Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The aim of this trial is to establish bioequivalence between EU-, US- and Japan-sourced Otezla® tablet formulations to assure comparability of results from Phase III trials of BI 730357 (new oral agent for treatment of psoriasis as well as other T helper 17 cells (Th17)-mediated diseases) regardless of whether only the EU-sourced Otezla® or EU and US-sourced Otezla®/Japan-sourced Otezla® have been used as an active comparator.

Detailed description:

Arms:
arm 1: Treatment sequence AEBDC is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 2: Treatment sequence BACED is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 3: Treatment sequence CBDAE is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 4: Treatment sequence DCEAB is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 5: Treatment sequence EDACB is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 6: Treatment sequence ABECD is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 7: Treatment sequence BCADE is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 8: Treatment sequence CDBEA is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 9: Treatment sequence DECAB is applied. The 5 treatments were separated by a washout period of at least 5 days. arm 10: Treatment sequence EADBC is applied. The 5 treatments were separated by a washout period of at least 5 days.

Interventions: intervention 1: EU-sourced Otezla® intervention 2: US-sourced Otezla® intervention 3: Japan-sourced Otezla®
Intervention descriptions: intervention 1: Test product intervention 2: Reference product 1 intervention 3: Reference product 2

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c30404410-03
EudraCT No.
2019-005037-37
BI Trial No.
1407-0041
Investigational
Medicinal Products
Otezla® (Apremilast) film-coated tablets sourced from three ICH 
regions (EU, US, and Japan)
Title
Bioequivalence of three different tablet formulations of 30 mg of 
apremilast (EU-sourced Otezla® vs. US-sourced Otezla® vs. 
Japan-sourced Otezla®) administered in healthy male and female 
subjects in the fasted state as well as (for EU-sourced Otezla® vs. 
US-sourced Otezla®) in the fed state (an open-label, randomised, 
single-dose, five-period, ten-sequence crossover study)
Lay Title
A study in healthy people to compare 3 different formulations of 
apremilast tablets taken with or without food
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal Investigator
Phone:
Fax:
Status
Final Protocol
(Revised Protocol (based on Global Amendment 2))
Version and Date
Version: 3.0
Date: 05 November 2020
Page 1 of 61
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
03 March 2020
Revision date
05 November 2020
BI trial number
1407-0041
Title of trial
Bioequivalence of three different tablet formulations of 30 mg of apremilast (EU-
sourced Otezla® vs. US-sourced Otezla® vs. Japan-sourced-Otezla®) administered in 
healthy male and female subjects in the fasted state as well (for EU-sourced Otezla®
vs. US-sourced Otezla®) as in the fed state (an open-label, randomised, single-dose, 
five-period, ten-sequence crossover study)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
The aim of this trial is to establish bioequivalence between EU-, US- and Japan-
sourced Otezla® tablet formulations to assure comparability of results from Phase 
III trials of BI 730357 (new oral agent for treatment of psoriasis 
 
 regardless of whether only the EU-sourced Otezla or EU-
and US-sourced Otezla /Japan-sourced Otezla® have been used as an active 
comparator.
Trial objectives
To demonstrate bioequivalence (BE) between EU-sourced Otezla® film-coated 
tablets, US-sourced Otezla® film-coated tablets and Japan-sourced Otezla® film-
coated tablets in the strength of 30 mg. For all tablet formulations their 
bioequivalence will be tested in the fasted state (BE under fasting conditions) as 
well as for the EU- and US-formulation in the fed state (BE under fed conditions).  
Trial design
Randomised, open-label, single-dose, five-period, ten-sequence crossover design
Trial endpoints
Primary endpoints: AUC0-tz, AUC0-, and Cmax of apremilast in plasma
Number of subjects 
total entered
40 subjects 
each treatment
40 subjects 
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male/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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Test product (T)
EU-sourced Otezla® (apremilast) film-coated tablet 30 mg (EU-approved) 
dose
30 mg apremilast
mode of admin.
Oral administration in the fasted and in the fed state (treatments Tfasted and Tfed), 
all with 240 mL of water after an overnight fast of at least 10 h
Reference product (R1)
US-sourced Otezla® (apremilast) film-coated tablet 30 mg (US-licensed)
dose
30 mg apremilast
mode of admin.
Oral administration in the fasted and in the fed state (treatments R1fasted and R1fed), 
all with 240 mL of water after an overnight fast of at least 10 h 
Reference product (R2)
Japan-sourced Otezla® (apremilast) film-coated tablet 30 mg (Japan-approved)
dose
30 mg apremilast
mode of admin.
Oral administration in the fasted state (treatment R2fasted) with 240 mL of water 
after an overnight fast of at least 10 h 
Duration of treatment
One day (single dose) for each of the five treatments
Statistical methods
The assessment of bioequivalence will be based upon 2-sided 90% confidence 
intervals (CIs) for the ratios of the geometric means (test/reference) for the primary 
endpoints using an acceptance range of 80.00 to 125.00%. This method corresponds 
to the two one-sided t-tests procedure, each at a 5% significance level. The 
statistical model will be an analysis of variance (ANOVA) on the logarithmic scale 
including effects for sequence, subjects nested within sequences, period, treatment
and metabolic state (fed or fasted) as well as the treatment-by-metabolic state 
interaction. CIs will be calculated based on the residual error from the ANOVA and 
quantiles from the t-distribution.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to
drug administration) [h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory 8
PK blood (Apremilast)
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-23 to -1
Screening (SCR)1
A
x
1/2/3/4/57
2/3/4/5/67
-1
-12:00
20:00 Admission to trial site
x5
x
-11:30
20:30 Snack (voluntary) 3
1
-1:00
07:00 Allocation to treatment 2 (visit 2 only)
B2
x2
x2
x2
-0:30
07:30 Start of high fat, high calorie breakfast 
prior to treatments Tfed and R1fed
0:00
08:00 Drug administration 
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00 240 mL fluid intake
x
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00 240 mL fluid intake
x
x
5:00
13:00 Lunch 3
x
6:00
14:00
x
8:00
16:00
x
10:00
18:00 Dinner
11:00
19:00
x
15:00
23:00
x
x
2
24:00
08:00 Breakfast (voluntary) 3, 
discharge from trial site
B
x
x
x
36:00
20:00 Ambulatory visit
x
x
3
48:00
08:00 Ambulatory visit
x
x
FU
7
5 to 11
End of trial (EoTrial) examination4
C
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 pregnancy test in 
women and drug screening), demographics (including determination of body height and weight, smoking status and 
alcohol history), 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 3h 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 trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory 
(including 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.
Five identical periods /visits separated by wash-out periods of at least 5 days between the administrations of apremilast.
8.  Letter A, B and C define different sets of safety laboratory examinations (see Section 5.2.3)


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Apremilast .............................................................................................13
1.2.2
Residual Effect Period..........................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................14
1.4
BENEFIT - RISK ASSESSMENT ...................................................................14
1.4.1
Procedure-related risks ........................................................................15
1.4.2
Drug-related risks and safety measures..............................................15
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 18
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......18
2.1.1
Main objectives......................................................................................18
2.1.2
Primary endpoints ................................................................................18
2.1.3
Secondary endpoint ..............................................................................18
2.2.2.2
Safety and tolerability..............................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 20
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................21
3.3
SELECTION OF TRIAL POPULATION ......................................................21
3.3.1
Main diagnosis for trial entry..............................................................21
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................22
3.3.4
Withdrawal of subjects from treatment or assessments ...................24
3.3.4.1
Discontinuation of trial treatment ............................................24
3.3.4.2
Withdrawal of consent to trial participation ............................25
3.3.4.3
Discontinuation of the trial by the sponsor..............................25
3.3.5
Replacement of subjects .......................................................................25


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4.
TREATMENTS........................................................................................ 26
4.1
INVESTIGATIONAL TREATMENTS ..........................................................26
4.1.1
Identity of the Investigational Medicinal Products ...........................26
4.1.2
Selection of doses in the trial................................................................27
4.1.3
Method of assigning subjects to treatment groups ............................27
4.1.4
Drug assignment and administration of doses for each subject .......27
4.1.5
Blinding and procedures for unblinding ............................................28
4.1.6
Packaging, labelling, and re-supply ....................................................28
4.1.7
Storage conditions.................................................................................29
4.1.8
Drug accountability ..............................................................................29
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................29
4.2.1
Other treatments and emergency procedures....................................29
4.2.2
Restrictions............................................................................................30
4.2.2.1
Restrictions regarding concomitant treatment .........................30
4.2.2.2
Restrictions on diet and life style.............................................30
4.3
TREATMENT COMPLIANCE.......................................................................30
5.
ASSESSMENTS....................................................................................... 31
5.1
ASSESSMENT OF EFFICACY.......................................................................31
5.2
ASSESSMENT OF SAFETY............................................................................31
5.2.1
Physical examination ............................................................................31
5.2.2
Vital signs...............................................................................................31
5.2.3
Safety laboratory parameters..............................................................31
5.2.4
Electrocardiogram................................................................................33
5.2.5
Other safety parameters.......................................................................34
5.2.6
Assessment of adverse events...............................................................34
5.2.6.1
Definitions of adverse events...................................................34
Adverse event ............................................................34
5.2.6.1.1
Serious adverse event ................................................34
5.2.6.1.2
AEs considered ‘Always Serious’.............................35
5.2.6.1.3
Adverse events of special interest .............................35
5.2.6.1.4
Intensity of AEs.........................................................36
5.2.6.1.5
Causal relationship of AEs ........................................36
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................37
AE collection.............................................................37
5.2.6.2.1
AE reporting to the sponsor and timelines ................37
5.2.6.2.2
Information required..................................................38
5.2.6.2.3
Pregnancy ..................................................................38
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................38
5.3.1
Assessment of pharmacokinetics .........................................................38
5.3.2
Methods of sample collection...............................................................38
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................38


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5.4
ASSESSMENT OF BIOMARKER(S) .............................................................39
5.5
BIOBANKING ...................................................................................................39
5.6
OTHER ASSESSMENTS .................................................................................39
5.6.1
Pharmacogenomic evaluation..............................................................39
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................40
6.
INVESTIGATIONAL PLAN.................................................................. 41
6.1
VISIT SCHEDULE............................................................................................41
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................41
6.2.1
Screening................................................................................................41
6.2.2
Treatment periods.................................................................................41
6.2.3
Follow-up period and trial completion ...............................................42
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 43
7.1
STATISTICAL DESIGN – MODEL ...............................................................43
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................43
7.3
PLANNED ANALYSES....................................................................................44
7.3.1
Primary endpoint analyses...................................................................45
7.3.2
Secondary endpoint analyses ...............................................................47
7.3.4
Safety analyses.......................................................................................47
7.4
INTERIM ANALYSES .....................................................................................48
7.5
HANDLING OF MISSING DATA ..................................................................48
7.5.1
Safety......................................................................................................48
7.5.2
Pharmacokinetics..................................................................................48
7.6
RANDOMISATION ..........................................................................................48
7.7
DETERMINATION OF SAMPLE SIZE ........................................................49
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 50
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................50
8.2
DATA QUALITY ASSURANCE .....................................................................51
8.3
RECORDS..........................................................................................................51
8.3.1
Source documents .................................................................................51
8.3.2
Direct access to source data and documents.......................................52
8.3.3
Storage period of records.....................................................................53
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................53


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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......53
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................53
8.6
TRIAL MILESTONES .....................................................................................54
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................54
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................58
10. APPENDICES .......................................................................................... 59
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 60
11.1
GLOBAL AMENDMENT 1 .............................................................................60
11.2
GLOBAL AMENDMENT 2 .............................................................................61


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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
BE
bioequivalence
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
cAMP
cyclic adenosine monophosphate
CI
confidence intervals
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CTFG
Clinical Trial Facilitation Group
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EEG
Electroencephalogram
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (US)
FSH
Follicle-stimulating hormone


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FU
Follow-up
GI
gastrointestinal
GCP
Good Clinical Practice
gCV
geometric coefficient of variation
gMean
Geometric mean
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
Informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
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
MRTpo
Mean residence time of the analyte in the body after oral administration
PDE4
phosphodiesterase 4
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period


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SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
T
Test product or treatment
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
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WOCBP
Woman of childbearing potential
XTC
Ecstasy 


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 730357 is being developed for the treatment of patients with moderate to severe plaque 
psoriasis and is also under development for the treatment of other disease indications such as 
psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease.
Boehringer Ingelheim (BI) intends to conduct two parallel pivotal Phase III trials designed to 
demonstrate the superiority of BI 730357 to apremilast (trade name Otezla®) as active 
comparator. 
BI currently assumes that each pivotal trial will be conducted globally and plans to use
apremilast (Otezla®) sourced from three ICH regions (EU, US, and Japan) as the active 
comparator in the planned Phase III studies of BI 730357. 
Apremilast, an inhibitor of phosphodiesterase 4 (PDE4), has been approved in the US since 
2014 for the treatment of patients with active psoriatic arthritis, and since 2015 for the 
treatment of moderate to severe plaque psoriasis. In the EU, apremilast is approved in both 
indications, psoriasis and psoriatic arthritis. In Japan, apremilast is approved since 2017 for 
the treatment of plaque psoriasis with inadequate response to topical treatment, and the 
treatment of psoriatic arthritis. In all tree ICH regions, the recommended maintenance dose of 
apremilast is 30 mg twice daily taken orally (following initial titration stating with 10 mg 
once daily) [R20-3168, R20-3173, R20-3422].


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BI intends to use either EU-sourced Otezla® only or EU-sourced Otezla® and US-sourced 
Otezla® as active comparator in the planned Phase III studies for marketing authorization.  
BI conducts this bioequivalence study for the 30 mg strength to demonstrate bioequivalence 
between EU-approved Otezla®, US-licensed Otezla® and Japan-approved Otezla® tablet 
formulations in order to allow bridging of the Japan-, US- and EU-sourced Otezla® drug 
products, i.e. the usage of either EU-approved Otezla® only, or EU-approved and US-licensed 
Otezla®/Japan-approved Otezla®, in the planned Phase III trials for marketing authorization.
1.2
DRUG PROFILE
1.2.1
Apremilast
Apremilast, an oral small-molecule PDE4 inhibitor, works intracellularly to modulate a 
network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine
monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 
inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory 
response by modulating the expression of tumor necrosis factor alpha (TNF-α), interleukin 
(IL)-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-
inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have 
been implicated in psoriatic arthritis and psoriasis [R20-3173]. The specific mechanism(s) by 
which apremilast exerts its therapeutic action is not well defined [R20-3168]. 
The recommended therapeutic dose of apremilast is 30 mg taken orally twice daily, with no 
food restrictions. An initial dose titration over the first five treatments days helps to reduce 
gastrointestinal (GI) symptoms associated with initial therapy.
Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with 
peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 
2.5 hours. Apremilast pharmacokinetics are linear, with a dose-proportional increase in 
systemic exposure in the dose range of 10 to 100 mg daily. Co-administration with food does 
not alter the extent of absorption of apremilast [R20-3168, R20-3173].
Human plasma protein binding of apremilast is approximately 68%. The mean apparent 
volume of distribution is 87 L, indicative of extravascular distribution [R20-3168].
Apremilast is extensively metabolised by both cytochrome P450 (CYP) and non-CYP 
mediated pathways including oxidation, hydrolysis, and conjugation, suggesting inhibition of 
a single clearance pathway is not likely to cause a marked drug-drug interaction. In vitro, 
oxidative metabolism of apremilast is primarily mediated by CYP3A4, with minor 
contributions from CYP1A2 and CYP2A6. After oral administration, apremilast is the major 
circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide 
conjugate of O-demethylated apremilast. The plasma clearance of apremilast is about 10 L/hr 
in healthy subjects, with a terminal elimination half-life of approximately 9 hours [R20-3168, 
R20-3173].
Co-administration of rifampicin, a strong CYP3A4 inducer, resulted in a reduction of 
systemic exposure of apremilast. Therefore, the use of rifampicin and other strong CYP3A4 
inducers (e.g. phenobarbital, carbamazepine, phenytoin and St. John’s Wort) with apremilast 
is not recommended. Co-administration of apremilast with multiple doses of 600 mg 


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rifampicin for 15 days resulted in a decrease in apremilast area-under-the-concentration
(AUC) time curve and maximum plasma concentration (Cmax) by approximately 72% and 
43%, respectively [R20-3168, R20-3173].
There was no clinically meaningful interaction between apremilast and ketoconazole, a potent 
CYP3A4 inhibitor. There was no pharmacokinetic interaction between apremilast and oral 
contraceptives containing ethinylestradiol and norgestimate, thus apremilast can be co-
administered with oral contraceptives [R20-3173].
The most commonly reported adverse reactions with apremilast are GI disorders including 
diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions are mostly mild to 
moderate in severity, with 0.3% of diarrhoea and 0.3% of nausea reported as severe. These 
GI adverse reactions generally occur within the first 2 weeks of treatment and usually resolve 
within 4 weeks. The other most commonly reported adverse reactions include upper 
respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%) and are 
mostly mild to moderate in severity [R20-3173].
The most common adverse reactions leading to discontinuation during the first 16 weeks of 
treatment are diarrhoea (1.7%), and nausea (1.5%) (frequencies are based on Phase III 
clinical studies).
For a detailed description of the apremilast profile, please refer to the to the German and 
European SmPC [R20-3610 and R20-3173], the US PI [R20-3168], or the Japanese SmPC
[R20-3422].
1.2.2
Residual Effect Period
The Residual Effect Period (REP) of apremilast is four days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects is still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
The aim of this trial is to demonstrate bioequivalence between EU-, US- and Japan-sourced  
Otezla® (apremilast 30 mg) tablet formulations to assure comparability of results from 
Phase III trials of BI 730357 (new oral agent for treatment of moderate to severe psoriasis
and psoriatic arthritis) regardless of whether only the EU-sourced Otezla® or EU- and US-
sourced Otezla® have been used as an active comparator in these trials.
In accordance with FDA guidance ‘Food-Effect Bioavailability and Fed Bioequivalence 
Studies’ [R03-2269] and FDA guidance ‘Bioequivalence Studies with Pharmacokinetic 
Endpoints for Drugs Submitted Under an ANDA’ [R15-4652], the bioequivalence of EU and 
US Otezla® (orally administered immediate release products) is to be investigated under fed
conditions in addition to fasting conditions. 
1.4
BENEFIT - RISK ASSESSMENT
Participation in this bioequivalence study is without any (therapeutic) benefit for healthy 
subjects. Their participation, however, is of major importance for the development of 
BI 730357, a new oral agent for the treatment of psoriasis  and psoriatic arthritis, to assure 
regulatory acceptance of results of Phase III trials, in which BI 730357 is compared with 


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apremilast. Subjects are exposed to risks of study procedures and risks related to the exposure 
to the trial medication.
1.4.1
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire study 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.
1.4.2
Drug-related risks and safety measures
Based on available nonclinical and clinical information about apremilast [R17-0919, 
R18-1249, R20-3610, R20-3168, R20-3173, R20-3422] as well the design of the trial, the 
sponsor (Boehringer Ingelheim) considers this trial to be ethically acceptable. Healthy 
subjects will not be exposed to undue risks and adverse events (AEs) in relation to the 
information are expected from this clinical trial. Both apremilast drug products are marketed
in the US or the EU for at least 5 years, and in Japan for 3 years (trade name Otezla®).  
The potential for side effects has been assessed to be minimal following single doses and thus 
acceptable. The planned single dose treatments (5 doses separated by at least 5 days) are 
expected to be well tolerated by participating subjects. This is confirmed by Phase I trials 
with the 30 mg single dose. For example, 24 healthy male or female (demographically 
matched control) subjects received a single oral dose of 30 mg of apremilast to investigate the 
impact of renal Impairment on the pharmacokinetics of apremilast and metabolite M12. 
Seven out of 24 (29%) subjects reported AEs. Of these, 5 out of 24 (21%) subjects had AEs 
considered possibly related to apremilast (one case each of cheilitis, nausea, vomiting, back 
pain, pain in the extremity, and increased blood creatinine phosphokinase). Most AEs were 
mild or moderate in severity and resolved without intervention [R20-0189]. In another trial,
apremilast was administered as a 30 mg single dose to 21 healthy male or female subjects in 
order to assess the impact of rifampicin co-administration on the pharmacokinetics of 
apremilast. Headache and rhinitis were the more frequently reported AEs. One subject was 
withdrawn from the trial after the first single dose of apremilast due to an AE (influenza) 
[R20-0188]. Both Phase I trials in healthy subjects revealed no clinically meaningful changes 
in clinical laboratory parameters, vital signs, ECGs or physical examination findings.
Potential risks for subjects will be minimized and addressed by eligibility criteria, safety 
laboratory examinations, vital sign measurements, in-house observation periods and AE 
questioning.
Apremilast is associated with an increased risk of psychiatric disorders such as insomnia and 
depression [R20-3173]. Instances of suicidal ideation and behaviour, including suicide, have 
been observed in patients with or without history of depression. During 16-week treatment 
periods in clinical trials, depression or depressed mood was reported by 1.0% of apremilast-


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treated patients with psoriatic arthritis and by 1.3% of apremilast-treated patients with 
psoriasis (versus 0.8% and 0.4% with placebo, respectively) [R20-3168]. In order to address 
these risks, although the overall incidence is low and minimized in addition by single doses 
of apremilast, subjects with depression, suicidal thoughts or behaviour, or clinically relevant 
insomnia are excluded from this clinical trial (refer to Section 3.3.3). The medical staff at the 
trial site will nevertheless be instructed to notify the investigator or designee of any changes 
in behaviour or mood and of any suicidal ideation. If after apremilast dosing a subject suffers 
from psychiatric symptoms assessed as clinically relevant by the investigator, or suicidal 
ideation or suicidal attempt is identified, subject’s treatment with apremilast is to be 
discontinued (refer to Section 3.3.4.1).
Non-clinical and clinical safety data of apremilast support clinical trials in both sexes, 
including women of childbearing potential (WOCBP). Because apremilast is contraindicated 
during pregnancy, WOCBP have to use a highly effective birth control method until 30 days 
after trial completion in accordance with the recommendations of the Clinical Trial 
Facilitation Group (CTFG) related to contraception and pregnancy testing in clinical trials 
[R16-0373] (see inclusion criteria of Section 3.3.2). In addition, negative highly sensitive 
pregnancy tests will be required at the screening visit, prior to each administration of 
apremilast, and during the end of trial examination. Effects of apremilast on pregnancy 
included embryofoetal loss in mice and monkeys, and reduced foetal weights and delayed 
ossification in mice at doses higher than the currently recommended highest human dose. No 
such effects were observed when exposure in animals was at 1.3-fold the clinical exposure 
[R20-3173]. No teratogenic findings attributed to apremilast were observed in mice or 
monkeys. Available pharmacovigilance data with apremilast use in pregnant women have not 
established a drug-associated risk of major birth defects, miscarriage or adverse maternal or 
foetal outcomes, but these data are extremely limited [R20-3168]. The decision not to 
exclude WOCBP from this clinical trial is based upon relevant regulatory guidelines (e.g. 
ICH M3 [R09-1400], CTFG recommendations related to contraception and pregnancy testing 
in clinical trials [R09-1400], and Guidance for Industry on Bioavailability and 
Bioequivalence Studies [R15-4651]. One of their common approaches to minimize and limit 
the possible risk is to prevent pregnancy during the clinical trials.
Up to now, there is no reliable evidence suggesting a link between the inhibition of PDE4 and 
susceptibility to SARS-CoV-2 infections. Nonetheless, as with other immunomodulatory 
treatments, apremilast might potentially increase the risk of infections in healthy volunteers 
participating in clinical trials. Therefore, several risk mitigation measures (e.g., repeated 
laboratory tests for SARS-CoV-2 infection, exclusion of subjects with a history or findings 
indicative of a SARS-CoV-2 infection, close monitoring of AEs) are considered for this 
clinical trial. Trial conduct and protocol-defined procedures do not impose additional risk to 
trial participants. To address potential risks associated with operational aspects related to the 
participation in clinical trials in the context of the COVID-19 pandemic, different risk 
mitigation measures are considered based on local requirements and development of the 
pandemic. Any subject with suspected or diagnosed SARS-CoV-2 infection should be treated 
according to standard of care, and discontinuation of trial medication should be considered.
If the investigator should have any clinical concern, the safety of subjects will be of upmost 
importance. The Investigator has the discretion to remove subjects from the trial should there 
be any safety concerns, or if the subjects’ wellbeing is at jeopardy.


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All in all, the risk of the participating volunteers is judged to be low considering the well-
known safety profile of apremilast and the planned administration of single doses. The risks 
involved in inclusion of females (particularly WOCBP) have been adequately assessed and 
can be managed safe and satisfactorily. With respect to the medical need for an effective and 
safe treatment of psoriasis and mediated diseases, the benefit of this trial is assessed to 
outweigh the potential risks.


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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 demonstrate bioequivalence (BE) between EU-sourced 
Otezla® film-coated tablets (Test, T), US-sourced Otezla® film-coated tablets (Reference 1, 
R1) and Japan-sourced Otezla® film-coated tablets (Reference 2, R2) in the strength of 
30 mg. All tablet formulations will be tested for bioequivalence in the fasted state (BE under 
fasting conditions, i.e. Tfasted versus R1fasted and Tfasted versus R2fasted) as well as for the EU-
and US-formulation in the fed state (BE under fed conditions, i.e. Tfed versus R1fed).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for apremilast:

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)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
Not applicable.


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


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, single-dose, five-period, ten-
sequence crossover trial in healthy male and female subjects in order to compare the test 
treatment (T) to the reference treatments (R) under fasting and fed conditions. 
All subjects will receive the following five treatments in a randomised order:
Tfasted (Test fasted):
One EU-sourced Otezla® film-coated tablet of 30 mg apremilast
administered in the fasted state (after an overnight fasting period)
R1fasted (Reference 1 fasted): One US-sourced Otezla® film-coated tablet of 30 mg apremilast 
administered in the fasted state (after an overnight fasting period)
Tfed (Test fed):
One EU-sourced Otezla® film-coated tablet of 30 mg apremilast 
administered in the fed state (after a high-fat, high-calorie meal)
R1fed (Reference 1 fed):
One US-sourced Otezla® film-coated tablet of 30 mg apremilast 
administered in the fed state (after a high-fat, high-calorie meal)
R2fasted (Reference 2 fasted): One Japan-sourced Otezla® film-coated tablet of 30 mg apremilast 
administered in the fasted state (after an overnight fasting period)
The subjects will be randomly allocated to ten treatment sequences according to the five 
period William’s design in Table 3.1: 1 below. For details, refer to Section 4.1.
Table 3.1: 1
Five period William’s design
Sequence
Period
1
2
3
4
5
1
Tfasted
R2fasted
R1fasted
R1fed
Tfed
2
R1fasted
Tfasted
Tfed
R2fasted
R1fed
3
Tfed
R1fasted
R1fed
Tfasted
R2fasted
4
R1fed
Tfed
R2fasted
R1fasted
Tfasted
5
R2fasted
R1fed
Tfasted
Tfed
R1fasted
6
Tfasted
R1fasted
R2fasted
Tfed
R1fed
7
R1fasted
Tfed
Tfasted
R1fed
R2fasted
8
Tfed
R1fed
R1fasted
R2fasted
Tfasted
9
R1fed
R2fasted
Tfed
Tfasted
R1fasted
10
R2fasted
Tfasted
R1fed
R1fasted
Tfed


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There will be a washout period of at least 5 days between the five treatments (administrations 
of apremilast).
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 bioequivalence trials, the crossover design is preferred because of its efficiency: since 
each subject serves as his/her own control, the comparison between formulations is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529].
For this bioequivalence trial, open-label treatment is acceptable, because the primary 
endpoints of this trial are pharmacokinetic endpoints derived from measurement of plasma 
concentrations of apremilast. These endpoints are not expected to be affected by knowledge 
of treatment.
Male and female subjects should be enrolled in bioequivalence trials unless there is a specific 
reason to exclude one sex. Female subjects should not be pregnant at the beginning of the 
trial and should not become pregnant during the trial [R15-4651]. The risk of WOCBP should 
be considered [R10-2509]. 
Because information on bioequivalence is required in both the fasted and fed states for the 
EU-sourced and the US-sourced Otezla® tablet formulation, it is acceptable to conduct a five-
period, ten sequence crossover study [R10-2509].
3.3
SELECTION OF TRIAL POPULATION
It is planned that 40 healthy male and female subjects (if feasible at least 12 of each sex) will 
enter the study. 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 study will be performed in healthy subjects.
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) 


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4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects, or female subjects 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)
- A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
-
Surgically sterilised (including hysterectomy or bilateral occlusion)
-
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. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including to the trial medication or its 
excipients) 


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11. 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)
12. 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
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for
males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. 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 
21. Clinically relevant insomnia (e.g., difficulty falling or staying asleep at least 3 nights a 
week for at least 1 month, associated with daytime impairment)
22. History of depression and/or suicidal thoughts or behaviour
23. Galactose intolerance, lactase deficiency or glucose-galactose malabsorption
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 30 days after the last administration of trial medication
25. Male subject who is unwilling to refrain from donating sperm from time point of first 
administration of trial medication until 30 days after the last administration of trial 
medication
26. Subject (male or female) who is unwilling to refrain from donating blood (other than for 
this clinical trial) from time point of first administration of trial medication until 30 days 
after the last administration of trial medication
27. For female subject, positive pregnancy test, pregnancy, or plans to become pregnant 
within 30 days after study completion
28. For female subject, lactation
29. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
For study restrictions, refer to Section 4.2.2.


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3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or 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). 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, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.2), 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.
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. 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 
5.2.6.2.4.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
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, 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
6. The subject suffers from psychiatric symptoms assessed as clinically relevant by the 
investigator, or suicidal ideation or suicidal attempt is identified 
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.


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Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
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 (no. 2 and no. 3 are mandatory discontinuation criteria):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. 
3. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in more than 25% of subjects, or occurrence of at least one drug-related 
serious adverse event. Moreover, the trial will be terminated if more than 50% of the 
subjects have drug-related and clinically relevant adverse events of at least moderate 
intensity.
4. Violation of GCP or the CTP impairing the appropriate conduct of the trial
5. The sponsor decides to discontinue the further development of the investigational product
BI 730357
3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial, the CT Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products will be supplied by BI Pharma GmbH & Co. KG. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Name:
Otezla® 30 mg film-coated tablets
Substance:
Apremilast
Pharmaceutical formulation:
Film-coated tablet
Source:
EU commercial market
Marketing authorization holder:
Unit strength:
30 mg
Posology:
1-0-0
Route of administration:
Oral
The characteristics of the reference product 1 are given below:
Name:
Otezla® (apremilast) tablets
Substance:
Apremilast 
Pharmaceutical formulation:
Film-coated tablet
Source:
US commercial market 
Marketing authorization holder:
Unit strength:
30 mg
Posology:
1-0-0
Route of administration:
Oral
The characteristics of the reference product 2 are given below: 
Name:
Otezla® Tablets 30 mg
Substance:
Apremilast 
Pharmaceutical formulation:
Film-coated tablet
Source:
Japanese commercial market 
Marketing authorization holder:
Unit strength:
30 mg
Posology:
1-0-0
Route of administration:
Oral
The manufacture batch numbers used will be reported in the CTR.


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4.1.2
Selection of doses in the trial
The 30 mg dose selected for this trial is the standard clinical dose of apremilast taken twice 
daily (see Section 1.2).
4.1.3
Method of assigning subjects to treatment groups
The randomisation list 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 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment 
sequence according to the randomisation list. Once a subject number has been assigned, it 
cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a 5-way crossover study. All subjects will receive the 5 treatments in randomised 
order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment Substance
Formulation
Source  Unit 
strength
Dosage / metabolic state at 
administration
Total  
dose
T fasted
Apremilast
film-coated tablet
  EU
30 mg
1 film-coated tablet / fasted
30 mg
R1 fasted
Apremilast film-coated tablet   US
30 mg
1 film-coated tablet / fasted
30 mg
T fed
Apremilast
film-coated tablet
  EU
30 mg
1 film-coated tablet / fed
30 mg
R1 fed
Apremilast
film-coated tablet
  US
30 mg
1 film-coated tablet / fed
30 mg
R2 fasted
Apremilast
film-coated tablet
Japan
30 mg
1 film-coated tablet / fasted
30 mg
Administration of trial medication in three treatment periods (treatments Tfasted, R1fasted, and 
R2fasted) will be performed after subjects have fasted overnight; fasting is to start no later than 
10 h before the scheduled dosing. 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, if correct dosage 
cannot be ensured otherwise.
In two treatment periods (treatments Tfed and R1fed), the subjects will start to consume a high-
fat, high-calorie meal 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 on 
Food-Effect Bioavailability and Fed Bioequivalence Studies [R03-2269] and the EMA 


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Guideline on the Investigation of Bioequivalence [R10-2509]. For restrictions with regard to 
diet, see Section 4.2.2.2.
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 5 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 (administrations of apremilast) will be separated by a wash-out phase of at 
least five days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
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 local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
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
(ICF).
No re-supply is planned.


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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 
local clinical monitor (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
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 medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
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.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 CT 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.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives. All
concomitant or rescue therapies will be recorded (including time of intake on study days) on 
the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
Poppy-seeds containing foods should not be consumed within 3 days before each admission 
to trial site, in order to avoid false-positive results in the drug screen.
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 5 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), 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.
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 the end of trial examination. 
Alcoholic beverages are not permitted from 2 days before each administration of trial 
medication until after the last PK sample of each trial period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to 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.
If female subjects of child-bearing potential are included in the trial, highly effective 
contraception is to be maintained throughout the course of the trial until 30 days after trial 
completion (see Section 3.3.2 for the definition of highly effective measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study 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 (results not mandatory to be entered into CRF or to be reported), 
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, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) 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 9 h. 
For retests, at the discretion of the investigator or designee, overnight fasting is not required. 
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
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]
A1
B1
C1
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
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands;  
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 
Prothrombin time – INR (International Normalization Ratio)
X
X
X
--
--
--
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated]
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
Urinalysis 2 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 2
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1 A, B and C are different sets of laboratory values. The Flow Chart details at which time point which set is to 
be investigated. 
2 Microscopic examination if erythrocytes, leukocytes, nitrite or protein are abnormal in urine


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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, it is planned to perform these tests 
during screening only. 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/XTC
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 study 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 HCG-K20 test, respectively, or comparable test 
systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
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.
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.


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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 study 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 modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
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 (at screening) 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
Adverse event
5.2.6.1.1
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 or not considered related to the medicinal product.
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.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 


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
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  

Requires 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
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further 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. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
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.
For this trial, depression, mood changes, suicidal ideation, and suicidal behaviour/attempt are 
considered as AESIs.


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Intensity of AEs
5.2.6.1.5
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
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, 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.
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

Additional arguments amongst those stated before, like 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


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5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
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 as well as the time of onset, end
time, and intensity of these events. 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.
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: 
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 or trial database 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 AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 


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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.
Information required
5.2.6.2.3
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 assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.2.6.2.4
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.
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 Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
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 Trials 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 apremilast plasma concentrations, 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 venepuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 


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stored in polypropylene tubes. If (depending on method development and validation results)
an additive should be required in order to stabilize the analyte, details will be described in a
Lab Manual.
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 60 min, with 
interim storage of blood samples in ice water or on ice. 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 -70°C or below at the trial site. The second 
aliquot will be transferred to the 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 -70°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
The study samples will be discarded after completion of the clinical trial but not later than 
5 years after the CTR is archived.
5.4
ASSESSMENT OF BIOMARKER(S) 
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 pharmacokinetic 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 Sections 2.1.2, 
2.1.3, 2.2.2.1, and 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.
The acceptable deviation from the scheduled time for vital signs and laboratory tests will be 
± 45 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling and measurement 
of vital signs have to be done first. Furthermore, if several measurements including 
venepuncture are scheduled for the same time, venepuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
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.
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 study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.3).
6.2.2
Treatment periods
Each subject is expected to participate in five treatment periods (each consisting of Days -1, 
1, 2, and 3. At least 5 days will separate the drug administrations of the first, second, third, 
fourth, and fifth treatment period.
On evening of Day -1 of each treatment period, study participants will be admitted to the trial 
site and kept under close medical surveillance for at least 24 h following drug administration. 
The subjects will then be allowed to leave the trial site after formal assessment and 


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confirmation of their fitness. On all other study 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 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
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 Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
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 EoTrial 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
STATISTICAL DESIGN – MODEL
The main objective of this trial is to establish the bioequivalence of 30 mg of EU-sourced 
Otezla® film-coated tablets (Test, T) compared with 30 mg of US-sourced Otezla® film-
coated tablets (Reference 1, R1) and 30 mg of Japan-sourced Otezla® film-coated tablets 
(Reference 2, R2) following oral administration on the basis of the primary pharmacokinetic 
endpoints, as listed in Section 2.1.2 and 2.1.3.
Relative bioequivalence will be tested in the fasted state (Tfasted versus R1fasted versus R2fasted) 
as well as in the fed state (Tfed versus R1fed). The trial is designed to allow intra-subject
comparisons and will be evaluated statistically by use of a linear model for logarithmically 
transformed PK endpoints.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Although there are multiple primary endpoints, an alpha adjustment is not needed because it 
is required that all primary endpoints meet the equivalence criterion as described below 
simultaneously. Therefore, a one-sided alpha of 5% will be used for testing.
The assessment of bioequivalence of 30 mg of EU-sourced Otezla® compared with 30 mg of 
US-sourced Otezla® under fed conditions (Tfed versus R1fed) and 30 mg of EU-sourced 
Otezla® compared with 30 mg of US-sourced Otezla® and 30 mg of Japan-sourced Otezla®
under fasted conditions (Tfasted versus R1fasted versus R2fasted) will be based upon two-sided 
90% confidence intervals (CIs) for the ratio of the geometric means (Tfed/R1fed, Tfasted/R1fasted, 
and Tfasted/R2fasted, respectively) for the primary endpoints using an acceptance range of 80.00
to 125.00%. This method is equivalent to the two-sided t-test procedure, each at the 5% 
significance level.
The following hypotheses are tested:
Null hypothesis H0 (Inequivalence):
δ
μ
μ
δ
μ
μ
R
T
R
T





or
where 
T

and 
R

are the means of the log-transformed endpoint for the test and reference 
treatments, respectively, and δ is the bioequivalence limit that defines the acceptance range 
on the logarithmic scale.
Alternative hypothesis Ha (Equivalence):
δ
μ
μ
δ
R
T




,
with T referring to the test treatment in fasted or fed state and R to the reference treatment in 
fasted or fed state.


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In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), 
this translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric 
means (Tfed/R1fed or Tfasted/R1fasted, Tfasted/R2fasted, respectively) for endpoints on the original
scale.
The rejection of the null hypothesis at the = 0.05 level is equivalent to the inclusion of the 
90% confidence interval for 
R
T



in the acceptance range (-δ, δ).
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study 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 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.
Further details will be given in the Trial statistical analysis plan (TSAP).
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the TSAP, IPVs will be identified no later than in the 
Report Planning Meeting, and the IPV categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2 for EU-sourced Otezla®, US-
sourced Otezla®, and Japan-sourced Otezla® will be calculated according to the relevant
Standard operating procedure (SOP) of the Sponsor (001-MCS-36-472). 
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.
Relevant 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


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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 is 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). 
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic
data will be not included in any statistical evaluations, in accordance with international
guidances. The individual pharmacokinetic parameters of such a subject will be calculated
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of
the subject’s Cmax value, the subject’s data without any adjustments will be included in all
pharmacokinetic measurements and calculations.
Every effort will be made to include all concentration data in an analysis. If not possible, a
case to case decision is required whether the value should only be excluded from half-life
estimation or the complete analysis.
If a concentration is only excluded from half-life determination, it will be used for all other
calculations (e.g. descriptive statistics) and for graphical presentation.
If a concentration value is excluded from all calculations, it will not be presented graphically
or used for the calculation of descriptive statistics and parameter determination. However the
excluded concentration itself will be listed in the clinical trial report associated with an
appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual
parameter estimates of a certain parameter are available. If the actual sampling time will not
be recorded or will be missing for a certain time point, the planned time will generally be
used for this time point instead.
7.3.1
Primary endpoint analyses
Primary analyses
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 


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sequences, period, treatment and metabolic state (fed or fasted) as well as the treatment-by-
metabolic state interaction. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijklm = + i + sim + j + k + γl + φkl + eijkm, where
yijklm = logarithm of response measured on subject m in sequence i receiving treatment 
k under metabolic state l in period j,
= the overall mean,
i = the ith sequence effect, i = 1, …, 10
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, …, 5
k = the kth treatment effect, k = 1, 2, 3
γl= the lth metabolic state, l= 1 (fed), 2 (fasted)
φkl=the kth treatment effect (k=1, 2, 3) in the the lth metabolic state (l=1 (fed), 2 
(fasted))
eijklm = the random error associated with the mth subject in sequence i who received
treatment k for metabolic state l in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijklm are independent random 
variables.
Point estimates for the ratios of the geometric means (Tfed/R1fed, Tfasted/R1fasted, and
Tfasted/R2fasted) 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(Tfed)-log(R1fed),
log(Tfasted)-log(R1fasted) and log(Tfasted)-log(R2fasted) 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.
Bioequivalence is considered established if the 90% confidence intervals of the geometric 
means for the primary endpoints are contained in the pre-defined acceptance range, see 
Section 7.2.


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7.3.2
Secondary endpoint analyses
Not applicable.
7.3.4
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 planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
REP (see Section 1.2.2) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. 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 final 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 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).


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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.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
The TSAP will provide further details.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised to one of the 10 treatment sequences in equal numbers. 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 list 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 list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).


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7.7
DETERMINATION OF SAMPLE SIZE
The sample size for this trial was determined using assumptions on the intra-individual
variability of the primary endpoints based on the relative bioavailability trial CC-10004-CP-
022 and food-effect trial CC-10004-BA-002 both reported by the European Medicines 
Agency in the Assessment Report for Otezla® [R18-1250]. For Cmax the geometric coefficient 
of variation (gCV) was estimated to be about 23% in CC-10004-CP-022 and about 28% in 
CC-10004-BA-002, while for AUC0-tz the gCV was about 8% and 20%, respectively. 
A sample size of 40 subjects is needed to achieve 90% power to reject both one-sided null 
hypotheses for Cmax each at the 5% level of significance in favor of bioequivalence. 
Due to the high correlation between the primary endpoints, only Cmax will be considered for 
power calculations. Using a sample size of 40 subjects (4 per sequence group), the power to 
reject both one-sided null hypotheses for one parameter each at the 5% level of significance 
in favour of bioequivalence is displayed in Table 7.7: 1, under various assumptions for the 
T/R ratio. To account for the uncertainty of the assumed gCV, a range of gCVs around 26% 
is also presented.
Table 7.7: 1
Power for concluding bioequivalence (acceptance range 80-125%) 
based on a geometric coefficient of variation around 26% and for 
different expected ratios of geometric means (T/R) in a five-period, 
ten-sequence crossover trial (N=40, 4 per sequence)
Ratio[%]*
gCV[%]
92.5
95
97.5
100
102.5
105
107.5
20
94.7
98.7
99.7
>99.9
99.8
98.9
96.0
26
81.1
91.0
96.0
97.5
96.1
91.7
83.6
28
76.0
87.0
93.2
95.1
93.3
87.8
78.7
*Ratio of geometric means (T/R) for a PK endpoint is defined by exp(T)/exp(R).
From the above table, a sample size of 40 will yield approximately 90% power to conclude 
bioequivalence for an assumed gCV of 26%, if the ratio is not more than 5% different from 
the ratio of 100%, which reflects no difference in exposure. In addition, this sample size still 
provides more than 80% power, if the ratio is not more than 7.5% different from 100% under 
the assumption of a gCV of 26% in both cases.
The calculations were performed as described in ‘Using SAS Proc Power to perform model-
based power analysis for clinical pharmacology studies [R20-3405] using SAS version 9.4. 


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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.
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 archiving 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.
For subjects enrolled during the COVID-19 pandemic: In addition to the study specific 
informed consent, separate written consent will be obtained for testing on SARS-CoV-2 
infection.
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 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.
ClinBaseTM
In the
– the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. 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.
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, 


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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: sex, 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 (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 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. 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.


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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.
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.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking 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

A fit for the purpose documentation (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 
biobanking ICF


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for 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 EC/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 patient 
(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.
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

ensure appropriate training and information of local clinical trial managers (CT 
Managers), Clinical Research Associates, 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 apremilast concentrations in plasma will be performed under the responsibility of 
the
 
at suitable contract research organisations.


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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 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
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.
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-
clinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals (June 2009, 
CPMP/ICH/286/95). http://www.emea.europa.eu; 2009
R10-2509
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on the investigation of bioequivalence 
(London, 20 January 2010, doc. ref.: CPMP/EWP/QWP/1401/98 rev. 
1/corr). http://www.emea.europa.eu; 2010.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R15-4651
Guidance for industry: bioavailability and bioequivalence studies 
submitted in NDAs or INDs - general considerations: draft guidance (this 
guidance document is being distributed for comment purposes only) 
(March 2014, biopharmaceutics). 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinfor
mation/guidances/ucm389370.pdf (access date: 19 August 2015); U.S. 
Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER); 2014.
R15-4652
Guidance for industry: bioequivalence studies with pharmacokinetic 
endpoints for drugs submitted under an ANDA: draft guidance (this 
guidance document is being distributed for comment purposes only) 
(December 2013, biopharmaceutics). 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinfor
mation/guidances/ucm377465.pdf (access date: 19 August 2015); U.S. 
Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER); 2013.
R16-0373
Recommendations related to contraception and pregnancy testing in 
clinical trials (final version - 2014-09-15). 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-about_HMA/ 
Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
(access date: 2 February 2016); Clinical Trial Facilitation Group (CTFG), 
Head of Medicine Agencies (HMA); 2014.


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R17-0919
Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA 
review and evaluation, application number: 205437Orig1s000. 
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.
R18-1249
Apremilast (Otezla), phosphodiesterase 4 (PDE4) inhibitor (Celgene 
Corporation): medical review(s), application number: 206088Orig1s000. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206088Orig1s0
00MedR.pdf  (access date: 22 March 2018) ; Center for Drug Evaluation 
and Research; 2014.
R18-1250
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): assessment report: Otezla, international non-
proprietary name: apremilast, procedure no. EMEA/H/C/003746 (note: 
assessment report as adopted by the CHMP with all information of a 
commercially confidential nature deleted) (20 November 2014, 
EMA/CHMP/476353/2014). 
https://www.ema.europa.eu/en/documents/assessment-report/otezla-epar-
public-assessment-report_en.pdf (access date: 22 March 2018); London: 
European Medicines Agency (EMA); 2014. 
R20-3610
Otezla 10 mg, 20 mg, 30 mg Filmtabletten (Amgen), Zusammenfassung 
der Merkmale des Arzneimittels (SmPC), April 2020.
R20-0188
Liu Y, Zhou S, Wan Y, Wu A, Palmisano M. The impact of co-
administration of ketoconazole and rifampicin on the pharmacokinetics of 
apremilast in healthy volunteers. Br J Clin Pharmacol 2014; 78(5): 1050-
1057.
R20-0189
Liu Y, Zhou S, Assaf M, Nissel J, Palmisano M. Impact of renal 
impairment on the pharmacokinetics of apremilast and metabolite M12. 
Clin Pharmacol Drug Dev 2016; 5(6): 469-479.
R20-3168
Otezla (apremilast) tablets, for oral use (Amgen) (U.S. prescribing   
information, revised:06/2020).
https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-
com/otezla/otezla_pi_english.ashx (access date: 28 September 2020); 
2020.
R20-3173
Otezla 10 mg, 20 mg, 30 mg film-coated tablets (Amgen) (summary of 
product characteristics, manufacturer responsible for batch release, 
conditions or restrictions regarding supply and use, other conditions and 
requirement of the marketing authorisation, conditions or restrictions with 
regard to the safe and effective use of the medicinal product, labelling and 
package leaflet, last updated: 21/07/2020). 
https://www.ema.europa.eu/en/documents/product-information/otezla-
epar-product-information_en.pdf (access date: 28 September 2020); 2020.


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R20-3405
Sung P. Using SAS Proc Power to perform model-based power analysis 
for clinical pharmacology studies. 
https://www.pharmasug.org/cd/papers/SP/SP05.pdf (access date: 
19 October 2020); PharmaSUG; 2010.    
R20-3422
Otezla tablets 10 mg, 20 mg, 30 mg (PDE4 inhibitor, apremilast tablets)
(Amgen), prescription-only (product information, revised: July 2020).
English translation from the Japanese original.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c09228382
Investigator Brochure BI 730357. Psoriasis - 1407.P01; Current version.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
16 April 2020
EudraCT number
2019-005037-37
BI Trial number
1407-0041
BI Investigational Medicinal 
Products
Otezla® (Apremilast) film-coated tablets sourced 
from two ICH regions (EU and US)
Title of protocol
Bioequivalence of two different tablet formulations 
of 30 mg of apremilast (EU-sourced Otezla® vs. 
US-sourced Otezla®) administered in healthy male 
and female subjects in the fasted state as well as in 
the fed state (an open-label, randomised, single-dose, 
four-period, four-sequence crossover study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1) 3.3.4.3
2) 5.2.6.1.4
3) 5.2.6.1.4
Description of change
1) Specification, which of the reasons mandatory 
lead to discontinuation of the trial. Limitation of 
severe non-serious adverse events considered as 
drug-related by the investigator to 25% of the 
subjects (refer to reason no. 3).
2) Definition of AESIs (depression, mood changes, 
suicidal ideation, and suicidal behaviour/attempt)
3) BI 730357 was specified as the investigational 
product whose development could be 
discontinued (refer to reason no. 5).
Rationale for change
1) Required by Competent Authority and IEC
2) Recommended by Competent Authority and IEC
3) Clarification by Sponsor


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11.2
GLOBAL AMENDMENT 2
Date of amendment
05 November 2020
EudraCT number
2019-005037-37
BI Trial number
1407-0041
BI Investigational Medicinal 
Products
Otezla® (Apremilast) film-coated tablets sourced 
from three ICH regions (EU, US, and Japan)
Title of protocol
Bioequivalence of three different tablet formulations 
of 30 mg of apremilast (EU-sourced Otezla® vs. US-
sourced Otezla® vs. Japan-sourced Otezla®) 
administered in healthy subjects in the fasted state as 
well as (for EU-sourced Otezla® vs. US-sourced 
Otezla®) in the fed state (an open-label, randomised, 
single-dose, five-period, ten-sequence crossover 
study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1) Title page, CTP synopsis, Flow chart, Sections 
1.1,  1.3, 1.4.2,  2.1.1, 3.1,  3.2,  3.3,  4.1.1,  
4.1.4,  6.2.2,  7.1,  7.2,  7.3,  7.6, and 7.7 
2) Sections 1.4.2,  3.3.3, and 8.1
3) Sections 1.1, 1.2.1,  1.4.2,  4.1.1, and 9.1
4) Section 5.3.2.1
Description of change
1) Adaption of CTP title, trial design, sample size, 
randomization, and statistical evaluation 
2) Addition of potential drug risk with respect to 
SARS-CoV-2 infection, addition of safety 
measures and exclusion criterion no. 29
3) Updating of marketing authorization holder and 
references in the text
4) Removal of further methodological investigations
Rationale for change
1) Extension of the bioequivalence comparison to 
include the Japanese Otezla formulation under 
fasting conditions
2) Consideration of the current COVID-19 
pandemic
3) Revised Otezla® SmPC/Prescribing Information
4) Not applicable for this clinical trial


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c30404410
3.0
clinical-trial-protocol-version-03
Bioequivalence of three different tablet formulations of 30 mg of apremilast
(EU-sourced Otezla® vs. US-sourced Otezla® vs. Japan-sourced Otezla®)
administered in healthy male and female subjects in the fasted state as well as (for
EU-sourced Otezla® vs. US-sourced Otezla®) in the fed state (an open-label,
randomised, single-dose, five-period, ten-sequence crossover study)
Author-Trial Statistician
09 Nov 2020 08:54 CET
Author-Clinical Trial Leader
09 Nov 2020 10:47 CET
Approval-Clinical Pharmacokinetics
09 Nov 2020 14:34 CET
Approval-Therapeutic Area
09 Nov 2020 19:02 CET
Verification-Paper Signature
Completion
10 Nov 2020 11:17 CET
Approval-Team Member Medicine
11 Nov 2020 17:48 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c30404410
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36743424-01
BI Trial No.:
1407-0041
Title:
Bioequivalence of three different tablet formulations of 30 mg of
apremilast (EU-sourced Otezla® vs. US-sourced Otezla® vs.
Japan-sourced Otezla®) administered in healthy male and female
subjects in the fasted state as well as (for EU-sourced Otezla® vs.
US-sourced Otezla®) in the fed state (an open-label, randomised,
single-dose, five-period, ten-sequence crossover study)
(Revised Protocol including Amendments 1 and 2 [c30404410-
03])
Investigational
Product(s):
BI 730357
Responsible trial 
statistician(s):
Phone:
Fax:
Date of statistical 
analysis plan:
30 SEP 2021 SIGNED
Version:
final
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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................3
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS(S).....................................................................................................8
5.1
PRIMARY ENDPOINT(S)...................................................................................8
5.2
SECONDARY ENDPOINT(S).............................................................................8
5.2.1
Key secondary endpoint(s) ...................................................................................8
5.2.2
Secondary endpoint(s)...........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................10
6.1
TREATMENT(S) ................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................14
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........17
7.2
CONCOMITANT DISEASES AND MEDICATION......................................17
7.3
TREATMENT COMPLIANCE ........................................................................18
7.4
PRIMARY ENDPOINT(S).................................................................................18
7.5
SECONDARY ENDPOINT(S)...........................................................................18
7.5.1
Key secondary endpoint(s) .................................................................................18
7.5.2
(Other) Secondary endpoint(s)...........................................................................18
7.7
EXTENT OF EXPOSURE .................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................19
7.8.2
Laboratory data...................................................................................................20
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG ......................................................................................................................21
7.8.5
Others ...................................................................................................................21
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............22
9. 
REFERENCES ....................................................................................................23
11.
HISTORY TABLE..............................................................................................25


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................10
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 11: 1
History table .....................................................................................................25


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AESI
Adverse event of special interest
ANOVA
Analysis of variance
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
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company Standard Displays
CV
Arithmetic coefficient of variation
F/U
Follow Up
gCV
Geometric coefficient of variation
gMean
Geometric mean
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SD
Standard deviation
SOC
System organ class
TS
Treated set


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Term
Definition / description
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on trial objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, 
).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The study was prematurely terminated with only 20 of the 40 planned subjects as the 
development program of BI 730357 had been terminated in all indications, for the treatment 
of adult patients with plaque psoriasis, axial spondyloarthritis, and psoriatic arthritis.
Consequently, an abbreviated clinical trial report is planned where data on trial subjects, 
safety, and PK concentrations will be reported. Only descriptive statistics of PK parameters 
will be provided; no statistical evaluation of PK parameters will be performed. 
In addition, the following change compared to the protocol will be made:
In CTP section 7.3 the following was defined: Important protocol deviation (IPD) categories 
will be suggested in the TSAP, IPVs will be identified no later than in the Report Planning 
Meeting, and the IPV categories will be updated as needed. Due to SOP changes, the iPD 
categories are no longer suggested in TSAP, but included in an iPD specification file (3). 


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP: 
The following pharmacokinetic parameters will be determined for apremilast:

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)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint(s)
This section is not applicable as no secondary endpoints have been defined in the CTP.
Safety and tolerability endpoints
Section 2.2.2.2 of the CTP: Safety and tolerability of apremilast will be assessed based on:

Adverse Events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on investigational products and selection of doses, please see 
CTP Sections 3 and 4.
The study was to be performed as an open-label, five-period, ten-sequence crossover design. 
In total, it was planned to assign 40 healthy male and female subjects. 
There will be a washout period of at least 5 days between the apremilast administrations.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short 
label
A
Otezla (EU source), 30 mg tablet, qd, fasted
T fasted
B
Otezla (US source), 30 mg tablet, qd, fasted
R1 fasted
C
Otezla (EU source), 30 mg tablet, qd, fed
T fed
D
Otezla (US source), 30 mg tablet, qd, fed
R1 fed
E
Otezla (Japan source), 30 mg tablet, qd, fasted
R2 fasted
The study was prematurely stopped after 20 subjects have been treated. Therefore,
all analyses will be performed for these subjects only.
Section 1.2.2 of CTP: The Residual Effect Period (REP) of apremilast is four days. This is 
the period after the last dose with measurable drug levels and/or pharmacodynamic effects is 
still likely to be present.
The following study phases will be defined for the analysis of adverse events (AEs):


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
Screening
o
Ranging from 0:00h on day of informed consent until administration time of 
apremilast in treatment period 1.

On treatment (labelled “Tfasted”, “Tfed”, “R1fasted”, “R1fed”, “R2fasted”)
o
EU-sourced Otezla fasted (”Tfasted”): Ranging from the time of 
administration of Otezla (EU source) in the fasted state until 4 days (96 h) 
thereafter OR until next administration of Otezla, whatever occurs first.
o
EU-sourced Otezla fed (”Tfed”): Ranging from the time of administration of 
Otezla (EU source) in the fed state until 4 days (96 h) thereafter OR until next 
administration of Otezla, whatever occurs first.
o
US-sourced Otezla fasted (”R1fasted”): Ranging from the time of 
administration of Otezla (US source) in the fasted state until 4 days (96 h) 
thereafter OR until next administration of Otezla, whatever occurs first.
o
US-sourced Otezla fed (”R1fed”): Ranging from the time of administration of 
Otezla (US source) in the fed state until 4 days (96 h) thereafter OR until next 
administration of Otezla, whatever occurs first.
o
Japan-sourced Otezla fasted (”R2fasted”): Ranging from the time of 
administration of Otezla (Japan source) in the fasted state until 4 days (96 h) 
thereafter OR until next administration of Otezla, whatever occurs first.

Follow-up (labelled “F/U Tfasted”, “F/U Tfed”, “F/U R1fasted”, “F/U R1fed”, 
“F/U R2fasted”)
o
F/U Tfasted: Ranging from the end of REP Tfasted until the next 
administration of Otezla OR until trial termination, whatever occurs first.
o
F/U Tfed: Ranging from the end of REP Tfed until the next administration of 
Otezla OR until trial termination, whatever occurs first.
o
F/U R1fasted: Ranging from the end of REP R1fasted until the next 
administration of Otezla OR until trial termination, whatever occurs first.
o
F/U R1fed: Ranging from the end of REP R1fed until the next administration 
of Otezla OR until trial termination, whatever occurs first.
o
F/U R2fasted: Ranging from the end of REP R2fasted until the next 
administration of Otezla OR until trial termination, whatever occurs first.
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
The following AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and follow-up periods will not be included in 
this analysis. 
The following totals will be provided in addition (Section 15.3 only):
a total over all on treatment phases included in this analysis ("Total")


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B) Section 15.4 of the CTR displays:
Screening 
On treatment (labelled with the name of the study treatment (short label))
Follow-up phases (labelled “F/U Tfasted”, “F/U Tfed”, “F/U R1fasted”, “F/U R1fed”, 
“F/U R2fasted”)
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan 
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
Section 7.3 of the CTP: Important protocol deviation (iPD) categories will be suggested in 
the TSAP, IPVs will be identified no later than in the Report Planning Meeting, and the IPV
categories will be updated as needed.
Due to SOP changes, the iPD categories are no longer suggested in TSAP, but included in an 
iPD specification file (3). 
If any iPDs are identified, they are to be summarised into categories and will be captured in
the iPD specification file and the decision log. The iPD specification file (e.g. the DV domain 
specifications) will be stored within the TMF in EDMS.
The iPDs will be summarized and listed in the CTR.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study 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 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.
[…]
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.
Relevant 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 is 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.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (4).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of Otezla in each 
treatment period. 
Section 6.1 of the CTP: 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.
The acceptable deviation from the scheduled time for vital signs and laboratory tests will be
± 45 min.
Adherence to time windows will be checked via the consistency check listings at the RPM.


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Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Descriptive data analysis of PK endpoints and concentrations will be performed by the 
department of
 at 
 and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (7)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (8).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit. The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be calculated 
using the individual values with the number of decimal places as provided by the evaluation 
program. Then the individual values as well as the descriptive statistics will be reported with 
three significant digits in the CTR.


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject 
set whether they have non-missing values or not). 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers. 
The category missing will be displayed only if there are actually missing values.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (9).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report, based on the TS.


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Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
It is not intended to list the compliance separately. Any deviation from complete intake will 
be addressed in the RPM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
The study was prematurely stopped after 20 subjects have been treated. Primary endpoints 
will be analysed descriptively only. The statistical evaluation of PK endpoints described in 
Section 7.3.1 of the CTP will not be performed.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable, as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoint(s)
This section is not applicable, as no secondary endpoint has been specified in the protocol


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Safety and tolerability endpoints
Refer to Section 7.8 for a description of the analysis of safety and tolerability.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administrations will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” [BI-KMED-BDS-HTG-0041] (10) and [BI-KMED-BDS-HTG-
0066] (11) will be applied. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on-treatment’ or ‘follow-up’ phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
According to the CTP, adverse events of special interest (AESI) will be analysed:
Section 5.2.6.1.4 of the CTP: For this trial, depression, mood changes, suicidal ideation, 
and suicidal behaviour/attempt are considered as AESIs.
According to ICH E3 (12), in addition to deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious adverse event 
that led to an action taken with study drug (e.g. discontinuation or dose reduced or 
interrupted).
An overall summary of AEs will be presented.


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The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with 
serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious adverse 
events and for subjects with AESIs. In addition, the frequency of subjects with AEs will be 
summarised by treatment, worst intensity, SOC and PT.
The SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (13). 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data including change from baseline will be calculated by 
planned time point based on the worst value of the subject at that planned time point (or 
assigned to that planned time point).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed.


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For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening). No separate ECG listing will be provided.
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE (when on treatment)
and will be summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database at trial initiation.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED. 
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
8.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
9.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
10. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
11. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical 
trials”, current version, KMED.
12. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
13. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
30-SEP-21
None
This is the final TSAP