambulatory 
fashion. 
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.  
The safety measurements performed during the treatment period are specified in Section 5.2 
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial 
examination. 
For details on times of all other trial procedures, refer to the Flow Chart. 
6.2.3 
Follow-up period and trial completion 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2. 
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit. 
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS 
Visit for continued safety monitoring. 
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.  

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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
NULL AND ALTERNATIVE HYPOTHESES 
The relative bioavailability of paediatric vs. adult formulation, i.e. T1 vs. R, and 
administering the paediatric formulation with or without food, i.e. T2 vs. T1,  will be 
estimated by the ratios of the geometric means (T1/R respectively T2/T1), and their 
corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. 
7.2 
PLANNED ANALYSES 
7.2.1 
General considerations 
7.2.1.1 
Analysis sets 
Statistical analyses will be based on the following analysis sets: 
• Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses. 
• Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS. 
Descriptions of additional analysis sets may be provided in the TSAP. 
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed. 
7.2.1.2 
Pharmacokinetics 
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for drug nerandomilast will 
be calculated according to the relevant BI internal procedures.  
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR. 
 
 

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Important protocol deviations may be 
• 
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to 
• 
Incorrect dose of trial medication taken 
• 
Use of restricted medications 
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example 
• The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),  
• A predose concentration is >5% Cmax value of that subject 
• Missing samples/concentration data at important phases of PK disposition curve 
 
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS. 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).  
7.2.2 
Primary endpoint analyses 
Primary analyses 
The two main objectives of this trial, see Section 2.1.1, will be analysed according to the 
statistical model described below. However, the statistical model will be applied only to data 
that contribute to the particular comparison of interest. 
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed.  
 

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The model is described by the following equation: 
 
yijkm =  + i + sim + j + k + eijkm, where 
 
yijkm = logarithm of response measured on subject m in sequence i receiving treatment   
k in period j, 
 
 = the overall mean, 
 
i = the ith sequence effect, i = 1, 2, 3 
 
sim = the effect associated with the mth subject in the ith sequence, 
 
m = 1, 2, ..., 5 
 
j = the jth period effect, j = 1, 2, 3 
 
k = the kth treatment effect, k = 1, 2, 3 
 
eijkm = the random error associated with the mth subject in sequence i who received 
 
treatment k in period j. 
where sim ~ N(0, σB
2) i.i.d., eijkm ~ N(0, σW
2 ) i.i.d. and sim, eijkm are independent random 
variables. 
Point estimates for the ratios of the geometric means (T1/R respectively T2/T1) for the 
primary endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will 
be provided. 
For each endpoint, the difference between the expected means for log(T1)-log(R) 
respectively log(T2)-log(T1) will be estimated by the difference in the corresponding 
adjusted means (Least Squares Means). Additionally their two-sided 90% confidence 
intervals will be calculated based on the residual error from the ANOVA and quantiles from 
the t-distribution. These quantities will then be back-transformed to the original scale to 
provide the point estimate and 90% CIs for each endpoint. 
Further exploratory analyses 
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects. 
In addition to the model based approach all primary endpoints will be analysed descriptively. 
7.2.3 
Secondary endpoint analyses 
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints (refer to Section 7.2.2). 

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7.2.5 
Safety analyses  
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned. 
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting). 
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data. 
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between trial medication intake and end of REP (see 
Section 1.2.1) will be assigned to the respective treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the last per protocol contact but entered before database 
lock will be reported to Pharmacovigilance only and will not be captured in the trial database. 
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP.  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.  
Relevant ECG findings will be reported as AEs. 
Previous and concomitant therapies will be presented per treatment without consideration of 
treatment periods. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings.  
 
Vital signs data will be assessed with regard to possible on-treatment changes from baseline. 
Baseline is defined as last measurement prior to drug administration of the respective 
treatment period. 
 

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7.2.6 
Interim analyses 
No interim analysis is planned. 
7.3 
HANDLING OF MISSING DATA 
7.3.1 
Safety 
It is not planned to impute missing values for safety parameters. 
7.3.2 
Pharmacokinetics 
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.  
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed. 
7.4 
RANDOMISATION 
Subjects will be randomised to one of the 3 treatment sequences (R-T1-T2, T1-T2-R, or T2-
R-T1) in a 1:1:1 ratio. The block size will be documented in the CTR. 
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation scheme will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.  
The randomisation scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5). 
7.5 
DETERMINATION OF SAMPLE SIZE 
It is planned to enter a total of 15 subjects in the trial including up to 3 PK non-evaluable 
subjects, because this sample size is considered sufficient to achieve the aims of this 
exploratory trial. With this sample size, the following precision in estimating the ratio of 
geometric means (test/reference, e.g. T1/R respectively T2/T1) can be expected with 95% 
probability. Precision is defined as the ratio of upper CI limit to the relative BA estimate. 
Note that the precision is independent of the actual ratio of geometric means. 
The observed intra-individual coefficient of variation (gCV) for nerandomilast in previous 
trial 1305-0028 [c40013550] was roughly 20% for Cmax and 7% for AUC. 
For various assumptions of the gCV up to 25%, Table 7.5: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T1/R or T2/T1 of geometric means. 
 

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Table 7.5: 1 
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T1/R or T2/T1) for different gCVs in a 3x3 
crossover trial (N = 12, 15). 
N 
gCV 
[%] 
Precision  
 upper CL** 
/ relative BA 
estimate 
90% CI [%] of respective ratio* 
80% 
100% 
150% 
12 
10 
1.09 
(73.26; 87.36) 
(91.57; 109.20) 
(137.36; 163.80) 
12 
15 
1.14 
(70.13; 91.25) 
(87.67; 114.07) 
(131.50; 171.10) 
12 
20 
1.19 
(67.17; 95.28) 
(83.97; 119.10) 
(125.95; 178.64) 
12 
25 
1.24 
(64.38; 99.41) 
(80.47; 124.27) 
(120.71; 186.40) 
15 
10 
1.08 
(74.15; 86.31) 
(92.68; 107.89) 
(139.03; 161.84) 
15 
15 
1.12 
(71.41; 89.63) 
(89.26; 112.03) 
(133.89; 168.05) 
15 
20 
1.16 
(68.80; 93.02) 
(86.00; 116.28) 
(129.00; 174.42) 
15 
25 
1.21 
(66.32; 96.50) 
(82.90; 120.63) 
(124.35; 180.94) 
*Ratio of geometric means (test/reference, i.e. T1/R or T2/T1) for a PK endpoint is defined by exp(T)/exp(R). 
**Confidence interval limit 
  
  
The expected 90% confidence interval limits in the table were derived by 
CI limitupper,lower = exp(ln(θ) ± ω), 
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.  
The calculation was performed as described by Julious [R11-5230] using R Version 4.2.2. 
 
 
 

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8. 
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE 
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’. 
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician. 
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP. 
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to finalisation of the CTR. 
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF. 
8.1 
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT 
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative. 
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent. 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. 

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The consent and re-consenting process should be properly documented in the source 
documentation. 
8.2 
DATA QUALITY ASSURANCE 
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.  
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.  
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial. 
8.3 
RECORDS 
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8. 
Electronic Study Documentation System: 
In the
 a validated 
electronic study documentation system (ClinBaseTM or successor Trial Complete Early Phase, 
TCEP) is used for processing information and controlling data collected in clinical trials. In 
addition to its function as a procedure control system, the study documentation system serves 
as databases. Instead of being entered into CRFs, selected data are directly entered into the 
system. 
8.3.1 
 Source documents 
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail). 
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. 
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable. 

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Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality. 
If the subject is not compliant with the protocol, any corrective action (e.g., re-training) must 
be documented in the subject file. 
For the CRF, data must be derived from source documents, for example: 
• Subject identification: gender, year of birth (in accordance with local laws and 
regulations) 
• Subject participation in the trial (substance, trial number, subject number, date subject 
was informed) 
• Dates of subject’s visits, including dispensing of trial medication 
• Medical history (including trial indication and concomitant diseases, if applicable) 
• Medication history 
• AEs and outcome events (onset date [mandatory], and end date [if available]) 
• SAEs (onset date [mandatory], and end date [if available]) 
• Concomitant therapy (start date, changes) 
• Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available) 
• ECG results (original or copies of printouts) 
• Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known) 
• Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial. 
Data directly entered into ClinBaseTM or successor Trial Complete Early Phase, TCEP (that 
is, without prior written or electronic record) are considered to be source data. The place 
where data are entered first will be defined in a trial specific Source Data Agreement. The 
data in ClinBaseTM or successor Trial Complete Early Phase, TCEP are available for 
inspection at any time. 
8.3.2 
Direct access to source data and documents 
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents.  

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The accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP. 
8.3.3 
Storage period of records 
Trial site: 
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial (whatever is longer). 
Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS 
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
Reporting suspected unexpected serious adverse reactions (SUSARs) to the EMA will be 
done via E2B transmission of Individual Case Safety Reports (ICSRs) to the Eudravigilance 
CT Module. 
8.5 
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY 
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook. 
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:  
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.  
8.5.1 
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular 
• Sample and data usage have to be in accordance with the informed consent 
• The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials. 
• An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place 

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• A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage 
• A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data 
• Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF 
8.6 
TRIAL MILESTONES 
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent. 
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’). 
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol. 
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it. 
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request. 
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state.  
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report. 
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject 
(EU or non-EU). 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL 
The trial is sponsored by Boehringer Ingelheim (BI). 
The trial will be conducted at the
 under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF. The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor. 
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to  
• Manage the trial in accordance with applicable regulations and internal SOPs 
• Direct the clinical trial team in the preparation, conduct, and reporting of the trial 

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• Ensure appropriate training and information of local Clinical Trial Mangers 
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites 
The trial medication will be provided by the
Safety laboratory tests will be performed by the local laboratory of the trial site
Analyses of nerandomilast concentrations in plasma will be performed at 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI. 
Data management and statistical evaluation will be done by BI, or a contract research 
organisation appointed by BI, according to BI SOPs.Tasks and functions assigned in order to 
organise, manage, and evaluate the trial are defined according to BI SOPs. A list of 
responsible persons and relevant local information can be found in the ISF. 
 
 

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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
P11-07084 
An official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary 
Fibrosis: Evidence-based Guidelines for Diagnosis and Management.  
Am J Respir Crit Care Med 2011, 183:6, 788-824. 
P12-03241 
King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis.  
Lancet 2011. 378: 1949-1961 
R03-2269 
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER) 
2002:1-9. 
R10-1555 
Daxas (roflumilast) in chronic obstructive pulmonary disease, NDA 22-
522, FDA Advisory Committee briefing document presented to: 
Pulmonary-Allergy Drugs Advisory Committee (briefing book, April 7, 
2010).http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMate
rials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/ucm207376.htm 
(access date: 23 November 2010) ; Jersey City: Forest Research Institute; 
2010. 
R10-1559 
Giembycz MA. Life after PDE4: overcoming adverse events with dual  
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005; 
5:238-244. 
R11-5230 
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010. 
R14-1795 
Otezla (apremilast) tablets, for oral use (Celgene) (U.S. prescribing 
information, revised: 3/2014). 
R17-0915 
Roflumilast 500 mcg tablets (Forest Research Institute): 
pharmacology/toxicology NDA/BLA review and evaluation, application 
number: 022522Orig1s000. Source: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s0
00PharmR.pdf (access date: 13 March 2017) ; Department of Health and 
Human Services, Public Health Service, Food and Drug Administration, 
Center for Drug Evaluation and Research; 2011. 
R17-0919 
Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA 
review and evaluation, application number: 205437Orig1s000. Source: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s0
00PharmR.pdf (access date: 13 March 2017) ; Department of Health and 
Human Services, Public Health Service, Food and Drug Administration, 
Center for Drug Evaluation and Research; 2014. 
 
 

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R17-1427 
Otezla 10 mg, 20 mg, 30 mg film-coated tablets, Otezla 30 mg film-coated 
tablets (Celgene) (summary for product characteristics, manufacturer 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet (first published 
16/02/2015). Source: https://ec.europa.eu/health/documents/community-
register/2015/20150115130395/anx _130395_en.pdf (access date: 19 April 
2017); 2015. 
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992 

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9.2 
UNPUBLISHED REFERENCES 
c02094779 
BI 1015550 - Investigator’s Brochure, current version 
c22991937 
Safety, tolerability and pharmacokinetics of single and multiple rising oral 
doses of BI 1015550 in healthy subjects. 1305-0011. 
c24902949 
Relative bioavailability of a single oral dose of BI 1015550 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects. 1305-0015. 
c25085412 
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of 
BI 1015550 in patients with idiopathic pulmonary fibrosis (IPF) on no 
background anti-fibrotic therapy. 1305-0012 
c36151567 
A Phase I, open-label, non-randomized, single-dose, single-arm, single-
period study to investigate the metabolism and pharmacokinetics of [C 14]-
labelled BI 1015550 after oral administration in healthy male subjects. 
1305-0016. 
c37065416 
A randomised, double-blind, placebo-controlled parallel group study in IPF 
patients over 12 weeks evaluating efficacy, safety and tolerability of BI 
1015550 taken orally. 1305-0013 
c40013550 
Clinical Trial Report Trial 1305-0028 
c40607236 
The effect of multiple oral doses of BI 1015550 on metabolism of 
midazolam administered orally in healthy male subjects.1305-0033 [draft 
report] 
U13-1792-01 
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 
1015550 in healthy male volunteers (a partially randomised, single-blinded, 
placebo-controlled Phase I study). 1305-0001 

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10. 
APPENDICES 
Not applicable.  

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BI-VQD-11906_40-106_AD-13 (8.0) 
11. 
DESCRIPTION OF GLOBAL AMENDMENTS 
11.1 
GLOBAL AMENDMENT 1 
Date of amendment 
  
09 April 2025 
EudraCT number 
EU number 
 
2024-511245-18-00 
BI Trial number 
 
1305-0029 
BI Investigational Medicinal 
Product(s) 
 
BI 1015550, nerandomilast 
Title of protocol 
 
Relative bioavailability of two different 
formulations of nerandomilast and investigation of 
the food effect on new formulation following oral 
administration in healthy adult male and female 
subjects (an open-label, randomised, single-dose, 
three-way crossover trial) 
 
Substantial Global Amendment due to urgent safety reasons  
 
Substantial Global Amendment  
 
Non-substantial Global Amendment  
 
 
Section to be changed 
 
1. Title Page 
2. Global Amendment 1 entry 
Description of change 
 
1. Clinical Trial Leader changed from 
to 
Rationale for change 
 
1. Change of CTL 
 

Signature Page for VV-TMF-986619 v2.0
Signature Page for VV-TMF-986619 v2.0
Reason for signing: Approved
Name:
Role: Verification-Paper Signature Completion
Date of signature: 14-Apr-2025 05:21:31
GMT+0000
Reason for signing: Approved
Name
Role: Approver
Date of signature: 14-Apr-2025 05:34:44
GMT+0000
Reason for signing: Approved
Name: 
Role: Author
Date of signature: 14-Apr-2025 06:25:53
GMT+0000
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 14-Apr-2025 10:01:57
GMT+0000